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

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

PSMAfore: A Phase III, Open-label, Multi-Center, Randomized Study Comparing 177Lu-PSMA-617 vs. a Change of Androgen Receptor-directed Therapy in the Treatment of Taxane Naïve Men With Progressive Metastatic Castrate Resistant Prostate Cancer

The purpose of this study is to determine whether 177Lu-PSMA-617 improves the rPFS or death compared to a change in ARDT in mCRPC participants that were previously treated with an alternate ARDT and not exposed to a taxane-containing regimen in the CRPC or mHSPC settings. Approximately 450 participants will be randomized (225 per treatment group).

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.

177Lu-PSMA-617, Androgen receptor-directed therapy, ARDT, Metastatic castrate resistant prostate cancer, mCRPC, Radiographic progression free survival, rPFS, Castrate resistant prostate cancer, CRPC, Prostate-specific membrane antigen, PSMA

Patients randomized to ARDT treatment have an option to crossover to 177Lu-PSMA-617 treatment after rPFS.

Participants will receive 7.4 GBq (200 mCi) +/- 10% 177Lu-PSMA-617 once every 6 weeks for 6 cycles. Best supportive care, including ADT may be used.

For participants randomized to the ARDT arm, the change of ARDT treatment will be administered per the physician's orders. Best supportive care, including ADT may be used.

single intravenous dose of approximately 150 MBq. Administered dose must not be lower than 111 MBq or higher than 185 MBq (3 - 5 mCi).

rPFS is defined as the time to radiographic progression by PCWG3-modified RECIST v1.1 (as assessed by Blinded independent central review) or death.

From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (estimated final OS analysis)

From date of randomization until date of death from any cause, assessed up to 43 months (estimated final OS analysis)

rPFS2 is defined as time from the date of crossover (ARDT to 177Lu-PSMA-617) to the date of radiographic disease progression by BICR or death from any cause

Only for participants that crossover from ARDT arm to Lu-PSMA treatment. From date of crossover until second radiographic progression or death, whichever comes first, assessed up to 43 months (estimated final OS analysis)

PFS is defined as time from date of randomization to the first documented progression by investigator's assessment (radiographic, clinical, or PSA progression) or death from any cause, whichever occurs first

From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 43 months (estimated final OS analysis)

PFS2 defined as time from date of randomization to the first documented progression by investigator's assessment (radiographic progression, clinical progression, PSA progression) or death from any cause, whichever occurs first, on next-line of therapy

From date of randomization until date of second progression or date of death from any cause, whichever comes first, assessed up to 43 months (estimated final OS analysis)

PSA50 defined as proportion of participants who achieved a ≥ 50% decrease from baseline that is confirmed by a second PSA measurement ≥ 4 weeks. PSA50 will be evaluated at 3, 6 and 12 months.

From date of randomization till 30 day safety follow-up, assessed up to 43 months (estimated final OS analysis)

Time to SSE (TTSSE) defined as date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first

From date of randomization till EOT or death, whichever happens first, assessed up to 43 months (estimated final OS analysis)

TTSTP defined as time from randomization to radiographic soft tissue progression per PCWG3-modified RECIST v1.1 (Soft Tissue Rules of Prostate Cancer Working Group modified Response Evaluation Criteria in Solid Tumors Version 1.1) as Assessed by Blinded Independent Central Review (BICR)

From date of randomization until date of soft tissue radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (estimated final OS analysis)

TTCT defined as time from randomization to initiation of the first subsequent chemotherapy or death, whichever occurs first

From date of randomization until date of subsequent chemotherapy or date of death from any cause, whichever comes first, assessed up to 43 months (estimated final OS analysis)

EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Higher scores indicated greater levels of problems across each of the five dimensions.

From randomization up till 30 day safety Follow-up or week 48 of long term Follow-up for patients prematurely discontinued, assessed up to 43 months (estimated final OS analysis)

FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment. It is a combination of the FACT- General + the Prostate Cancer Subscale (PCS). The FACTGeneral (FACT-G) is a 27 item Quality of Life (QoL) measure that provides a total score as well as subscale scores: Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24). The total score range is between 1-108, higher scores indicates better for total score and subscale scores. PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (Range 0-48, higher scores better). The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0-156. Higher scores indicate higher degree of functioning and better quality of life.

From randomization up till 30 day safety Follow-up or week 48 of long term Follow-up for patients prematurely discontinued, assessed up to 43 months (estimated final OS analysis)

The BPI-SF is a publicly available instrument to assess the pain and includes severity and interference scores. BPI-SF is an 11-item selfreport questionnaire that is designed to assess the severity and impact of pain on daily functions of a participant. Pain severity score is a mean value for BPI-SF questions 3, 4, 5 and 6 (questions inquiring about the extent of pain, where the extent is ranked from 0 [no pain] to 10 [pain as bad as you can imagine]). Pain severity progression is defined as an increase in score of 30% or greater from baseline without decrease in analgesic use.

From screening up till 30 day safety Follow-up or week 48 of long term Follow-up for patients prematurely discontinued, assessed up to 43 months (estimated final OS analysis)

The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Treatment emergent adverse events falling into the category of myelosuppression, renal toxicity or second malignancy will be recorded beyond 30 day safety observation period.

From randomization till 30 day safety follow-up, assessed up to 43 months (estimated final OS analysis).

Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Participants must be adults >= 18 years of age. Participants must have an ECOG performance status of 0 to 1. Participants must have histological pathological, and/or cytological confirmation of adenocarcinoma of the prostate. Participants must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the sponsor's central reader. Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L). 7a. Participants must have progressed only once on prior second generation ARDT (abiraterone, enzalutamide, darolutamide, or apalutamide). First generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but not considered as prior ARDT therapy. Second generation ARDT must be the most recent therapy received. 8. Participants must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria: Serum/plasma PSA progression defined as 2 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression. Soft-tissue progression defined [PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016)]. Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016)). 9a. Participants must have >= 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained prior to randomization. 10. Participants must have recovered to =< Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, etc.) except alopecia. 11. Participants must have adequate organ function: Bone marrow reserve: ANC >= 1.5 x 109/L Platelets >= 100 x 109/L Hemoglobin >= 9 g/dL Hepatic: Total bilirubin < 2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome =< 3 x ULN is permitted. ALT or AST =< 3.0 x ULN OR =< 5.0 x ULN for participants with liver metastases. Renal: eGFR >= 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation. 12. Albumin >= 2.5 g/dL. 13a. Candidates for change in ARDT as assessed by the treating physician: Participants cannot have previously progressed nor had intolerable toxicity to both enzalutamide and abiraterone. Exclusion Criteria: Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy. 3a. Prior treatment with cytotoxic chemotherapy for castration resistant or castrate sensitive prostate cancer (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or biological therapy [including monoclonal antibodies]. [Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed]. 4. Any investigational agents within 28 days prior to day of randomization. 5. Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar classes. 6a. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy, or investigational therapy. 7. Transfusion or use of bone marrow stimulating agents for the sole purpose of making a participant eligible for study inclusion. 8a. Participants with a history of CNS metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with CNS metastases are eligible if received therapy (surgery, radiotherapy, gamma knife), asymptomatic and neurologically stable without corticosteroids. Participants with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired. 9. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression. 10. History or current diagnosis of the following ECG abnormalities indicating significant risk of safety for study participants: Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block). History of familial long QT syndrome or known family history of Torsades de Pointe. Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or CABG within 6 months prior to starting study treatment. 11a. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation. HIV-infected participants who are at a low risk of AIDS-related outcomes may participate in this trial. Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance). 12a. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease free and treatment free for more than 3 years prior to randomization, are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer. 13a. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF. 14a. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: Participant with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed. 15. History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study. 16. Any condition that precludes raised arms position. 17a. Eligible for treatment(s) other than ARDT based on presence of any mutations or biomarkers that are known as predictors of better response (e.g., AR-V7 or BRCA). 18. Not able to understand and to comply with study instructions and requirements.

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