Summary

This phase III trial compares the addition of rucaparib to enzalutamide with enzalutamide alone for the treatment of men with prostate cancer that has spread to other places in the body (metastatic) and has become resistant to androgen-deprivation therapy. Testosterone is a hormone made mainly in the testes and is needed to develop and maintain male sex characteristics, such as facial hair, deep voice, and muscle growth. It also plays role in prostate cancer development. Enzalutamide may help fight prostate cancer by blocking the use of testosterone by the tumor cells for growth. PARPs are proteins that help repair deoxyribonucleic acid (DNA) mutations. PARP inhibitors, such as rucaparib, can keep PARPs from working, so tumor cells can't repair themselves. This may stop tumor cells from growing. Giving enzalutamide and rucaparib may prolong patients’ survival and/or prevent their cancer from growing or spreading for a longer time. It may also help doctors learn if a mutation in any of the specific DNA repair (homologous recombination) genes is helpful in selecting the most appropriate treatment for the patient.

Objectives

PRIMARY OBJECTIVES:
I. To compare radiographic progression-free survival (rPFS) and overall survival (OS) with enzalutamide and rucaparib camsylate (rucaparib) versus enzalutamide alone for patients with metastatic castration resistant prostate cancer commencing first-line therapy.
II. To compare quality of life as measured by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Trial Outcome Index in patients with metastatic castration-resistant prostate cancer (mCRPC) who receive enzalutamide plus rucaparib versus (vs) enzalutamide alone at the 12-month time point (primary quality of life [QOL] timepoint). (QUALITY OF LIFE)

SECONDARY OBJECTIVES:
I. To evaluate the effects of concurrent administration of rucaparib on rPFS and OS within homologous-recombination repair (HRR) mutant and wild-type patients
II. To evaluate the effects of concurrent administration of rucaparib on time to unequivocal clinical progression.
III. To evaluate the effects of concurrent administration of rucaparib on best radiographic response using Prostate Cancer Working Group 3 (PCWG3) criteria.
IV. To evaluate the effects of concurrent administration of rucaparib on duration of overall response.
V. To evaluate the effects of concurrent administration of rucaparib on prostate specific antigen (PSA) response rate.
VI. To evaluate the effects of concurrent administration of rucaparib on best response by serum PSA by months 7 and 13 using categorical and continuous measures.
VII. To evaluate the effects of concurrent administration of rucaparib on time to first symptomatic skeletal event (SSE).
VIII. To evaluate the effects of concurrent administration of rucaparib on safety and tolerability as measured by National Cancer Institute (NCI) Common Toxicity Criteria; trial discontinuation for treatment emergent toxicities.
XI. To compare quality of life as measured by FACT-P Trial Outcome Index in patients with mCRPC who receive enzalutamide plus rucaparib vs enzalutamide alone at other timepoints. (QUALITY OF LIFE)
XII. To compare quality-adjusted life years which accounts for survival and utility (measured by European Quality of Life Five Dimension Five Level Scale [EQ-5D-5L]) in patients with mCRPC who receive enzalutamide plus rucaparib vs enzalutamide alone. (QUALITY OF LIFE)

EXPLORATORY OBJECTIVE:
I. To compare quality of life as measured by other scales of the FACT-P in patients with mCRPC who receive enzalutamide plus rucaparib vs enzalutamide alone at 12 months, and across measurement timepoints (QUALITY OF LIFE)

CORRELATIVE SCIENCE OBJECTIVES:
I. To evaluate radiographic progression-free survival (rPFS) with enzalutamide plus rucaparib vs enzalutamide plus placebo within BRCA1/2 or PALB2 versus wild-type patients. (INTEGRATED)
II. To evaluate sensitivity of plasma-based genomic profiling in detection of HRRm in mCRPC. (INTEGRATED)
III. To determine the association between circulating tumor-derived deoxyribonucleic acid (ctDNA) dynamics including early ctDNA decline (defined as within the first 12 weeks of treatment) and response (overall response rate [ORR], rPFS, OS) to therapy. (EXPLORATORY)
IV.To evaluate OS and ORR with enzalutamide plus rucaparib vs enzalutamide plus placebo in BRCA1/2 or PALB2 mutant versus wild-type patients. (EXPLORATORY)
V. To evaluate rPFS with enzalutamide plus rucaparib vs enzalutamide plus placebo in non-BRCA1/2 or PALB2 HRR mutant wild-type patients. (EXPLORATORY)
VI. To evaluate rPFS, OS and ORR with enzalutamide plus rucaparib vs enzalutamide plus placebo in patients with or without an androgen receptor (AR) activating alteration. (EXPLORATORY)
VII. To determine rate of HRR reversion mutation(s) in patients with known HRR mutant mCRPC progressing on therapy. (EXPLORATORY)
VIII. To bank tissue and plasma for future studies evaluating promising biomarkers for benefit from the combination therapy. (EXPLORATORY)

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive enzalutamide orally (PO) once daily (QD) and rucaparib PO twice daily (BID). Patients who did not undergo bilateral orchiectomy also receive androgen deprivation therapy (ADT) consisting of leuprolide acetate intramuscularly (IM), goserelin acetate subcutaneously (SC) every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive enzalutamide PO QD and placebo PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After the completion of study treatment, patients are followed every 3 months for 2 years, then every 6 months for 3 years.