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

Phase 3Active Not RecruitingNCT04689828

Novartis Pharmaceuticals469 enrolled

Overview

The purpose of this study is to determine whether 177Lu-PSMA-617 improves the Radiographic progression-free survival (rPFS) or Overall Survival (OS) compared to a change in Androgen receptor-directed therapy (ARDT) in metastatic castrate resistant prostate cancer (mCRPC) participants that were previously treated with an alternate ARDT and not exposed to a taxane-containing regimen in the CRPC or mHSPC settings. 469 participants were randomized (235 in the 177Lu-PSMA-617 group and 234 in the ARDT group.

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.

Eligibility

Sex: MALEMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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). * 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. * 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)). * Participants must have \>= 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained prior to randomization. * 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. * Albumin \>= 2.5 g/dL. -. 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. * 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 \[including monoclonal antibodies\]. \[Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed\]. * Any investigational agents within 28 days prior to day of randomization. * Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar classes. -. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy, or investigational therapy. * Transfusion or use of bone marrow stimulating agents for the sole purpose of making a participant eligible for study inclusion. * 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. * Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression. * 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. * 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). * 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. * 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. * 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. * History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study. * Any condition that precludes raised arms position. * 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). * Not able to understand and to comply with study instructions and requirements.

Outcomes

Primary Outcomes

Radiographic Progression Free Survival (rPFS)

rPFS is defined as the time to radiographic progression by Prostate cancer working Group 3 (PCWG3)-modified RECIST v1.1 as assessed by Blinded independent central (BICR) review or death.

Time frame: median FU (randomization to event or censoring) 3.65 months (range 0-12.3)

Secondary Outcomes

Overall Survival (OS) (Key Secondary Endpoint)

OS is defined as time to death for any cause.

Time frame: approx. 26.9 months from randomization to cut-off

Radiographic Progression Free Survival 2 (rPFS2) by Blinded Independent Central Review (BICR)

rPFS2 by BICR 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 for participants who crossover from ARDT arm to Lu-PSMA treatment.

Time frame: From date of crossover until second radiographic progression or death, whichever comes first, assessed up to approx. 32 months

Progression Free Survival (PFS) by Investigator's Assessment

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

Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed upFrom date of randomization until date of death from any cause, assessed up to approx. 32 months

Second Progression Free Survival (PFS2) by Investigator's Assessment

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. Next-line therapy was defined as the first new (systemic) anti-neoplastic therapy initiated after discontinuation of study treatment regardless of end of treatment (EoT) reason.

Time frame: From date of randomization until date of second progression or date of death from any cause, whichever comes first, assessed up to approx. 32 months

PSA50 Response

PSA50 response was defined as the percentage of participants who achieved a ≥ 50% decrease from baseline that is confirmed by a second Prostate specific antigen (PSA) measurement ≥ 4 weeks.

Time frame: Weeks 12, 24, 48 and anytime during randomized phase

Time to First Symptomatic Skeletal Event (TTSE)

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

Time frame: From date of randomization till EOT or death, whichever happens first, assessed up to approx. 32 months

Time to Radiographic Soft Tissue Progression (TTSTP) Per BICR

TTSTP defined as time from randomization to radiographic soft tissue progression per Prostate cancer working Group 3 (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).

Time frame: From date of randomization until date of soft tissue radiographic progression or date of death from any cause, whichever comes first, assessed up to approx. 32 months

Time to Chemotherapy (TTCT)

TTCT defined as time from randomization to initiation of the first subsequent chemotherapy or death, whichever occurs first. Since participants in ARPI arm were allowed to crossover to \[177Lu\]Lu-PSMA-617 (AAA617) arm upon confirmation of rPD by BICR, TTCT was delayed for participants who had crossed over.

Time frame: 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)

European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D- 5L)

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.

Time frame: 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

Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire

The FACT-P total score determines the level of prostate cancer specific health related quality of life (HRQoL). The higher the FACT-P score, the better the QoL. 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.

Time frame: 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

Brief Pain Inventory - Short Form (BPI-SF) Questionnaire

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.

Time frame: 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)

Number of Participants With Treatment Emergent Adverse Events

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.

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

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

Overview

Conditions

Interventions

Eligibility

Locations (72)

Outcomes

Primary Outcomes

Secondary Outcomes