Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with ≥2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining ¹⁷⁷Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post ¹⁷⁷Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%).

Grade 3-4 AEs occurred in 32 (33%) of men who received ¹⁷⁷Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the ¹⁷⁷Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%).

A larger retrospective multicenter analysis of 145 patients treated with 248 therapy cycles of ¹⁷⁷Lu-PSMA-617 at 12 nuclear medicine centers throughout Germany between 2014 and 2015 was conducted. Patients had received 1-4 therapy cycles of treatment. In their analysis, the biochemical response rate (defined as a 50% or greater drop in PSA) was 45% after all therapy cycles. Grade 3 or 4 hematotoxicity occurred in 18 patients (12%) and xerostomia occurred in 11 patients (8%).

Grade 3-4 AEs occurred in 32 (33%) of men who received ¹⁷⁷Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the ¹⁷⁷Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%).

Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of ¹⁷⁷Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen.

Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively).

Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively).

Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively).

In addition, lower grade thrombopenia and leukopenia were observed in 9 (14%) and 11 (17%) patients at baseline, respectively. During the observation period, severe (grade 3) anaemia, thrombopenia and leukopenia occurred in 5 (8%), 2 (3%) and 1 (2%) patients, all of whom suffered from disseminated or diffuse bone involvement according to promise criteria and none of whom experienced biochemical response over the course of therapy

Significant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT.

Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade ≥ 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade ≥ 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline ≥ 1) in 8/17 (47%) of patients.

Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18-8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000-1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade ≥ 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively.

Grade 3-4 AEs occurred in 32 (33%) of men who received ¹⁷⁷Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the ¹⁷⁷Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%).

Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%).

Patient follow-up was of over 51 months, with the median follow-up (reverse Kaplan-Meier estimator) being 39.1 months (95% CI 32.1-46.1). Median survival was 12.0 (95% CI 10.8-13.2) months, with five patients (19%) still alive at the last follow-up. There were no therapy-related deaths documented. At w16, 14 patients (52%) stated an improvement in pain status from the baseline of at least one tier/level, 11 of which were biochemical responders.

Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

A prospective phase II pilot study enrolled fourteen patients with progressive and symptomatic mCRPC despite taxane and novel anti-androgen therapy to receive up to four cycles of ¹⁷⁷Lu PSMA-617 every six weeks. Ten out of the 14 patients had a mean PSA reduction of 59%, with five patients having over a 50% reduction, and nine patients having over a 30% reduction in PSA levels. At baseline testing, the PSMA PET SUV predicted a reduction in PSA of more than 30%, with an SUV max value of 17 ± 9 compared to 44 ± 15 (p < 0.007), and a PSMA SUV mean of 6 ± 4 compared to 10 ± 4 (p < 0.04).

Fifty patients were studied prospectively with PSMA-avid prostate cancer metastases who underwent a median of three cycles (range 1-4) of ¹⁷⁷Lu PSMA-617 therapy. Nine were deemed ¹⁷⁷Lu PSMA-617 refractory prior to death with a total of twelve deaths in the study. A PSA decline was noted in 23 patients, with 11 patients having a PSA decline of ≥50% after the first cycle of treatment. 12 patients had a PSA decline of <50% ranging from 11.3 to 43.5%. The remaining 23 patients experienced a PSA increase after the first ¹⁷⁷Lu PSMA-617 cycle (range 19.7-100%).

Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received ¹⁷⁷Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Four (21%) patients showed no response (PD) to the ¹⁷⁷Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming ¹⁷⁷Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months.

Another real-world prospective cohort study included twenty-one treatments refractory mCRPC patients at Bushehr Department of Nuclear Medicine between December 2016 to December 2018 treated with ¹⁷⁷Lu-PSMA-617 every 8 weeks. Patients had to have PSMA secreting lesions detected by PSMA imaging with 68Ga-PSMA PET or ¹⁷⁷Lu/99Tc-PSMA before to undergoing treatment. The mean age of patients was 70.3 ± 9.6 (range 54-88) with a median of two cycles of treatment (range 1-4). The primary endpoint of the study was to assess biochemical response (BCR), which was defined as a drop in the PSA of more than 50. Additional secondary endpoints included response by ECOG and overall survival. A BCR was seen in 62% of patients. The estimated overall survival was seen to be 62.69 weeks (95% confidence interval: 42.06-83.33) with a median follow-up period of 9 months (range 1-25 months).

Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%).

Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%).

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

The first major multi-center retrospective study on ¹⁷⁷Lu-PSMA-617 was published by Rahbar et al., reporting 145 patients with mCRPC who progressed after second-line systemic therapies. The overall response rate in terms of serum PSA decline >50% was seen in 45% of patients after all ¹⁷⁷Lu-PSMA-617 cycles. On imaging, 21 (45%) patients and 13 (28%) patients had PR and SD, respectively. There was grade 3-4 toxicity in 18 patients (13%), which included severe anemia, thrombocytopenia, and leukopenia. They found elevated alkaline phosphatase and visceral metastases as negative predictors of response to ¹⁷⁷Lu-PSMA-617. A major drawback of this study was the variable cycles and doses of ¹⁷⁷Lu-PSMA-617 given to patients

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%).

Yadav et al. provided a meta-analysis of ¹⁷⁷Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used ¹⁷⁷Lu-PSMA-617, 2 articles used ¹⁷⁷Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after ¹⁷⁷Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that ¹⁷⁷Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments.

A retrospective single center study looked at therapeutic outcomes of ¹⁷⁷Lu-PSMA-617 in mCRPC based on post-treatment imaging findings. 36 patients (aged 67 ± 8.8 years) were included out of which 23 received 2 cycles of treatment. Eleven patients (47.8%) were considered responsive in the post-therapeutic scans by ¹⁷⁷Lu-PSMA-617, two of which experienced complete response. Nine (39.1%) patients had stable disease while three (13%) experienced disease progression.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received ¹⁷⁷Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy.

Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of ¹⁷⁷Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen.

Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

The primary endpoint of this study is undetectable PSA (PSA ≤0.2 ng/mL) at 12 months after initiation of protocol therapy. In the CHAARTED study, 27% of all mHNPC patients treated with ADT+ docetaxel attained a PSA ≤0.2 ng/mL at 12 months. We have assumed that 25% of patients in the control arm (Arm B) will have PSA ≤0.2 ng/mL at 12 months. With 140 patients randomized 1:1 between the treatment arms, the study will have 85% power to reject the null hypothesis that the 12-month undetectable PSA rate is the same between the arms if the true 12-month undetectable PSA rate in the experimental arm (Arm A) is 50%.

Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade ≥ 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade ≥ 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline ≥ 1) in 8/17 (47%) of patients.

¹⁷⁷Lu PSMA-617 has been shown to have a low, but significant, rate of adverse events (AE) in several clinical studies. In the phase III VISION study, 52.7% of patients experienced a grade 3 or higher AE, as compared to 38.0% of patients with similar events in the control group. Anemia was the most common grade ≥3 AE, observed in 12.9% of subjects

Mean follow-up time was 53.2±24 months. While there were 61 patients at the baseline, 46 (75%) patients were able to complete the fourth cycle, and 18 (30%) patients were able to complete the eighth cycle. Median 4 (IQR: 2-6) cycles and 800 (IQR: 470-1150) mCi ¹⁷⁷Lu-PSMA-617 were applied. During the ¹⁷⁷Lu-PSMA-617 therapy period, androgen receptor signaling inhibitor was continued in 8 (13%) patients and chemotherapy was continued in 3 (5%) patients. According to the PCWG3 PSA response patterns, 18 (30%) patients had fitted into pattern 1 (PSA reduction of 50% or more from baseline and sustained), 12 (20%) patients into pattern 2 (PSA decrease of more than 50% followed by a modest rise), and 31 (51%) patients into pattern 3 (PSA progression of more than 25%). No significant difference was found between PSA patterns according to baseline inflammation indices (P values for NLR, dNLR, MLR, PLR, SII, PIV were.298,.105,.137,.774,.727,.944, respectively).

At w16, 16 patients (59%) achieved a biochemical response according to the PCWG3 criteria (mean %PSAw16 -77 ± 13). Four patients (15%) displayed PSA progression (mean %PSAw16 103 ± 62), and three patients were biochemically stable (mean %PSAw16 -19 ± 22). In all patients, the biochemical response status was confirmed in the PSA follow-up. %PSAw16 had no correlation to previous treatments or other relevant pretherapeutic parameters (p ≥ 0.15)

After the first treatment cycle, only 58% of the patients (n = 19) showed a decrease in serum PSA, and only 32% showed a decrease of more than 50%. After all treatment cycles were completed, 65% of the patients responded with a PSA drop greater than 50%. An even higher group of 84% responded with a general decrease in PSA levels. The highest reduction of PSA levels was observed from 139.1 to 0.24 ug/L (99.83%). Before PSMA RLT treatment, the mean serum PSA level was 258.12 ug/L (range, 0.42-3305.00 ug/L) and after 2 to 9 treatment cycles, it decreased to 79.61 ug/L (range, 0.24-869.10 ug/L).

Im Median erhielten die Patienten 2 Zyklen der ¹⁷⁷Lu-PSMA-RLT. Die Mehrheit der Patienten erhielt 3,5-7,5 GBq (im Median 6,0 GBq) Aktivitt pro Zyklus. ber den gesamten Beobachtungszeitraum zeigten 45 % der Patienten eine PSA50. Irgendein PSA-Abfall trat bei 60 % der Patienten auf. (The patients received a median of 2 cycles of ¹⁷⁷Lu-PSMA-RLT. The majority of the patients received 3.5-7.5 GBq (a median of 6.0 GBq) of activity per cycle. Throughout the entire observation period, 45% of the patients exhibited a PSA50. Some decrease in PSA levels occurred in 60% of the patients.)

After the first treatment cycle, only 58% of the patients (n = 19) showed a decrease in serum PSA, and only 32% showed a decrease of more than 50%. After all treatment cycles were completed, 65% of the patients responded with a PSA drop greater than 50%. An even higher group of 84% responded with a general decrease in PSA levels. The highest reduction of PSA levels was observed from 139.1 to 0.24 ug/L (99.83%). Before PSMA RLT treatment, the mean serum PSA level was 258.12 ug/L (range, 0.42-3305.00 ug/L) and after 2 to 9 treatment cycles, it decreased to 79.61 ug/L (range, 0.24-869.10 ug/L).

He showed remarkable symptomatic improvement, with complete resolution of pain by 6 wk following the first cycle, and his ECOG performance score improved to zero. At 12 wk after the second cycle, his serum PSA had decreased from 100 ng/ml to 0.25 ng/ml (99.8% reduction from baseline) and repeat 68Ga-PSMA-11 PET/CT showed a near-complete molecular response with a marked reduction in the extent and tracer avidity of the lesions.

The -fetoprotein serum level increased from 248 to 578 kUI/L after the second treatment. We concluded that the prostatic disease exhibited a positive response to ¹⁷⁷Lu PSMA-617, evidenced by a significant decrease in PSA serum levels (from 1.26 ng/mL to undetectable levels after the second treatment). However, there was no observable effect on HCC nodules, prompting the patients readmission for chemoembolization. Notably, there is a high PSMA expression in various solid tumors neovessels, among others HCC.

A 56-year-old man with metastatic castration-resistant prostate cancer underwent 3 cycles of radioligand therapy (RLT) with ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA). The patient showed a dramatic response, a drop in prostate-specific antigen level from 11 ng/mL at baseline to 1.14 ng/mL at 2 months after the third cycle of the therapy, along with reduced bone pain.

A study sought to analyze the prognostic significance of monitoring PSA levels during ¹⁷⁷Lu-PSMA-617 treatment. The study included thirty mCPRC patients who had baseline Ga-68 PSMA PET/CT prior to undergoing ¹⁷⁷Lu-PSMA-617 treatment. Patients were treated with a fixed dose of 180 mCi of ¹⁷⁷Lu-PSMA-617 every six to eight weeks. A total of 171 cycles of treatment were administered with a median of four cycles per patients (range 3-7). A PSA decline greater than 50% was seen in 33% of patients after one cycle of treatment and increased to 43% of patients at the conclusion of the last cycle of treatment. Of the 20 patients who did not have a 50% reduction in PSA levels after the first cycle, four of these patients eventually had a PSA decline of greater than 50% after the conclusion of the last cycle of treatment. The median OS was statistically significant in those who had a greater than 50% decline in PSA level 21 ± 10 (95% CI: 1.2-40.7) compared to those who did not 8.0 ± 2.6 (95% CI: 2.7-13.2) months (p = 0.012). Any PSA decline was seen in 50% of patients after just one cycle of treatment and remained stable at 46% of patients at the conclusion of treatment, but did not have a statistically significant impact on median OS; however it was significant for any PSA decline after the last cycle of treatment (13 ± 1, 95% CI: 10.9-15 months for responders versus 6.0 ± 1.9, 95% CI: 2.2-9.7 months for non-responders).

A study sought to analyze the prognostic significance of monitoring PSA levels during ¹⁷⁷Lu-PSMA-617 treatment. The study included thirty mCPRC patients who had baseline Ga-68 PSMA PET/CT prior to undergoing ¹⁷⁷Lu-PSMA-617 treatment. Patients were treated with a fixed dose of 180 mCi of ¹⁷⁷Lu-PSMA-617 every six to eight weeks. A total of 171 cycles of treatment were administered with a median of four cycles per patients (range 3-7). A PSA decline greater than 50% was seen in 33% of patients after one cycle of treatment and increased to 43% of patients at the conclusion of the last cycle of treatment. Of the 20 patients who did not have a 50% reduction in PSA levels after the first cycle, four of these patients eventually had a PSA decline of greater than 50% after the conclusion of the last cycle of treatment. The median OS was statistically significant in those who had a greater than 50% decline in PSA level 21 ± 10 (95% CI: 1.2-40.7) compared to those who did not 8.0 ± 2.6 (95% CI: 2.7-13.2) months (p = 0.012). Any PSA decline was seen in 50% of patients after just one cycle of treatment and remained stable at 46% of patients at the conclusion of treatment, but did not have a statistically significant impact on median OS; however it was significant for any PSA decline after the last cycle of treatment (13 ± 1, 95% CI: 10.9-15 months for responders versus 6.0 ± 1.9, 95% CI: 2.2-9.7 months for non-responders).

Forty-five patients were treated with total of 164 cycles of RNT. Fifteen patients (33%) had PSA decline of ≥50%, 23 patients (51%) showed any PSA decline and 20 patients (44%) showed PSA increase of ≥25%. Median OS and PFS were 17,1 months and 7,4 months. Patients had any or ≥50% PSA response after the first cycle, lower initial ALP (<120U/L) had longer OS and PFS. Patients had normal Hb showed longer OS and patients had lower initial PSA (<51ng/mL) had longer PFS. Patients had PSA progression of ≥25% had shorter OS and PFS.

A 79-year-old man with a history of metastatic prostate cancer was initially treated with Eligard and switched to relugolix in 2021. The 2022 bone scan presented superscan and extensive osseous metastatic lesions; some had intense PSMA uptake on the initial PSMA PET scan without nodal or visceral metastatic lesions. We treated him with Pluvicto and relugolix. The intermediate PSMA scan demonstrated prominent bone marrow PSMA uptake. However, PSA decreased 58.5%. We hypothesized that the patient might have a bone flare. The final PSMA scan confirmed our hypothesis. Based on our knowledge, this is the first case of Pluvicto-induced bone flare.

A subsequent retrospective study, the first evaluating multiple administrations of ¹⁷⁷Lu-PSMA-617, was reported by the same group. The authors reviewed 28 consecutive patients who received 50 infusions of ¹⁷⁷Lu-PSMA-617 between 2014 and 2015. In their report, a PSA decline was noted in 59% and 75% of patients after 1 and 2 therapies, respectively, and a PSA decline of 50% or greater occurred in 32% and 50%, respectively. The estimated median survival was 29.4 weeks compared to 19.7 weeks in the historical best supportive care group which was statistically significant (HR 44; 95% CI 0.20-0.95; P=.031). Authors of the study also noted no significant changes in hematologic or renal parameters

A retrospective analysis studied 28 patients with mCRPC who were treated with ¹⁷⁷Lu-PSMA-617 [Citation47]. The estimated median survival was 29.4 weeks, significantly longer than survival in the supportive care group (HR, 0.44; 95% confidence interval, 0.20-0.95]; P = 0.031). Results of the study noted any PSA decline in 59% of patients after one cycle and 75% of patients after two cycles of treatment, while there was a noted PSA decline of 50% or greater in 32% of patients after one cycle of treatment and in 50% of patients after two cycles of treatment. Although this study found a 50% or greater PSA decline in majority of treated patients, 83% of patients reported a stable or improved quality of life after treatment.

The first major multi-center retrospective study on ¹⁷⁷Lu-PSMA-617 was published by Rahbar et al., reporting 145 patients with mCRPC who progressed after second-line systemic therapies. The overall response rate in terms of serum PSA decline >50% was seen in 45% of patients after all ¹⁷⁷Lu-PSMA-617 cycles. On imaging, 21 (45%) patients and 13 (28%) patients had PR and SD, respectively. There was grade 3-4 toxicity in 18 patients (13%), which included severe anemia, thrombocytopenia, and leukopenia. They found elevated alkaline phosphatase and visceral metastases as negative predictors of response to ¹⁷⁷Lu-PSMA-617. A major drawback of this study was the variable cycles and doses of ¹⁷⁷Lu-PSMA-617 given to patients

One of the earliest experiences with ¹⁷⁷Lu-PSMA-617 radioligand therapy (RLT) was described by Ahmadzadehfar et al. in 2015. Ten patients with mCRPC were recruited to undergo ¹⁷⁷Lu-PSMA-617 RLT and received one cycle of therapy (dose 6 GBq). At eight-week follow-up, 70% (7/10) experienced PSA decline, and 50% (5/10) experienced >50% decline in PSA levels. After those initial encouraging results, in a follow-up study with an expanded cohort, 24 patients with progressive mCRPC underwent ¹⁷⁷Lu-PSMA-617 RLT. After one cycle, 79.1% (19/24) showed a decline in PSA levels; 41.7% (10/24) showed >50% decline. Twenty-two out of the 24 patients were selected for a second cycle, and 68.2% (15/22) had a PSA decline, with 13 (59%) experiencing >50% decline. Since then, numerous retrospective studies with larger groups of patients have been published by the same group. In 2017, Ahmadzadehfar et al. reported a cohort of 52 patients who each received between three and six cycles of therapy (mean: 3.6 cycles, mean dose: 6 GBq). Dosing was administered in eight-week intervals and the median cumulative dose was 18.5 GBq. Of note, 80.8% (42/52) experienced a PSA decline eight weeks after the first cycle. Median overall survival was 60 weeks, with patients who had PSA responses having significantly longer survival compared to those who did not (68 vs. 33 weeks). In a cohort of 99 patients who received between one to four cycles of therapy (mean: 1.7 cycles) with 8-12 week intervals, 65.6% (45/99) had PSA response after the first cycle. In a cohort of 104 patients, described in 2018, 67.3% (70/104) experienced a PSA decline after one cycle of therapy. Patients underwent an average of 3.4 cycles of therapy, with eight-week intervals. The average dose was 6.1 GBq per cycle and 18.8 GBq cumulatively. The median overall survival was 56 weeks; again, those who responded had longer survival (62.9 vs. 47 weeks).

One study retrospectively analyzed 82 mCRPC patients who received a single dose of Lu-PSMA. Tolerability and response to treatment were assessed using hematologic parameters, renal scintigraphy, clinical data, and prostate-specific antigen (PSA) levels. A PSA decline from baseline was noted in 64% patients with 31% of patients having a greater than 50% decline, while 47% patients had stable disease with a 25-50% decrease in PSA levels. Only 25% of patients showed an increase in PSA levels indicating disease progression, and 7% of patients died due to extensive disease.

Another retrospective study evaluated 56 mCPRC patients with a median age of 69.5 (range 55-84) who received one to four cycles of ¹⁷⁷Lu-PSMA-617. Biochemical response was defined using Prostate Cancer Working Group Criteria 3 (PCWG3). A total of 139 cycles of treatment were performed with a decline of greater than 50% in 54% of patients and any PSA decline in 65% of patients. Estimated median overall survival was 16 months versus 14 months in the chemotherapy alone group. Longer OS was observed in patients with a PSA decline of >50%, a baseline ALP level <220 U/l, more than two cycles of treatment, and cumulative activity of greater than 15 GBq.

Though the first experience with PSMA-targeted ¹⁷⁷Lu dates to 2013 at Bad Burka, this experience was not reported until later. The first report on safety and efficacy came from investigators at University Hospital Bonn and University Hospital Muenster. The authors retrospectively evaluated the results of 10 consecutive patients with mCRPC who were treated with a single dose of ¹⁷⁷Lu-DKFZ-617 (later called simply PSMA-617) PSMA between 2013 and 2014. They showed that after 8 weeks, 7 patients (70%) showed a PSA decline with 5 patients (50%) having more than a 50% decline in PSA. Grade 3 or higher hematotoxicity was seen in only one patient and there was no relevant nephrotoxicity or hepatotoxicity.

¹⁷⁷Lu-PSMA-617 was offered to thirty patients with PSMA-positive prostate tumor. Treatment efficacy was retrospectively assessed by PSA levels with 70% of patients demonstrating a decrease in PSA levels. 18 patients were noted to have PSA decline greater than 25%, while 13 patients had a decline greater than 50%. Six of these patients were restaged using PSMA PET/CT (positron emission tomography/computed tomography), and all six patients had a response rate of more than 50% in SUVmax (maximum standardized uptake value) of the tumor.

A small two center study was conducted in 2015, which followed ten mCRPC patients treated with ¹⁷⁷Lu-PSMA-617. Response was evaluated by change in PSA. Eight weeks after therapy, seven out of the 10 study subjects, experienced a decline in PSA. Six out of ten patients had a decline more than 30%, while five patients had a decline of more than 50% in their PSA levels. Three patients showed an increase in PSA indicative of progression of disease. Post-treatment PSA levels declined significantly in this study, indicating positive treatment response.

Since initial retrospective studies had a limited number of patients and a heterogeneous population, the WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) planned a multi-center retrospective study to evaluate response rate, OS, and the impact of prior therapies on OS in more than 300 mCRPC patients treated with ¹⁷⁷Lu-PSMA-617. The study included 416 mCRPC patients who received a total of 1493 cycles of ¹⁷⁷Lu-PSMA-617, with a median of 3 cycles per patient. Post-¹⁷⁷Lu-PSMA-617, serum PSA decline was seen in 282 (71.8%) patients, of whom 163 (41.5%) showed a serum PSA decline of ≥50%, whereas 111 patients (28.2%) showed an increase in serum PSA levels. A median OS of 11.1 months (95% CI 9.7-12.5 months) was observed. Prior chemotherapy, the presence of bone and liver metastases, and poor ECOG status were significant adverse prognosticators for survival in both univariate and multivariate analyses. No imaging response evaluation and no determination of PFS after ¹⁷⁷Lu-PSMA-617 were major limitations for this study.

The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with ≥2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining ¹⁷⁷Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post ¹⁷⁷Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%).

An additional retrospective study of 52 mCRPC patients (mean age of 70, range 48-87 years) evaluated the PSA response of those treated with ¹⁷⁷Lu-PSMA-617 after one to three cycles of radioligand therapy (RLT) every eight weeks. A total of 190 cycles of RLT (3-6 cycles per patient) were given and 80% of patients showed a decline after the first cycle with 44% of patients showing a PSA response of more than 50%. After the third cycle, 73% of patients showed any PSA decline. The median OS was 60 weeks for all patients and median OS was statistically longer for those who responded with decline in PSA after first cycle compared to those without (68 vs 33 weeks).

A subsequent retrospective study, the first evaluating multiple administrations of ¹⁷⁷Lu-PSMA-617, was reported by the same group. The authors reviewed 28 consecutive patients who received 50 infusions of ¹⁷⁷Lu-PSMA-617 between 2014 and 2015. In their report, a PSA decline was noted in 59% and 75% of patients after 1 and 2 therapies, respectively, and a PSA decline of 50% or greater occurred in 32% and 50%, respectively. The estimated median survival was 29.4 weeks compared to 19.7 weeks in the historical best supportive care group which was statistically significant (HR 44; 95% CI 0.20-0.95; P=.031). Authors of the study also noted no significant changes in hematologic or renal parameters

A retrospective analysis studied 28 patients with mCRPC who were treated with ¹⁷⁷Lu-PSMA-617 [Citation47]. The estimated median survival was 29.4 weeks, significantly longer than survival in the supportive care group (HR, 0.44; 95% confidence interval, 0.20-0.95]; P = 0.031). Results of the study noted any PSA decline in 59% of patients after one cycle and 75% of patients after two cycles of treatment, while there was a noted PSA decline of 50% or greater in 32% of patients after one cycle of treatment and in 50% of patients after two cycles of treatment. Although this study found a 50% or greater PSA decline in majority of treated patients, 83% of patients reported a stable or improved quality of life after treatment.

Yordanova et al., evaluated the response rate and clinical toxicity of re-challenge ¹⁷⁷Lu-PSMA-617 in progressive prostatic cancer patients who previously benefited from this therapy. In this retrospective study, a total of 30 patients were re-treated with a median of 3 (range 1-6) cycles of ¹⁷⁷Lu-PSMA-617. They found that 75-90% of patients demonstrated favorable serum PSA responses following re-challenge cycles, with a median OS of 12 months after the first re-challenge cycle and without any life-threatening grade-4 adverse event. The authors concluded that the majority of patients benefited from re-challenging ¹⁷⁷Lu-PSMA-617 with a longer OS in biochemically responsive patients. At present, data on re-challenge ¹⁷⁷Lu-PSMA-617 is limited and requires a prospective randomized trial before a definitive conclusion.

An additional retrospective study of 52 mCRPC patients (mean age of 70, range 48-87 years) evaluated the PSA response of those treated with ¹⁷⁷Lu-PSMA-617 after one to three cycles of radioligand therapy (RLT) every eight weeks. A total of 190 cycles of RLT (3-6 cycles per patient) were given and 80% of patients showed a decline after the first cycle with 44% of patients showing a PSA response of more than 50%. After the third cycle, 73% of patients showed any PSA decline. The median OS was 60 weeks for all patients and median OS was statistically longer for those who responded with decline in PSA after first cycle compared to those without (68 vs 33 weeks).

A 70-year-old man with history of prostate cancer was referred to our department for 68Ga-PSMA PET/CT. He had been diagnosed with prostate adenocarcinoma 12 years earlier, with a Gleason score of 5 + 5 = 10. He had a complaint of skin nodules on the pubis and the left lower extremity swelling that had appeared for a few months. Physical examination revealed multiple indurated, erythematous, and infiltrating papulonodular lesions with the largest 3.5 2.3 cm over the pubis (A). The PSA level was 755 ng/mL. Increased 68Ga-PSMA uptakes were seen to correspond to most of the cutaneous lesions on pubis, with a mean SUVmax of 25. In addition, there were multiple pelvic and retroperitoneal lymph nodes showing increased PSMA uptake (SUVmax, 17) highly suggestive of lymph node metastasis (B) and increased PSMA uptakes in the cutaneous and subcutaneous tissues and edema in the left lower extremity (C). Given the patient history, skin nodules showing increased 68Ga-PSMA uptake were suspected to be metastatic lesions from prostate carcinoma as well. Histological evaluation and immunohistochemical staining with PSA, prostate-specific acid phosphatase (PSAP), cytokeratin 20 (CK20), and CDX2 were consistent with metastatic prostate adenocarcinoma to cutaneous tissue. ¹⁷⁷Lu-PSMA radioligand treatment was planned because the lesions showed increased PSMA uptakes. After a total of 3 cycles ¹⁷⁷Lu-PSMA-617 (with a mean activity of 5.5 GBq per cycle and an interval of 6-8 weeks), it was observed that the existing all skin lesions disappeared. Also 68Ga-PSMA PET/CT scan revealed that all lesions showing increased PSMA uptake disappeared (D). The PSA level has dropped to 75 ng/mL.

Another study retrospectively studied fifty-nine mCRPC patients after receiving at least one antihormonal drug as well as chemotherapy. These patients were treated with a median of three cycles of ¹⁷⁷Lu-PSMA-61. The primary end point was overall survival, and secondary end point was decrease in PSA level. Follow-up data was available for forty-five patients with 91% showing a PSA decline. A decline in PSA levels of greater than or equal to 50% occurred in 53% of the patients. The median overall survival was 32 weeks. An initial alkaline phosphatase (ALP) level less than 220 U/L and a PSA decline after the first cycle were associated with a longer overall survival (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). Toxicity overview showed grade 3 leukopenia and thrombocytopenia in 3% patients and grade 3 anemia in 19%. No grade 3 or 4 nephrotoxicity or grade 4 blood toxicity was observed. This study showed a statistically significant decline in ALP levels after the first cycle of ¹⁷⁷Lu-PSMA-617.

Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of ¹⁷⁷Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life.

A prospective phase II pilot study enrolled fourteen patients with progressive and symptomatic mCRPC despite taxane and novel anti-androgen therapy to receive up to four cycles of ¹⁷⁷Lu PSMA-617 every six weeks. Ten out of the 14 patients had a mean PSA reduction of 59%, with five patients having over a 50% reduction, and nine patients having over a 30% reduction in PSA levels. At baseline testing, the PSMA PET SUV predicted a reduction in PSA of more than 30%, with an SUV max value of 17 ± 9 compared to 44 ± 15 (p < 0.007), and a PSMA SUV mean of 6 ± 4 compared to 10 ± 4 (p < 0.04).

Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%).

Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%).

Four (21%) patients showed no response (PD) to the ¹⁷⁷Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming ¹⁷⁷Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months.

A retrospective single center study looked at therapeutic outcomes of ¹⁷⁷Lu-PSMA-617 in mCRPC based on post-treatment imaging findings. 36 patients (aged 67 ± 8.8 years) were included out of which 23 received 2 cycles of treatment. Eleven patients (47.8%) were considered responsive in the post-therapeutic scans by ¹⁷⁷Lu-PSMA-617, two of which experienced complete response. Nine (39.1%) patients had stable disease while three (13%) experienced disease progression.

Another real-world prospective cohort study included twenty-one treatments refractory mCRPC patients at Bushehr Department of Nuclear Medicine between December 2016 to December 2018 treated with ¹⁷⁷Lu-PSMA-617 every 8 weeks. Patients had to have PSMA secreting lesions detected by PSMA imaging with 68Ga-PSMA PET or ¹⁷⁷Lu/99Tc-PSMA before to undergoing treatment. The mean age of patients was 70.3 ± 9.6 (range 54-88) with a median of two cycles of treatment (range 1-4). The primary endpoint of the study was to assess biochemical response (BCR), which was defined as a drop in the PSA of more than 50. Additional secondary endpoints included response by ECOG and overall survival. A BCR was seen in 62% of patients. The estimated overall survival was seen to be 62.69 weeks (95% confidence interval: 42.06-83.33) with a median follow-up period of 9 months (range 1-25 months).

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Yadav et al. provided a meta-analysis of ¹⁷⁷Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used ¹⁷⁷Lu-PSMA-617, 2 articles used ¹⁷⁷Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after ¹⁷⁷Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that ¹⁷⁷Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments.

Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received ¹⁷⁷Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy.

Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of ¹⁷⁷Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen.

Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received ¹⁷⁷Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Fifty patients were studied prospectively with PSMA-avid prostate cancer metastases who underwent a median of three cycles (range 1-4) of ¹⁷⁷Lu PSMA-617 therapy. Nine were deemed ¹⁷⁷Lu PSMA-617 refractory prior to death with a total of twelve deaths in the study. A PSA decline was noted in 23 patients, with 11 patients having a PSA decline of ≥50% after the first cycle of treatment. 12 patients had a PSA decline of <50% ranging from 11.3 to 43.5%. The remaining 23 patients experienced a PSA increase after the first ¹⁷⁷Lu PSMA-617 cycle (range 19.7-100%).

Of the 1003 patients who underwent scanning, 831 (82.9%) were judged to have met all the trial eligibility criteria, including the PSMA imaging criteria, and were randomly assigned, between June 4, 2018, and October 23, 2019, to receive either ¹⁷⁷Lu-PSMA-617 plus protocol-permitted standard care (551 patients) or standard care alone (280).

In an international phase III randomized controlled trial (VISION), men with PSMA positive mCRPC, previously treated with at least one ARAT and one or two taxane regimens, were randomly assigned in a 2 : 1 ratio to either ¹⁷⁷Lu-PSMA-617 for four to six cycles and protocol-permitted standard of care vs. standard of care therapy alone. The addition of Lu-PSMA-617 to a standard of care therapy improved the imaging-based PFS (8.7 vs. 3.4 months, hazard ratio: 0.40, 99% CI, 0.29-0.57) and OS (15.3 vs. 11.3 months, hazard ratio: 0.62, 95% CI: 0.52-0.74).

The C-index of the overall survival model was 071 (95% CI 069-073). Similar C-indices were achieved at internal validation (071 [069-073]) and external validation (072 [068-076]). The C-index of the PSA-progression-free survival model was 070 (95% CI 068-072). Similar C-indices were achieved at internal validation (070 [068-072]) and external validation (071 [068-074]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (249 months [95% CI 168-273] vs 74 months [40-108]; p<00001) and PSA-progression-free survival (66 months [60-71] vs 25 months [12-38]; p=0022).

The VISION trial was an international open-label phase 3 trial that assigned 581 mCRPC patients who previously received a novel hormonal agent and chemotherapy to either the treatment group (receiving ¹⁷⁷Lu-PSMA-617 and standard of care) or control group (standard of care alone). Primary end points were progression-free survival, median overall survival, and median follow-up. Median progression-free survival was 8.7 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 3.4 months in the control group (HR for progression or death, 0.40; 99.2% confidence interval, 0.29 to 0.57; P < 0.001). Median overall survival was 15.3 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P < 0.001). The median follow-up was 20.3 months (95% CI, 19.8 to 21.0) in the ¹⁷⁷Lu-PSMA-617 group and 19.8 months (95% CI, 18.3 to 20.8) in the control group. Secondary end points included median time to the first symptomatic skeletal event or death and PSA level. The median time to the first symptomatic skeletal event or death was 11.5 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 6.8 months in the control group (P < 0.001). The proportions of patients with confirmed decreases in the PSA level of at least 50% and 80% from baseline were higher in the ¹⁷⁷Lu-PSMA-617 group than in the control group.

A randomized, parallel group, open label, and non-inferiority phase II trial conducted between 2019 and 2021 studied a group of thirty five chemo-naive patients with mCPRC and high expressing PSMA lesions on 68Ga-PSMA-11 on PET/CT. Patients were randomized in 1:1 ratio to either ¹⁷⁷Lu PSMA-617 (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m²/cycle, every 3 weeks, for up to 10 cycles), with fifteen and twenty patients in each group, respectively. The primary endpoint was best PSA response rate (PSA-RR), which is defined as a ≥ 50% decline in PSA from baseline. The ¹⁷⁷Lu PSMA-617 arm PSA-RR was 60% versus 40% in docetaxel group with a difference in PSA-RR of 20% (95% CI: 1-47, p = 0.025) and met the pre-specified criterion for non-inferiority which was defined as margin of 15% decline in PSA-RR. The PFS rate for ¹⁷⁷Lu PSMA-617 was 30% versus 20% for docetaxel (95% CI: 18-38, p = 0.5). The number of treatment-related adverse events grade 3 or higher occurred less in the ¹⁷⁷Lu PSMA-617 arm than the docetaxel arm (30% versus 50% respectively, p = 0.2).

A phase II study followed forty patients with PET/CT-68Ga-PSMA positive mCRPC treated with ¹⁷⁷Lu PSMA-617. ¹⁷⁷Lu PSMA-617 was given for up to four cycles (median number of three cycles, range 2-5) every eight to twelve weeks. With a median follow-up of 15.5 months (range 6-22 ), 37.5% of patients had a greater than 50% PSA decline and 50% had a PSA decline greater than 30%. The median PFS was 7.5 months (95% CI: 4.8-10.5) and median OS was 12.4 months (95% CI 7.4-20.3 months).

The Thera-P trial was a phase II prospective multicenter trial looking at those with mCPRC who progressed after docetaxel chemotherapy and were randomly assigned to ¹⁷⁷Lu PSMA-617 or cabazitaxel. Initial reported results found that those who were treated with ¹⁷⁷Lu PSMA-617 treatment led to improvement in PSA response rate (66% vs 37%), RECIST response rate (49% vs 24%), PFS (HR 0.63), less G3-G4 toxicities (33% vs 53%), and overall better patient reported outcomes.

Although there are some different approaches regarding the use of ¹⁷⁷Lu-PSMA therapy in different countries, this type of therapy is generally safe, with a low toxicity profile. From the oncological point of view, a PSA (prostate specific antigen) decline of ≥50% was seen in 10.6-69% of patients with mCRPC; whereas progression-free survival (PFS) was reported to be 3-13.7 months in different studies.

A real-world study evaluated 191 patients with mCPRC treated with ¹⁷⁷Lu-PSMA-617. Patients had confirmation of PSMA expressing lesions by 68Ga-PSMA-ligand PET/CT. The majority of individuals (90%) had first- and second-line systemic treatment prior to being treated with ¹⁷⁷Lu-PSMA-617. Patients received one to five cycles of treatment and specific endpoints included biochemical response, radiologic response, PSA PFS, and OS. A PSA RR (defined as a decline of ≥50% in PSA) was found in 56% of patients, and any PSA decline occurred in 75% of patients. The median radiographic progression-free survival was found to be six months (range 3-10), PSA PFS (n = 132) was 4 months (range 3-8), and the overall survival (n = 191) was 12 months (range 5-18).

The REALITY (REgistry to Assess Outcome and Toxicity of Targeted RadionucLIde TherapY) study was a prospective real world cohort of 254 patients with mCRPC who received ¹⁷⁷Lu-PSMA-617 as experimental salvage therapy after conventional treatments had failed. The primary end points were efficacy, reflected by PSA-PFS, (prostate specific antigen-progression-free survival) OS, (overall survival) and safety which was reflected by the incidence of treatment-related (AEs). Over the entire course of ¹⁷⁷Lu-PSMA-617 RLT (radioligand therapy), 52.0% patients had a greater than 50% decline in their PSA response. At a median (minimum - maximum) follow-up of 14.9 (5.0-64.4) months, the median PSA-PFS was 5.5 (4.4-6.6) months, while the median OS was 14.5 (11.5-17.5) months.

A real-world study evaluated 191 patients with mCPRC treated with ¹⁷⁷Lu-PSMA-617. Patients had confirmation of PSMA expressing lesions by 68Ga-PSMA-ligand PET/CT. The majority of individuals (90%) had first- and second-line systemic treatment prior to being treated with ¹⁷⁷Lu-PSMA-617. Patients received one to five cycles of treatment and specific endpoints included biochemical response, radiologic response, PSA PFS, and OS. A PSA RR (defined as a decline of ≥50% in PSA) was found in 56% of patients, and any PSA decline occurred in 75% of patients. The median radiographic progression-free survival was found to be six months (range 3-10), PSA PFS (n = 132) was 4 months (range 3-8), and the overall survival (n = 191) was 12 months (range 5-18).

There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258).

There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258).

Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received ¹⁷⁷Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy.

A single center retrospective study reviewed 43 mCRPC patients with a median age of 71 (range 51-88) and ¹⁷⁷Lu-PSMA-617 treatments every six to twelve weeks. A total of 112 cycles of RLT were conducted with a median of three cycles (range 1-6). Endpoints included PSA response, toxicity, median OS, and median PSA PFS. A PSA decline of greater than 90% was seen in 23% of patients, while a decline of greater than 50% was seen in 65% of patients. A median OS was 52 weeks, while a PSA PFS was found to be 20 weeks.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

The VISION trial was an international open-label phase 3 trial that assigned 581 mCRPC patients who previously received a novel hormonal agent and chemotherapy to either the treatment group (receiving ¹⁷⁷Lu-PSMA-617 and standard of care) or control group (standard of care alone). Primary end points were progression-free survival, median overall survival, and median follow-up. Median progression-free survival was 8.7 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 3.4 months in the control group (HR for progression or death, 0.40;99.2% confidence interval, 0.29 to 0.57;P < 0.001). Median overall survival was 15.3 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62;95% CI, 0.52 to 0.74;P < 0.001). The median follow-up was 20.3 months (95% CI, 19.8 to 21.0) in the ¹⁷⁷Lu-PSMA-617 group and 19.8 months (95% CI, 18.3 to 20.8) in the control group. Secondary end points included median time to the first symptomatic skeletal event or death and PSA level. The median time to the first symptomatic skeletal event or death was 11.5 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 6.8 months in the control group (P < 0.001). The proportions of patients with confirmed decreases in the PSA level of at least 50% and 80% from baseline were higher in the ¹⁷⁷Lu-PSMA-617 group than in the control group.

A prospective phase II pilot study enrolled fourteen patients with progressive and symptomatic mCRPC despite taxane and novel anti-androgen therapy to receive up to four cycles of ¹⁷⁷Lu PSMA-617 every six weeks. Ten out of the 14 patients had a mean PSA reduction of 59%, with five patients having over a 50% reduction, and nine patients having over a 30% reduction in PSA levels. At baseline testing, the PSMA PET SUV predicted a reduction in PSA of more than 30%, with an SUV max value of 17 ± 9 compared to 44 ± 15 (p < 0.007), and a PSMA SUV mean of 6 ± 4 compared to 10 ± 4 (p < 0.04).

Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of ¹⁷⁷Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life.

Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of ¹⁷⁷Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of ¹⁷⁷Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen.

Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received ¹⁷⁷Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

The co-primary endpoint of OS was statistically significant, with patients randomized to receive ¹⁷⁷Lu-PSMA-617 plus BSoC having prolonged OS (median estimate 15.3 months) compared to BSoC alone (median estimate 11.3 months), hazard ratio (HR) 0.62 (95% CI: 0.52, 0.74, p<0.001). The planned interim OS analysis was not necessary as the targeted number of OS events were observed before the targeted number of rPFS events. Therefore, the final OS analysis was evaluated at the time of rPFS analysis.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Fifty patients were studied prospectively with PSMA-avid prostate cancer metastases who underwent a median of three cycles (range 1-4) of ¹⁷⁷Lu PSMA-617 therapy. Nine were deemed ¹⁷⁷Lu PSMA-617 refractory prior to death with a total of twelve deaths in the study. A PSA decline was noted in 23 patients, with 11 patients having a PSA decline of ≥50% after the first cycle of treatment. 12 patients had a PSA decline of <50% ranging from 11.3 to 43.5%. The remaining 23 patients experienced a PSA increase after the first ¹⁷⁷Lu PSMA-617 cycle (range 19.7-100%).

Yadav et al. provided a meta-analysis of ¹⁷⁷Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used ¹⁷⁷Lu-PSMA-617, 2 articles used ¹⁷⁷Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after ¹⁷⁷Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that ¹⁷⁷Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Yordanova et al., evaluated the response rate and clinical toxicity of re-challenge ¹⁷⁷Lu-PSMA-617 in progressive prostatic cancer patients who previously benefited from this therapy. In this retrospective study, a total of 30 patients were re-treated with a median of 3 (range 1-6) cycles of ¹⁷⁷Lu-PSMA-617. They found that 75-90% of patients demonstrated favorable serum PSA responses following re-challenge cycles, with a median OS of 12 months after the first re-challenge cycle and without any life-threatening grade-4 adverse event. The authors concluded that the majority of patients benefited from re-challenging ¹⁷⁷Lu-PSMA-617 with a longer OS in biochemically responsive patients. At present, data on re-challenge ¹⁷⁷Lu-PSMA-617 is limited and requires a prospective randomized trial before a definitive conclusion.

The first major multi-center retrospective study on ¹⁷⁷Lu-PSMA-617 was published by Rahbar et al., reporting 145 patients with mCRPC who progressed after second-line systemic therapies. The overall response rate in terms of serum PSA decline >50% was seen in 45% of patients after all ¹⁷⁷Lu-PSMA-617 cycles. On imaging, 21 (45%) patients and 13 (28%) patients had PR and SD, respectively. There was grade 3-4 toxicity in 18 patients (13%), which included severe anemia, thrombocytopenia, and leukopenia. They found elevated alkaline phosphatase and visceral metastases as negative predictors of response to ¹⁷⁷Lu-PSMA-617. A major drawback of this study was the variable cycles and doses of ¹⁷⁷Lu-PSMA-617 given to patients

Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received ¹⁷⁷Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy.

Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%).

Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%).

Four (21%) patients showed no response (PD) to the ¹⁷⁷Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming ¹⁷⁷Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months.

Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%).

Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of ¹⁷⁷Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen.

Patient follow-up was of over 51 months, with the median follow-up (reverse Kaplan-Meier estimator) being 39.1 months (95% CI 32.1-46.1). Median survival was 12.0 (95% CI 10.8-13.2) months, with five patients (19%) still alive at the last follow-up. There were no therapy-related deaths documented. At w16, 14 patients (52%) stated an improvement in pain status from the baseline of at least one tier/level, 11 of which were biochemical responders.

Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade ≥ 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade ≥ 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline ≥ 1) in 8/17 (47%) of patients.

The C-index of the overall survival model was 071 (95% CI 069-073). Similar C-indices were achieved at internal validation (071 [069-073]) and external validation (072 [068-076]). The C-index of the PSA-progression-free survival model was 070 (95% CI 068-072). Similar C-indices were achieved at internal validation (070 [068-072]) and external validation (071 [068-074]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (249 months [95% CI 168-273] vs 74 months [40-108]; p<00001) and PSA-progression-free survival (66 months [60-71] vs 25 months [12-38]; p=0022).

The VISION trial was an international open-label phase 3 trial that assigned 581 mCRPC patients who previously received a novel hormonal agent and chemotherapy to either the treatment group (receiving ¹⁷⁷Lu-PSMA-617 and standard of care) or control group (standard of care alone). Primary end points were progression-free survival, median overall survival, and median follow-up. Median progression-free survival was 8.7 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 3.4 months in the control group (HR for progression or death, 0.40; 99.2% confidence interval, 0.29 to 0.57; P < 0.001). Median overall survival was 15.3 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P < 0.001). The median follow-up was 20.3 months (95% CI, 19.8 to 21.0) in the ¹⁷⁷Lu-PSMA-617 group and 19.8 months (95% CI, 18.3 to 20.8) in the control group. Secondary end points included median time to the first symptomatic skeletal event or death and PSA level. The median time to the first symptomatic skeletal event or death was 11.5 months in the ¹⁷⁷Lu-PSMA-617 group, as compared with 6.8 months in the control group (P < 0.001). The proportions of patients with confirmed decreases in the PSA level of at least 50% and 80% from baseline were higher in the ¹⁷⁷Lu-PSMA-617 group than in the control group.

A phase II study followed forty patients with PET/CT-68Ga-PSMA positive mCRPC treated with ¹⁷⁷Lu PSMA-617. ¹⁷⁷Lu PSMA-617 was given for up to four cycles (median number of three cycles, range 2-5) every eight to twelve weeks. With a median follow-up of 15.5 months (range 6-22 ), 37.5% of patients had a greater than 50% PSA decline and 50% had a PSA decline greater than 30%. The median PFS was 7.5 months (95% CI: 4.8-10.5) and median OS was 12.4 months (95% CI 7.4-20.3 months).

Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of ¹⁷⁷Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life.

The Thera-P trial was a phase II prospective multicenter trial looking at those with mCPRC who progressed after docetaxel chemotherapy and were randomly assigned to ¹⁷⁷Lu PSMA-617 or cabazitaxel. Initial reported results found that those who were treated with ¹⁷⁷Lu PSMA-617 treatment led to improvement in PSA response rate (66% vs 37%), RECIST response rate (49% vs 24%), PFS (HR 0.63), less G3-G4 toxicities (33% vs 53%), and overall better patient reported outcomes.

A prospective phase II pilot study enrolled fourteen patients with progressive and symptomatic mCRPC despite taxane and novel anti-androgen therapy to receive up to four cycles of ¹⁷⁷Lu PSMA-617 every six weeks. Ten out of the 14 patients had a mean PSA reduction of 59%, with five patients having over a 50% reduction, and nine patients having over a 30% reduction in PSA levels. At baseline testing, the PSMA PET SUV predicted a reduction in PSA of more than 30%, with an SUV max value of 17 ± 9 compared to 44 ± 15 (p < 0.007), and a PSMA SUV mean of 6 ± 4 compared to 10 ± 4 (p < 0.04).

A prospective single center phase II study included 31 patients with mCRPC who had progressed despite second-line hormonal therapy and/or docetaxel chemotherapy. The patients underwent an average of two cycles (range 1-4) of ¹⁷⁷Lu-DKFZ-PSMA-617 therapy. The primary endpoints of the study were to determine radiographic progression-free survival (RPFS) using PET/CT scans and overall survival (OS). The treatment response was evaluated based on biochemical response using serum PSA, molecular response using PET/CT scans, and clinical response using VAS (visual analogue scale), AS (analgesic score) and ECOG (Eastern Cooperative Oncology Group) performance status. Biochemical response showed that the mean serum PSA level after three months of initial therapy was 141.75 ± 187.43 ng/mL (range 2.5-807). The mean serum PSA level three months after the second cycle was 153.07 ± 204 ng/mL (range 1.34-762). The molecular response estimated by the mean SUVmax (maximum standardized uptake value) of tumor lesions before and after therapy was 56.7 and 18.2 respectively. In two patients it was reduced from 32.67 to 0.38 after ¹⁷⁷Lu-DKFZ-PSMA-617 therapy, thus indicating a complete remission. The clinical response was estimated using the mean VASmax and AS. The pre-therapy VASmax was 7.5 ± 1, and post-therapy was 3 ± 0.9 (p < 0.0001), while the mean AS pre-therapy and post therapy was 2.5 ± 1.09 and 1.8 ± 0.98 (p = 0.009) respectively, and mean ECOG performance status improved from 2.54 ± 0.85 to 1.78 ± 0.92 after completion of therapy (p = 0.001). The median overall survival was 16 months, and progression-free survival was 12 months. 16.1% patients died due to disease during follow-up. This trial particularly highlighted an improvement in the ECOG performance status in patients receiving ¹⁷⁷Lu-DKFZ-PSMA-617 for the treatment of mCRPC.

A real-world study evaluated 191 patients with mCPRC treated with ¹⁷⁷Lu-PSMA-617. Patients had confirmation of PSMA expressing lesions by 68Ga-PSMA-ligand PET/CT. The majority of individuals (90%) had first- and second-line systemic treatment prior to being treated with ¹⁷⁷Lu-PSMA-617. Patients received one to five cycles of treatment and specific endpoints included biochemical response, radiologic response, PSA PFS, and OS. A PSA RR (defined as a decline of ≥50% in PSA) was found in 56% of patients, and any PSA decline occurred in 75% of patients. The median radiographic progression-free survival was found to be six months (range 3-10), PSA PFS (n = 132) was 4 months (range 3-8), and the overall survival (n = 191) was 12 months (range 5-18).

The REALITY (REgistry to Assess Outcome and Toxicity of Targeted RadionucLIde TherapY) study was a prospective real world cohort of 254 patients with mCRPC who received ¹⁷⁷Lu-PSMA-617 as experimental salvage therapy after conventional treatments had failed. The primary end points were efficacy, reflected by PSA-PFS, (prostate specific antigen-progression-free survival) OS, (overall survival) and safety which was reflected by the incidence of treatment-related (AEs). Over the entire course of ¹⁷⁷Lu-PSMA-617 RLT (radioligand therapy), 52.0% patients had a greater than 50% decline in their PSA response. At a median (minimum - maximum) follow-up of 14.9 (5.0-64.4) months, the median PSA-PFS was 5.5 (4.4-6.6) months, while the median OS was 14.5 (11.5-17.5) months.

There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258).

There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258).

Another real-world prospective cohort study included twenty-one treatments refractory mCRPC patients at Bushehr Department of Nuclear Medicine between December 2016 to December 2018 treated with ¹⁷⁷Lu-PSMA-617 every 8 weeks. Patients had to have PSMA secreting lesions detected by PSMA imaging with 68Ga-PSMA PET or ¹⁷⁷Lu/99Tc-PSMA before to undergoing treatment. The mean age of patients was 70.3 ± 9.6 (range 54-88) with a median of two cycles of treatment (range 1-4). The primary endpoint of the study was to assess biochemical response (BCR), which was defined as a drop in the PSA of more than 50. Additional secondary endpoints included response by ECOG and overall survival. A BCR was seen in 62% of patients. The estimated overall survival was seen to be 62.69 weeks (95% confidence interval: 42.06-83.33) with a median follow-up period of 9 months (range 1-25 months).

Median OS was significantly longer with lutetium Lu 177 vipivotide tetraxetan plus BSoC (n = 551) than with BSoC alone (n = 280) [15.3 vs 11.3 months [HR 0.62 (95% CI 0.52-0.74); p < 0.001]. Median rPFS was 8.7 months in the lutetium Lu 177 vipivotide tetraxetan plus BSoC arm (n = 385) compared with 3.4 months in the BSoC alone arm (n = 196) [HR for progression or death 0.40 (99.2% CI 0.29-0.57); p < 0.001). The overall response rate was also significantly higher in lutetium Lu 177 vipivotide tetraxetan arm (n = 319 patients with evaluable disease at baseline) than in the BSoC alone arm (n = 120) [30% vs 2%; p < 0.001].

A randomized, parallel group, open label, and non-inferiority phase II trial conducted between 2019 and 2021 studied a group of thirty five chemo-naive patients with mCPRC and high expressing PSMA lesions on 68Ga-PSMA-11 on PET/CT. Patients were randomized in 1:1 ratio to either ¹⁷⁷Lu PSMA-617 (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m²/cycle, every 3 weeks, for up to 10 cycles), with fifteen and twenty patients in each group, respectively. The primary endpoint was best PSA response rate (PSA-RR), which is defined as a ≥ 50% decline in PSA from baseline. The ¹⁷⁷Lu PSMA-617 arm PSA-RR was 60% versus 40% in docetaxel group with a difference in PSA-RR of 20% (95% CI:1-47, p = 0.025) and met the pre-specified criterion for non-inferiority which was defined as margin of 15% decline in PSA-RR. The PFS rate for ¹⁷⁷Lu PSMA-617 was 30% versus 20% for docetaxel (95% CI:18-38, p = 0.5). The number of treatment-related adverse events grade 3 or higher occurred less in the ¹⁷⁷Lu PSMA-617 arm than the docetaxel arm (30% versus 50% respectively, p = 0.2).

The Thera-P trial was a phase II prospective multicenter trial looking at those with mCPRC who progressed after docetaxel chemotherapy and were randomly assigned to ¹⁷⁷Lu PSMA-617 or cabazitaxel. Initial reported results found that those who were treated with ¹⁷⁷Lu PSMA-617 treatment led to improvement in PSA response rate (66% vs 37%), RECIST response rate (49% vs 24%), PFS (HR 0.63), less G3-G4 toxicities (33% vs 53%), and overall better patient reported outcomes.

A systematic review on the comparison of ¹⁷⁷Lu-PSMA-PRLT with third-line treatments such as abiraterone, enzalutamide, and cabazitaxel was published by Von Eyben et al. A significant difference of PSA response was seen between the two groups (a PSA decline of ≥50% in 44% of patients in Lu-PSMA-PRLT group versus only 22% of patients in third-line treatment group). The authors mentioned that, despite variations in doses and number of cycles, ¹⁷⁷Lu-PSMA-PRLT group showed a favorable response rate as compared to the third-line treatment group, and they also mentioned more side effects and discontinuation of third-line treatment as compared to ¹⁷⁷Lu-PSMA- PRLT group.

In 2018, a phase II trial on ¹⁷⁷Lu-PSMA-617 (LuPSMA trial) was published by Hofman et al. In this study, they included a total of 30 mCRPC patients who showed PD on standard therapies and received 1-4 cycles with 7.5 GBq of ¹⁷⁷Lu-PSMA-617 (range: 4.4-8.7 GBq). They found >50% PSA decline in 17 patients (57%) and an objective response rate of 40%, 37%, and 37% of patients on 68Ga PSMA-11, FDG-PET/CT, and bone imaging, respectively. The median PFS was 7.6 months, and the median OS was 13.5 months after ¹⁷⁷Lu-PSMA-617. Improvement in pain level was noted in 27 patients (90%), which significantly contributed to a better quality of life. ¹⁷⁷Lu-PSMA-617 was well tolerated with minimal side effects. Commonly seen side effects were grade 1 dryness of mouth (87%), grade 1-2 transient nausea (50%) and fatigue (50%). Uncommonly seen side effects included grade 3-4 thrombocytopenia (13%), grade 3 anemia (13%), and neutropenia (7%). This was the first prospective single-arm, single-center, phase II study on the use of ¹⁷⁷Lu-PSMA-617 in mCRPC patients.

Grade 3-4 AEs occurred in 32 (33%) of men who received ¹⁷⁷Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the ¹⁷⁷Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%).

Serious adverse reactions occurred in 36% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received ¹⁷⁷Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with ≥2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining ¹⁷⁷Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post ¹⁷⁷Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%).

Of the 1003 patients who underwent scanning, 831 (82.9%) were judged to have met all the trial eligibility criteria, including the PSMA imaging criteria, and were randomly assigned, between June 4, 2018, and October 23, 2019, to receive either ¹⁷⁷Lu-PSMA-617 plus protocol-permitted standard care (551 patients) or standard care alone (280).

Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%.

In the VISION trial, which enrolled patients with mCRPC who had received at least one line of ARPI treatment and one line of chemotherapy, ¹⁷⁷Lu-PSMA-617 improved imaging-based progression-free survival (PFS) by 60% (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.29-0.57; p < 0.001) and OS by 38% (HR = 0.62; 95% CI 0.52-0.74; p < 0.001) vs. trial-permitted best standard of care (SOC). The median imaging-based PFS was 8.7 months and median OS was 15.3 months for the ¹⁷⁷Lu-PSMA-617 arm, vs. 3.4 months and 11.3 months, respectively, for the SOC arm.

In PSMAfore, which enrolled patients who were chemotherapy-nave, at the time of the second interim analysis median imaging-based PFS was 6.4 months longer in the ¹⁷⁷Lu-PSMA-617 arm vs. the ARPI change arm (HR = 0.43; 95% CI 0.33-0.54; p < 0.0001), while there was no significant difference in median OS, which was 19.25 vs. 19.71 months in the ¹⁷⁷Lu-PSMA-617 and ARPI change arms, respectively (HR = 1.18; 95% CI 0.83-1.64). It is important to note that a high crossover rate occurred, with 84.2% of patients who progressed in the ARPI change arm subsequently receiving ¹⁷⁷Lu-PSMA-617, thus likely diminishing the between-arm differences.

A subsequent retrospective study, the first evaluating multiple administrations of ¹⁷⁷Lu-PSMA-617, was reported by the same group. The authors reviewed 28 consecutive patients who received 50 infusions of ¹⁷⁷Lu-PSMA-617 between 2014 and 2015. In their report, a PSA decline was noted in 59% and 75% of patients after 1 and 2 therapies, respectively, and a PSA decline of 50% or greater occurred in 32% and 50%, respectively. The estimated median survival was 29.4 weeks compared to 19.7 weeks in the historical best supportive care group which was statistically significant (HR 44; 95% CI 0.20-0.95; P=.031). Authors of the study also noted no significant changes in hematologic or renal parameters

Median OS was significantly longer with lutetium Lu 177 vipivotide tetraxetan plus BSoC (n = 551) than with BSoC alone (n = 280) [15.3 vs 11.3 months [HR 0.62 (95% CI 0.52-0.74); p < 0.001]. Median rPFS was 8.7 months in the lutetium Lu 177 vipivotide tetraxetan plus BSoC arm (n = 385) compared with 3.4 months in the BSoC alone arm (n = 196) [HR for progression or death 0.40 (99.2% CI 0.29-0.57); p < 0.001). The overall response rate was also significantly higher in lutetium Lu 177 vipivotide tetraxetan arm (n = 319 patients with evaluable disease at baseline) than in the BSoC alone arm (n = 120) [30% vs 2%; p < 0.001].

Primary outcomes measured radiographic progression-free survival (rPFS) and OS between ¹⁷⁷Lu PSMA-617 RLT plus SOC versus standard of care (SOC) alone. When compared to SOC alone, ¹⁷⁷Lu PSMA-617 plus SOC significantly prolonged rPFS (median, 8.7 vs. 3.4 months; HR for progression or death 0.40; 99.2% CI, 0.29 to 0.57) and median OS (15.3 vs. 11.3 months; HR for death, 0.62; 95% CI, 0.52 to 0.74; p < 0.001).

The co-primary endpoint of OS was statistically significant, with patients randomized to receive ¹⁷⁷Lu-PSMA-617 plus BSoC having prolonged OS (median estimate 15.3 months) compared to BSoC alone (median estimate 11.3 months), hazard ratio (HR) 0.62 (95% CI: 0.52, 0.74, p<0.001). The planned interim OS analysis was not necessary as the targeted number of OS events were observed before the targeted number of rPFS events. Therefore, the final OS analysis was evaluated at the time of rPFS analysis.

A ≥ 50% reduction in PSA was seen in 52.0% of patients (132/254); at a median follow-up of 14.5 months, median PSA PFS was 5.5 months and median OS was 14.5 months. The median dose of lutetium Lu 177 vipivotide tetraxetan was 6.5 GBq/cycle (median cumulative dose 21.2 GBq), the median number cycles was 3, delivered at a median interval of 5.7 weeks.

A phase 1/2 study (NCT03042468) found that a single cycle of fractionated-dose of lutetium Lu 177 vipivotide tetraxetan [7.4-22 GBq on days 1 and 15 in the phase 1 dose-escalation cohort (n = 29); 22GBq on days 1 and 15 in the phase 2 cohort (n = 21); 27 patients treated at 22 GBq] was effective in patients with progressive mCRPC. A >50% PSA reduction was seen in 27 of 50 patients (54%); median PSA PFS was 5.6 months and median OS was 15.2 months.

A > 50% reduction in PSA after administration of up to 6 cycles of lutetium Lu 177 vipivotide tetraxetan plus idronoxil (a synthetic flavonoid derivative with radiosensitising properties) was seen in 34 of 56 (61%) patients with progressive mCRPC previously treated with AR pathway inhibition and taxanes in the phase 1/2 LuPin trial (ACTRN12618001073291). The median PSA PFS was 7.5 months and median OS was 19.7 months. Patients received lutetium Lu 177 vipivotide tetraxetan 7.5 GBq on day 1 of each 6-week cycle, with escalating doses of NOX66 on days 1-10 of a 6-week cycle.

In the VISION trial, which enrolled patients with mCRPC who had received at least one line of ARPI treatment and one line of chemotherapy, ¹⁷⁷Lu-PSMA-617 improved imaging-based progression-free survival (PFS) by 60% (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.29-0.57; p < 0.001) and OS by 38% (HR = 0.62; 95% CI 0.52-0.74; p < 0.001) vs. trial-permitted best standard of care (SOC). The median imaging-based PFS was 8.7 months and median OS was 15.3 months for the ¹⁷⁷Lu-PSMA-617 arm, vs. 3.4 months and 11.3 months, respectively, for the SOC arm.

In PSMAfore, which enrolled patients who were chemotherapy-nave, at the time of the second interim analysis median imaging-based PFS was 6.4 months longer in the ¹⁷⁷Lu-PSMA-617 arm vs. the ARPI change arm (HR = 0.43; 95% CI 0.33-0.54; p < 0.0001), while there was no significant difference in median OS, which was 19.25 vs. 19.71 months in the ¹⁷⁷Lu-PSMA-617 and ARPI change arms, respectively (HR = 1.18; 95% CI 0.83-1.64). It is important to note that a high crossover rate occurred, with 84.2% of patients who progressed in the ARPI change arm subsequently receiving ¹⁷⁷Lu-PSMA-617, thus likely diminishing the between-arm differences.

Yordanova et al., evaluated the response rate and clinical toxicity of re-challenge ¹⁷⁷Lu-PSMA-617 in progressive prostatic cancer patients who previously benefited from this therapy. In this retrospective study, a total of 30 patients were re-treated with a median of 3 (range 1-6) cycles of ¹⁷⁷Lu-PSMA-617. They found that 75-90% of patients demonstrated favorable serum PSA responses following re-challenge cycles, with a median OS of 12 months after the first re-challenge cycle and without any life-threatening grade-4 adverse event. The authors concluded that the majority of patients benefited from re-challenging ¹⁷⁷Lu-PSMA-617 with a longer OS in biochemically responsive patients. At present, data on re-challenge ¹⁷⁷Lu-PSMA-617 is limited and requires a prospective randomized trial before a definitive conclusion.

Another retrospective study studied 25 patients less than 55 years of age at prostate cancer diagnosis who were treated with a median of four cycles (range 2-6) of ¹⁷⁷Lu-PSMA-617. The median PFS was 3.8 months (95% CI 2.5-5.3) and OS was 8.5 months (95% 6.2-10.8). An initial PSA reduction of greater than 50% was seen in 36% of patients but not associated with OS benefit (p = 0.601). A PSA response greater than 50% at three months was seen in 48% of patients and associated with improvement in OS (16 months, 95% CI 7.4-24.6 versus 4.0 months, 95% CI: 1.1-6.9, p = 0.002). They also used 68Ga-PSMA-PET/CT and correlated imaging response after up to three cycles in 44% of patients. Responders had a longer median PFS (8.7 months, 95% CI 1.3-16.1 vs. 1.9 months, 95% CI 1.7-2.2, p < 0.001) and OS (16.0 months, 95% CI 7.6-24.4 vs. 4.0 months, 95% CI 0.9-7.1; p = 0.002).

A single center retrospective analysis studied 62 men with mCRPC who were treated with ¹⁷⁷Lu-PSMA-617. A median of 3 treatment cycles (2-5) were administered over 4 weeks. Progression-free survival and overall survival were 4.9 months (2.4-9.6) and 17.2 months (6-26.4) respectively. Greater than 50% PSA response was found in 58.7% of patients (p < 0.004).

Median OS and PSA-PFS were 17.7 (95% confidence interval [CI]: 15.2-20.2) and 6.6 months (95% CI: 4.5-8.8), respectively. Primary resistance to PSMA-RLT (hazard ratio [HR]: 12.57, 95% CI: 2.4-65.2, p: 0.003), <30% PSA response rate after first cycle of PSMA-RLT (HR: 1.016, 95% CI: 1.006-1.03, p: 0.003), FDG > PSMA disease (HR: 4.9, 95% CI: 1.19-20.62, p: 0.03), PSA doubling time (PSA DT) of ≤2.4 months (HR: 15.7, 95% CI: 3.7-66.4, p: <0.0001), and low hemoglobin levels (HR: 0.59, 95% CI: 0.41-0.83, p: 0.003) were correlated with poor OS in the multivariate analysis. Bone scintigraphy > PSMA disease (HR: 5.6; 95% CI: 1.8-17, p: 0.002) and high C-reactive protein (HR: 1.4, 95% CI: 1.1-1.7, p: 0.001) were significant predictive biomarkers for PFS in the multivariate analysis.

Suman et al. evaluated the efficacy of ¹⁷⁷Lu-PSMA-617 in heavily pre-treated mCRPC patients. A total of 40 mCRPC patients who received at least 2 cycles of ¹⁷⁷Lu-PSMA-617 were included in this study. Twenty-one (52.5%) patients were responders (CR, PR, and SD) and 19 (47.5%) patients were non-responders (PD) on both symptomatic and biochemical scales. As per PET response criteria in solid tumor (PERCIST) criteria, 16 patients (43%) and 21 patients (57%) were responders and non-responders, respectively, on 68Ga-PSMA-11 PET/CT imaging. Metastatic nodal lesions responded better compared to liver and bony lesions. The median OS of 12 months and the median PFS of 7 months were registered without any grade 3/4 toxicity. The authors concluded that ¹⁷⁷Lu-PSMA-617 controlled disease with good symptomatic and biochemical response rates without any high-grade clinical toxicity.

Forty-five patients were treated with total of 164 cycles of RNT. Fifteen patients (33%) had PSA decline of ≥50%, 23 patients (51%) showed any PSA decline and 20 patients (44%) showed PSA increase of ≥25%. Median OS and PFS were 17,1 months and 7,4 months. Patients had any or ≥50% PSA response after the first cycle, lower initial ALP (<120U/L) had longer OS and PFS. Patients had normal Hb showed longer OS and patients had lower initial PSA (<51ng/mL) had longer PFS. Patients had PSA progression of ≥25% had shorter OS and PFS.

Progression occurred in all patients, with a median time to the event of 7.5 mo (95% CI, 4.7-10.3 mo). An %IDred value above the median in both LNM and BM was associated with shorter survival. Moreover, higher %ID within the LNM correlated with longer survival. The kinetics of ¹⁷⁷Lu-PSMA-617 within the organ metastasis had no prognostic implications.

In 2018, a phase II trial on ¹⁷⁷Lu-PSMA-617 (LuPSMA trial) was published by Hofman et al. In this study, they included a total of 30 mCRPC patients who showed PD on standard therapies and received 1-4 cycles with 7.5 GBq of ¹⁷⁷Lu-PSMA-617 (range: 4.4-8.7 GBq). They found >50% PSA decline in 17 patients (57%) and an objective response rate of 40%, 37%, and 37% of patients on 68Ga PSMA-11, FDG-PET/CT, and bone imaging, respectively. The median PFS was 7.6 months, and the median OS was 13.5 months after ¹⁷⁷Lu-PSMA-617. Improvement in pain level was noted in 27 patients (90%), which significantly contributed to a better quality of life. ¹⁷⁷Lu-PSMA-617 was well tolerated with minimal side effects. Commonly seen side effects were grade 1 dryness of mouth (87%), grade 1-2 transient nausea (50%) and fatigue (50%). Uncommonly seen side effects included grade 3-4 thrombocytopenia (13%), grade 3 anemia (13%), and neutropenia (7%). This was the first prospective single-arm, single-center, phase II study on the use of ¹⁷⁷Lu-PSMA-617 in mCRPC patients.

In the period between 2016 and 2018, 58 patients were referred for [¹⁷⁷Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients.

Yadav et al. provided a meta-analysis of ¹⁷⁷Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used ¹⁷⁷Lu-PSMA-617, 2 articles used ¹⁷⁷Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after ¹⁷⁷Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that ¹⁷⁷Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments.

The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with ≥2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining ¹⁷⁷Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post ¹⁷⁷Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%).

Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of ¹⁷⁷Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen.

Four (21%) patients showed no response (PD) to the ¹⁷⁷Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming ¹⁷⁷Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months.