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 where it is considered appropriate to delay taxane-based chemotherapy.

The study aims at evaluating the superiority of 177Lu-PSMA-617 over a change of ARDT treatment in prolonging rPFS. The primary endpoint of rPFS will be assessed via blinded independent centralized review of radiographic images provided by the treating physician and as outlined in PCWG3 Guidelines.

The study will also evaluate 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 will be assessed for eligibility and will 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 will be randomized.

Randomization period The participants will be randomized 1:1 to receive 177Lu-PSMA-617 or a change of the ARDT treatment. The ARDT change will include approved Androgen Receptor (AR) axis targeted therapy (abiraterone or enzalutamide). Supportive care will be 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 must not be administered during the study treatment period. ARDT must not be administered concomitantly with 177Lu-PSMA-617.

Treatment period • 177Lu-PSMA-617 treatment arm Participants randomized to the investigational arm will receive 7.4 GBq +/- 10% of 177Lu-PSMA-617 once every 6 weeks for 6 cycles. Best supportive care, including ADT, may be used.

After the last day of study treatment period of 177Lu-PSMA-617 (i.e. after completion of 6 cycles of treatment OR treatment discontinuation for any reason), the participants must 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 will be selected by the treating physician prior to randomization and will be administered per the physician's orders. Best supportive care, including ADT, may be used. After the last day of study treatment (treatment discontinuation for any reason) or upon radiographic progression as assessed by blinded centralized review, the participants must have an End of Treatment (EOT) and enter the Post-treatment Follow-up.

End of Treatment

Randomized treatment may be discontinued if:

Evidence of tumor progression determined by BICR
Unacceptable toxicity as assessed by Investigator
Participant non-compliance or voluntary withdrawal from study treatment
Required use of a prohibited treatment
Evidence that the participant is no longer clinically benefiting from study treatment
At the sponsor's or investigator's discretion
If the treatment (with 177Lu-PSMA-617 or ARDT) is interrupted for more than 4 weeks for any reason (in case of delay of treatment due to interruption of study drug supply, participants can restart study treatment if recovered from all toxicities, no demonstrated progression, no other anticancer therapy was started).

It is important that the scheduled imaging assessments continue until BICR-determined progression. 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 is to enter the post-treatment Follow-up period of the study and before the initiation of any subsequent anticancer treatment, outside of what is allowed in the study.

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 will either be allowed to crossover to receive 177Lu-PSMA-617 within 28 days of central confirmation of radiographic progression or may 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 change in ARDT arm to cross over to receive 177Lu-PSMA-617, he must meet the following criteria:

Confirmed radiographical progression as assessed by BICR
No intervening antineoplastic therapy is administered after the randomized treatment
Any unresolved toxicity from prior therapy should be controlled and must 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 crossover at that time. Such participant should continue to receive randomized study treatment until progression determined by BICR.

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.

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) 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 should 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 accrual of events for the planned OS-based analysis (key secondary endpoint).

In long term follow-up safety and efficacy information will be collected:

Safety: all medically significant adverse events (all SAEs) deemed to be related to 177Lu-PSMA-617. This will include potential late onset radiation toxicity. For participants who received 177Lu-PSMA-617 in the 177Lu-PSMA-617 arm or in crossover, the following adverse events will be 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.
Efficacy: In any participant entering long term follow-up discontinuing for reasons other than BICR-determined radiographic progression, 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

The long-term follow-up period will also include 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 will be carried out every 12 weeks (± 28 days) until death, lost to follow-up, withdrawal of consent or accrual of the number of events required for the planned analyses for OS for the study, whichever occurs first.

This follow-up will allow to collect information on medically significant long-term toxicities such as long-term radiotoxicity.

Duration of long term follow-up is expected to continue till end of study. Participants who have received 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

If the participant withdraws consent for the collection of blood samples, PROs, and imaging assessments during the long-term follow-up, information on survival and AEs per above will be collected.