¹⁷⁷Lu-PSMA 7.5 GBq was given to the patient (-fetoprotein: 38,669 ng/mL), and posttherapy imaging was performed 48 hours after the intravenous administration of ¹⁷⁷Lu-PSMA. Adequate uptakes were detected in metastatic lesions on whole-body posttherapy images (A, B) similar to pretreatment 68Ga-PSMA PET/CT. The patient well tolerated the treatment without any adverse effects. However, in follow-up at month 1, -fetoprotein level progressed to 62,600 ng/mL, and 68Ga-PSMA PET/CT was planned.

A subjective clinical benefit, based on the clinical evaluation by the treating oncologist, was observed in 28 patients (52%). The first PSA was measured following a median of 1.2 months from the start of treatment (range 0.4-3.7 months). PSA nadir was achieved within a median of 1.4 months (range 0.4-13.4). A maximal PSA decline of at least 20% was observed in 26 patients (50%), a maximal PSA decline of at least 50% was observed in 18 patients (35%), and a maximal PSA decline of at least 90% was observed in 7 patients (16%). Thirty patients (58%) had any PSA decline (PSA decline greater than 10%) upon their first PSA assessment.

Another study retrospectively examined outcomes in 68 patients with a mean of 71 years of age (range 46-89) who were treated with a mean of three cycles of ¹⁷⁷Lu-PSMA-617 (median of 3, range 1-7 cycles) every six weeks. The 18-month overall survival was 63.8%. Those with a baseline PSA <20 ug/L had a higher 18-month survival estimate (79.9%) versus those with PSA levels greater than 20 ug/L (53.8%, p = < 0.05). Those with an SUVmax greater than 15 had a higher 18-month survival rate of 56% compared to those with SUVmax less than 15 (p = < 0.05). Their study found any decrease in PSA levels after two cycles of treatment was indicative of greater chance of overall survival (p = < 0.01).

A subjective clinical benefit, based on the clinical evaluation by the treating oncologist, was observed in 28 patients (52%). The first PSA was measured following a median of 1.2 months from the start of treatment (range 0.4-3.7 months). PSA nadir was achieved within a median of 1.4 months (range 0.4-13.4). A maximal PSA decline of at least 20% was observed in 26 patients (50%), a maximal PSA decline of at least 50% was observed in 18 patients (35%), and a maximal PSA decline of at least 90% was observed in 7 patients (16%). Thirty patients (58%) had any PSA decline (PSA decline greater than 10%) upon their first PSA assessment.

Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline ≥50 or ≥30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment.

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.

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 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.

A PSA response (PSA reduction of ≥ 50% from baseline) was seen in 32 of 50 patients (64%) with progressive, PSMA-positive, symptomatic mCRPC who received up to 4 cycles of lutetium Lu 177 vipivotide tetraxetan every 6 weeks in the LuPSMA study (ACTRN12615000912583). 22 of 50 patients (44%) had a ≥ 80% decrease in PSA. At a median follow-up of 31.4 months, median OS was 13.3 months in the overall population and 18.4 months in those achieving a PSA response.

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.

60% of patients (9/15) in the lutetium Lu 177 vipivotide tetraxetan arm and 40% (8/20) in the docetaxel arm achieved a ≥ 50% decline in PSA from baseline [between-group difference 20%; 95% CI -12 to 47 (noninferiority margin of -15 in per protocol analysis achieved)]. Patients were administered lutetium Lu 177 vipivotide tetraxetan (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m²/cycle, every 3 weeks, up to 10 cycles).

A PSA response (PSA reduction of ≥ 50% from baseline) was seen in 32 of 50 patients (64%) with progressive, PSMA-positive, symptomatic mCRPC who received up to 4 cycles of lutetium Lu 177 vipivotide tetraxetan every 6 weeks in the LuPSMA study (ACTRN12615000912583). 22 of 50 patients (44%) had a ≥ 80% decrease in PSA. At a median follow-up of 31.4 months, median OS was 13.3 months in the overall population and 18.4 months in those achieving a PSA response.

Seventy-five patients were screened to identify 50 evaluable patients. Sixteen patients were excluded because of either low PSMA expression (n = 8) or discordant sites of 18F-FDG-positive PSMA-negative disease. Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of ¹⁷⁷Lu-PSMA every 6 wk.

65 of 99 patients treated with lutetium Lu 177 vipivotide tetraxetan 6.0-8.5 GBq every 6 weeks for up to 6 cycles (n = 99) compared with 37 of 101 patients receiving cabazitaxel 20 mg/m² every 3 weeks for up to 10 cycles achieved a PSA reduction of ≥ 50% from baseline [66% vs 37%; treatment difference 29% (95% CI 16-42); p < 0.0001 (ITT analysis)]. Lutetium Lu 177 vipivotide tetraxetan also delayed disease progression [HR 0.63 (95% CI 0.46-0.86;) p = 0.0028], radiographic progression [0.64 (95% CI 0.46-0.88); p = 0.0070] and PSA PFS [0.60 (95% CI 0.44-0.83); p = 0.0017] compared with cabazitaxel.

A pilot study (NCT03828838) showed that treatment with lutetium Lu 177 vipivotide tetraxetan was effective in patients with PSMA-expressing, low volume (≥ 1 but ≤ 10 positive lesions on PSMA-PET) metastatic hormone-sensitive prostate cancer (mHSPC). After 2 cycles of lutetium Lu 177 vipivotide tetraxetan (a first cycle of 3 GBq, followed by a second cycle with 3-6 GBq after 7-9 weeks), 5 of 10 patients showed a > 50% PSA reduction and in one patient, PSA was undetectable.

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.

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).

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).

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.

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.

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).

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).

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.

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).

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.

A total of 104 patients with mCRPC who were previously treated with one line of chemotherapy (docetaxel and/or cabazitaxel) and at least one of antihormonal therapies (enzalutamide and/or abiraterone) were retrospectively studied after being treated with ¹⁷⁷Lu-PSMA-617 RLT. A median of three cycles were administered (1-8 cycles). Results of the study noted a median overall survival of 56.0 weeks (95% CI: 50.5-61.5) and PSA decline >50% in 33% patients after receiving first cycle of treatment.

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).

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).

A subjective clinical benefit, based on the clinical evaluation by the treating oncologist, was observed in 28 patients (52%). The first PSA was measured following a median of 1.2 months from the start of treatment (range 0.4-3.7 months). PSA nadir was achieved within a median of 1.4 months (range 0.4-13.4). A maximal PSA decline of at least 20% was observed in 26 patients (50%), a maximal PSA decline of at least 50% was observed in 18 patients (35%), and a maximal PSA decline of at least 90% was observed in 7 patients (16%). Thirty patients (58%) had any PSA decline (PSA decline greater than 10%) upon their first PSA assessment.

A 2014-2015 retrospective multi-institutional study looked to evaluate the efficacy and safety of ¹⁷⁷Lu-PSMA-617 in a larger population of patients. 145 patients with a median age of 73 years (range 43-88) with mCRPC were treated with a range of 1-4 cycles of treatment. Median follow-up time was sixteen weeks (range 2-30). The primary endpoint of the study was biochemical response, which was defined as a decline in PSA greater than 50% from baseline and secondary endpoints included toxicity. A total of 248 cycles of treatment were carried out in 145 patients with the overall biochemical response rate of 45% after conclusion of all treatment and 40% of patients becoming responders after only one cycle of treatment.

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.

Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline ≥50 or ≥30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment.

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).

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.

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 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.

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%).

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.)

A 2014-2015 retrospective multi-institutional study looked to evaluate the efficacy and safety of ¹⁷⁷Lu-PSMA-617 in a larger population of patients. 145 patients with a median age of 73 years (range 43-88) with mCRPC were treated with a range of 1-4 cycles of treatment. Median follow-up time was sixteen weeks (range 2-30). The primary endpoint of the study was biochemical response, which was defined as a decline in PSA greater than 50% from baseline and secondary endpoints included toxicity. A total of 248 cycles of treatment were carried out in 145 patients with the overall biochemical response rate of 45% after conclusion of all treatment and 40% of patients becoming responders after only one cycle of 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

A prospective trial investigated the efficacy and toxicity of ¹⁷⁷Lu-PSMA-617 in fourteen patients with mCRPC. Biochemical response using PSA level and clinical symptoms were evaluated after two or more cycles of treatment. PSA levels declined in 11 out of 14 (78.6%) patients, with greater than 50% decline in 45.4% patients over a period of 8 weeks. Progressive disease, defined by a PSA increase of 25% or greater occurred in 21.4% patients. The mean serum alkaline phosphatase level declined from 569.5 U/L to 498.4 U/L, but this was not statistically significant (P = 0.17). At baseline, nine patients with bone metastases reported skeletal bone pain. Eight of these patients showed improvement in pain after treatment.

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 study reviewed 24 mCPRC patients with a median age of 81.7 (range 75.1-91.9 years old) and median of four prior lines of treatments who were treated with ¹⁷⁷Lu-PSMA-617. 54% of patients had bone and lymph node metastasis. Primary endpoints were response, which was defined as a decrease in PSA level over 50% from baseline and toxicity. Patients were treated with one to four cycles. A PSA decline over 50% was seen in 48% (n = 11) of patients.

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.

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.

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.

Von Eyben et al. published a review and meta-analysis on ¹⁷⁷Lu-PSMA-PRLT with the inclusion of 2346 patients. They found a median OS of 16 months after PRLT and longer survival in asymptomatic patients and those with only lymph node metastatic disease as compared to symptomatic patients and those with extensive disease. They also demonstrated ≥50% PSA decline in 50% of patients with longer survival as compared to those with <50% PSA decline. Hematologic toxicity was observed in approximately 10% of the patients with anemia of grade 3 as the most severe adverse effect of ¹⁷⁷Lu-PSMA-PRLT. The authors mentioned that the intensified schedule of ¹⁷⁷Lu-PSMA-PRLT (increased dose activity up to 9 GBq per cycle with a shortened time interval between cycles) increases the survival and efficacy of PRLT without increasing hematological toxicity.

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.

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.

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.

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 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.

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).

Thirty patients received treatment in this study out of 43 screened patients, thus only 70% of patients were treated. A PSA response was seen in 17 patients (57%). There were no treatment-related deaths in the study and the most common AEs were grade 1 dry mouth in 26 patients (87%), grade 1-2 nausea in 15 patients (50%), and grade 1-2 fatigue in 15 patients (50%).

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.

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).

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).

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.

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%).

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%).

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).

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).

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.

The phase II TheraP trial, compared ¹⁷⁷Lu PSMA-617 to cabazitaxel in 200 men with mCRPC. The primary endpoint was PSA response defined by a reduction of PSA ≥ 50% from baseline. In contrast to the VISION trial, TheraP set PSMA SUVmax requirements of at least one lesion on 68Ga-PSMA-11 PET with SUVmax > 20, and the remaining metastatic lesions SUVmax > 10, and no discordant hypermetabolic disease. PSA responses were more frequent among men in the ¹⁷⁷Lu PSMA-617 group versus the cabazitaxel group (66% vs. 37%, respectively).

Of the patients with PET screening in TheraP, approximately 27% were excluded from treatment. Investigators found that patients who received ¹⁷⁷Lu-PSMA-617 were more likely to receive a PSA response (66% vs. 37% in the intent-to-treat group, P<.0001). Updated survival analysis was presented at a 2022 meeting, and overall survival was similar between ¹⁷⁷Lu-PSMA-617 and cabazitaxel at 19.1 months versus 19.6 months was not significantly different between the 2 arms. The finding of survival equivalence in a PSMA-selected patient population was surprising to some but it is well known that cabazitaxel is an important life-prolonging therapy in mCRPC.

Most patients underwent three treatment cycles (n=12); at least 2 cycles (n=6) or at most 8 cycles (n=1) were performed. Out of 30 cases, PSA response after the first cycle was observed in 73% (n=22). Compared to baseline, QoL was significantly improved at 2-month follow-up revealing increase in global health status (p=0.025), role functioning (p=0.017) and emotional functioning (0.010), and decrease in pain (p=0.033). Global health status variation can be explained up to 20.5% by response in PSA (p=0.012), this improved with PSA reduction.

A subjective clinical benefit, based on the clinical evaluation by the treating oncologist, was observed in 28 patients (52%). The first PSA was measured following a median of 1.2 months from the start of treatment (range 0.4-3.7 months). PSA nadir was achieved within a median of 1.4 months (range 0.4-13.4). A maximal PSA decline of at least 20% was observed in 26 patients (50%), a maximal PSA decline of at least 50% was observed in 18 patients (35%), and a maximal PSA decline of at least 90% was observed in 7 patients (16%). Thirty patients (58%) had any PSA decline (PSA decline greater than 10%) upon their first PSA assessment.

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.

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.

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.

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

Additionally, a recently published meta-analysis of 250 studies with a total of 1192 patients similarly found that while grade 3 and 4 toxicities were uncommon, anemia was the highest reported adverse event for both ¹⁷⁷Lu PSMA-617 (0.19 [0.06-0.15]) and ¹⁷⁷Lu PSMAI&T (0.09 [0.05-0.16]). Greater than 35% of patients in the treatment group of the VISION trial experienced fatigue, dry mouth, or nausea, though almost entirely grade ≤ 2 AE.

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.

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.

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%).

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.

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).

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)

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)

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 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 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).

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.

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.

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.

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 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.

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.

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.

65 of 99 patients treated with lutetium Lu 177 vipivotide tetraxetan 6.0-8.5 GBq every 6 weeks for up to 6 cycles (n = 99) compared with 37 of 101 patients receiving cabazitaxel 20 mg/m² every 3 weeks for up to 10 cycles achieved a PSA reduction of ≥ 50% from baseline [66% vs 37%; treatment difference 29% (95% CI 16-42); p < 0.0001 (ITT analysis)]. Lutetium Lu 177 vipivotide tetraxetan also delayed disease progression [HR 0.63 (95% CI 0.46-0.86;) p = 0.0028], radiographic progression [0.64 (95% CI 0.46-0.88); p = 0.0070] and PSA PFS [0.60 (95% CI 0.44-0.83); p = 0.0017] compared with cabazitaxel.

65 of 99 patients treated with lutetium Lu 177 vipivotide tetraxetan 6.0-8.5 GBq every 6 weeks for up to 6 cycles (n = 99) compared with 37 of 101 patients receiving cabazitaxel 20 mg/m² every 3 weeks for up to 10 cycles achieved a PSA reduction of ≥ 50% from baseline [66% vs 37%; treatment difference 29% (95% CI 16-42); p < 0.0001 (ITT analysis)]. Lutetium Lu 177 vipivotide tetraxetan also delayed disease progression [HR 0.63 (95% CI 0.46-0.86;) p = 0.0028], radiographic progression [0.64 (95% CI 0.46-0.88); p = 0.0070] and PSA PFS [0.60 (95% CI 0.44-0.83); p = 0.0017] compared with cabazitaxel.

65 of 99 patients treated with lutetium Lu 177 vipivotide tetraxetan 6.0-8.5 GBq every 6 weeks for up to 6 cycles (n = 99) compared with 37 of 101 patients receiving cabazitaxel 20 mg/m² every 3 weeks for up to 10 cycles achieved a PSA reduction of ≥ 50% from baseline [66% vs 37%; treatment difference 29% (95% CI 16-42); p < 0.0001 (ITT analysis)]. Lutetium Lu 177 vipivotide tetraxetan also delayed disease progression [HR 0.63 (95% CI 0.46-0.86;) p = 0.0028], radiographic progression [0.64 (95% CI 0.46-0.88); p = 0.0070] and PSA PFS [0.60 (95% CI 0.44-0.83); p = 0.0017] compared with cabazitaxel.

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%).

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%).

In total, 61 RNT cycles were evaluated in 34 patients with age of 65 ± 2.83 (median ± SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05).

In total, 61 RNT cycles were evaluated in 34 patients with age of 65 ± 2.83 (median ± SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05).

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.

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.

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.

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.

Grade 1 xerostomia was reported in 13 (14.3%) patients at the baseline and in 22 (24.2%) patients after two cycles of Lu-177 PSMA-I&T/-617 (p < 0.01), with a correlated significant increase of the median sXI-score from 7 (IQR 5.3-9) before to 8 (IQR 6.3-11) after PRLT (p < 0.05). In addition, a moderate correlation of xerostomia symptoms and the sXI-score was found during follow-up (r = 0.43, p < 0.01).

From the baseline to follow-up, xerostomia became more frequent (grade 1 in 2 (5%) patients at baseline, grade 1 in 15 (37.5%) patients, and grade 2 in 1 (2.5%) patient at follow-up; p < 0.001). No grade 3 xerostomia occurred. The data of the sXI questionnaires were available only at the follow-up, showing a moderate but significant correlation to the subjective dryness of mouth (r = 0.41, p < 0.05).

One-third (6/18) of the patients reported grade 1 xerostomia at the baseline, while, after one cycle of Tandem-PRLT, xerostomia grade 1 in 10/18 patients and grade 2 in 2/18 patients was observed (p = 0.001), and 6/18 patients did not report any xerostomia at the follow-up. There was no patient-requested treatment discontinuation. The sXI-score increased significantly from 9.5 (95%CI: 7.0-14.2) before to 14.0 (95%CI: 11.5-19.6) after Tandem-PRLT (p = 0.005).

Thirty patients received treatment in this study out of 43 screened patients, thus only 70% of patients were treated. A PSA response was seen in 17 patients (57%). There were no treatment-related deaths in the study and the most common AEs were grade 1 dry mouth in 26 patients (87%), grade 1-2 nausea in 15 patients (50%), and grade 1-2 fatigue in 15 patients (50%).

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

Thirty patients received treatment in this study out of 43 screened patients, thus only 70% of patients were treated. A PSA response was seen in 17 patients (57%). There were no treatment-related deaths in the study and the most common AEs were grade 1 dry mouth in 26 patients (87%), grade 1-2 nausea in 15 patients (50%), and grade 1-2 fatigue in 15 patients (50%).

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

Thirty patients received treatment in this study out of 43 screened patients, thus only 70% of patients were treated. A PSA response was seen in 17 patients (57%). There were no treatment-related deaths in the study and the most common AEs were grade 1 dry mouth in 26 patients (87%), grade 1-2 nausea in 15 patients (50%), and grade 1-2 fatigue in 15 patients (50%).

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

No grade ≥ 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 ± 18.0 mL/min/1.73 m2 at baseline to 73.4 ± 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 ± 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 ± 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 ± 7 vs. 30 ± 10 GBq, p = 0.036). No grade ≥ 3 hematological toxicity was observed during intermittent ¹⁷⁷Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent ¹⁷⁷Lu-PSMA-RLT. Mean Hb declined from 12.7 ± 1.4 to 12.0 ± 1.6 g/dL (p = 0.021), WBC declined from 7.4 ± 2.8 109/L to 5.9 ± 1.6 109/L (p = 0.005), and PLT declined from 233 ± 76 109/L to 218 ± 71 109/L (p = 0.047). Significant xerostomia was not detected during ¹⁷⁷Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

From the baseline to follow-up, xerostomia became more frequent (grade 1 in 2 (5%) patients at baseline, grade 1 in 15 (37.5%) patients, and grade 2 in 1 (2.5%) patient at follow-up; p < 0.001). No grade 3 xerostomia occurred. The data of the sXI questionnaires were available only at the follow-up, showing a moderate but significant correlation to the subjective dryness of mouth (r = 0.41, p < 0.05).

One-third (6/18) of the patients reported grade 1 xerostomia at the baseline, while, after one cycle of Tandem-PRLT, xerostomia grade 1 in 10/18 patients and grade 2 in 2/18 patients was observed (p = 0.001), and 6/18 patients did not report any xerostomia at the follow-up. There was no patient-requested treatment discontinuation. The sXI-score increased significantly from 9.5 (95%CI: 7.0-14.2) before to 14.0 (95%CI: 11.5-19.6) after Tandem-PRLT (p = 0.005).

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

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.

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.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

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.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to ¹⁷⁷Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all.

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%).

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).

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 the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT.

In the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT.

In the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT.

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.

In all patients, the value of troponin I was in normal range. In all patients, the median values of serum troponin I before and after treatment were 0.2 ± 0.02 (range: 0.00-0.42) and 0.28 ± 0.02 (range: 0.00-0.46) ng/ml, respectively (p > 0.05). In the prostate cancer patients, the median values of serum troponin I before and after treatment were 0.26 ± 0.04 (0.04-0.42) and 0.30 ± 0.04 (0.00-0.41) ng/ml, respectively (p > 0.05). In the NET patients, the median values of serum troponin I before and after treatment were 0.18 ± 0.03 (0.00-0.42) and 0.17 ± 0.03 (0.00-0.46) ng/ml, respectively (p > 0.05).

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.