177Lu-PSMA-617 vs. Androgen Receptor-Directed Therapy in the Treatment of Progressive Metastatic Castrate Resistant Prostate Cancer

This is a phase III, open label, multicenter randomized study evaluating the superiority of 177Lu-PSMA-617 over a change of ARDT treatment in prolonging rPFS. The primary endpoint of rPFS is to assess via blinded independent centralized review (BICR) of radiographic images provided by the treating physician and as outlined in PCWG3 modified RECIST v 1.1 Guidelines. The study also evaluates whether 177Lu-PSMA-617 improves the overall survival (OS) in participants with progressive PSMA-positive mCRPC compared to participants treated with a change in ARDT treatment. OS is defined as the time from randomization to death due to any cause. Treatment duration: approximately 43 months. Screening period At screening, the participants are assessed for eligibility and undergo a 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) scan to evaluate PSMA positivity. Only participants with PSMA positive cancer and confirmed eligibility criteria are randomized. Randomization period The participants are randomized 1:1 to receive 177Lu-PSMA-617 or a change of the ARDT treatment. The ARDT change includes approved Androgen Receptor (AR) axis targeted therapy (abiraterone or enzalutamide). Supportive care is allowed in both arms at the discretion of the investigator and includes available care for the eligible participant according to best institutional practice for mCRPC treatment, including androgen deprivation therapy (ADT). Investigational agents, biological products, immunotherapy, cytotoxic chemotherapy, other systemic radioisotopes (e.g. radium-223), poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or hemi-body radiotherapy treatment is not to be administered during the study treatment period. ARDT is not to be administered concomitantly with 177Lu-PSMA-617. After implementation of Protocol Amendment v4, crossover will be allowed regardless of radiographic progression. Treatment period • 177Lu-PSMA-617 treatment arm Participants randomized to the investigational arm receive 7.4 GBq +/- 10% of 177Lu-PSMA-617 once every 6 weeks for 6 cycles. Best supportive care, including ADT, could be used. After the last day of study treatment, the participants have to have an End of Treatment (EOT) visit and enter the Post-treatment Follow-up. • ARDT treatment arm For participants randomized to the ARDT treatment arm, the change of ARDT treatment for each participant is selected by the treating physician prior to randomization and is administered per the physician's orders. Best supportive care, including ADT, could be used. After, the participants have to have an End of Treatment (EOT) and enter the Post-treatment Follow-up. In absence of safety concerns, every effort should be made to keep the participant on the randomized treatment until BICR-determined radiographic progression (up to implementation of Protocol Amendment v4). End of Treatment Randomized treatment may be discontinued if: * The participant, sponsor or investigator chooses to discontinue treatment * Toxicity * Completion of the 6 cycles of 177Lu-PSMA-617 * Serious non-compliance to the protocol * Disease progression (determined by BICR up to implementation of Protocol Amendment v4) * Upon implementation of Protocol Amendment v4, participants with ongoing treatment with ARDT will discontinue study drug and either crossover or receive SOC per their treating physician off trial PSA progression is strongly discouraged as a criterion for initiation of a new neoplastic therapy prior to BICR-determined progression. PCWG3 guidelines should be followed to guide discontinuation of treatment End of Treatment visit must be performed ≤ 7 days after the last day of study treatment period. EOT is to occur before the participant ienters the post-treatment Follow-up period of the study and before the initiation of any subsequent anticancer treatment, . If a participant withdraws consent for the treatment period of the study, an EOT must be done and the participant will enter the Post-treatment Follow-up unless he specifically withdraws post-treatment Follow-up. Crossover period Upon confirmation of rPFS by BICR, participants randomized to the ARDT arm could either be allowed to crossover to receive 177Lu-PSMA-617 within 28 days of central confirmation of radiographic progression or could continue to receive any other therapy per the discretion of the treating physician in the Post-treatment Follow-up. In order for a participant randomized to the ARDT arm to cross over to receive 177Lu-PSMA-617, he must meet the following criteria: * Confirmed radiographical progression as assessed by BICR. (After implementation of Protocol Amendment v4, radiographic progression is not required.) * No intervening antineoplastic therapy is administered after the randomized treatment * Any unresolved toxicity from prior therapy has to be controlled and can be no greater than CTCAE grade 2 or baseline at the time of registration for crossover. * ECOG performance status 0-1 at the time of registration for crossover * Adequate organ function at the time of registration for crossover * Agreement to continue with the study visit schedule A participant, who is deemed to have disease progression per investigator assessment, but not by BICR, is not eligible to cross over at that time. Such participant should continue to receive randomized study treatment until progression determined by BICR up to implementation of Protocol Amendment v4. If crossover to 177Lu-PSMA-617 is selected, then 177Lu-PSMA-617 will be administered with the same dose/schedule as for participants who were initially randomized to receive 177Lu-PSMA-617 as described above. After the last day of study treatment period of 177Lu-PSMA-617 or upon second radiographic progression (rPFS2), the participants must have a second End of Treatment (EOT2) visit performed ≤ 7 days and enter the Post-treatment Follow-up. The participant can receive any other therapy per the discretion of the treating physician in the Post-treatment Follow-up. Post-treatment Follow-up period: * 30-day Safety Follow-up: All randomized and/or treated participants are to have a safety follow-up conducted approximately 30 days after the EOT visit. * Long term follow-up: Long term follow-up starts after the 30 Days Safety follow-up and lasts until the patient expires, is lost to follow-up or withdraws consent. In long term follow-up safety and efficacy information is collected: * Safety: all medically significant adverse events (all SAEs) deemed to be related to 177Lu-PSMA-617. This includes potential late onset radiation toxicity. For participants who receive 177Lu-PSMA-617 in the 177Lu-PSMA-617 arm or in crossover, the following adverse events is captured beyond the 30 day safety period regardless of relationship to study treatment and whether new anticancer therapy has been initiated: hematologic toxicities with primary focus on myelosuppression and thrombocytopenia (including need for transfusion or use of growth factors), renal failure, xerostomia, xerophthalmia, secondary malignancies. After implementation of Protocol Amendment v4, 177Lu-PSMA-617 exposed participants will be discontinued from the trial once enrolled in the Long-term Safety study. * Efficacy: Tumor assessments must be performed every 8 weeks after first dose of study treatment for the first 24 weeks (week 9, 17, 25) and then every 12 weeks (week 37, 49, etc.) until confirmation of radiographic progression by BICR regardless of whether treatment has been discontinued or new anticancer therapy initiated. After implementation of Protocol Amendment v4, tumor assessments need to continue only for patients actively treated with 177Lu-PSMA-617 as crossover therapy. The long-term follow-up period also includes the collection of survival information and other assessments. Other: Other data collected during long-term follow-up includes short physical exam, blood sampling for hematology, chemistry testing, coagulation, DNA and tumor samples for biomarkers. The visits are carried out every 12 weeks (± 28 days) . Participants who receive 177Lu-PSMA-617 and remain in follow-up on the trial at the sponsor's completion of the study will be asked to join a separate study of long-term safety for a duration of up to 10 years from start of 177Lu-PSMA-617 treatment. If the participant withdraws consent for the collection of blood samples, PROs, and imaging assessments during the long-term follow-up, information on survival subsequent therapy, and related SAEs is collected.