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.

Eligibility

1. Histologic/cytologic documentation of prostate adenocarcinoma
2. Adequate archival tumor specimen or archival slides must be available to be tested as part of the trial screening (most recent metastatic site biopsy preferred, but primary prostate biopsy allowed if metastatic biopsy is not available or inadequate. A new biopsy is not required for enrollment in the trial as long as sufficient archival tissue is available). Due to significant variability between tests, results from an existing targeted next-generation exome sequencing test may not be used for this trial
3. Progressive disease must be demonstrated at study entry while the patient is on continuous androgen deprivation therapy (ADT) or status post orchiectomy. Progressive disease is defined as one or more of the following criteria: * PSA progression, defined by at least 2 consecutive rising PSA values at a minimum of 1-week intervals with the most recent PSA value being 1.0 ng/mL or higher, if confirmed PSA rise is the only indication of progression. Patients who received an anti-androgen must have PSA progression after withdrawal of anti-androgen therapy * Radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for soft tissue lesions * Bone metastasis progression per Prostate Cancer Working Group 3 (PCWG3) criteria for bone lesions
4. Measurable or non-measurable metastatic disease
5. No prior therapy for metastatic castration-resistant prostate cancer, defined as a treatment given for prostate cancer with radiographically-detectable metastasis and a serum testosterone level less than 50 ng/dl (1.73 nmol/L) at the time of pre-registration
6. >= 2 weeks or 5 half-lives (whichever is longer) since prior therapy with flutamide, dutasteride, bicalutamide, niltamide, finasteride, aminoglutethimide, estrogens, cytoproterone, chemotherapy, abiraterone, apalutamide, or darolutamide
7. >= 4 weeks or 5 half-lives (whichever is longer) since any prior investigational therapy
8. >= 4 weeks since a major surgery or radiation
9. No prior therapy with enzalutamide, rucaparib or any other PARP inhibitor, or platinum chemotherapy
10. Prior docetaxel and/or novel anti-androgen use is allowed only if given in the hormone-sensitive disease setting
11. Patient must have discontinued all previous treatments for cancer (except ADT and bone anti-responsive therapies such as denosumab or zoledronic acid) and must have recovered from all acute side effects of prior therapy or surgical procedures to =< grade 1 or baseline prior to randomization, with the exception of fatigue, alopecia or peripheral neuropathy
12. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
13. Absolute neutrophil count (ANC) >= 1,500/mm^3
14. Platelet count >= 100,000/mm^3
15. Hemoglobin >= 10 g/dL
16. Serum testosterone =< 50 ng/dl (=< 1.73 nmol/L)
17. Serum creatinine =< 1.5 x upper limit of normal (ULN)
18. Total bilirubin =< 1.5 x upper limit of normal (ULN)
19. Aspartate transaminase (AST)/alanine transferase (ALT) =< 2.5 x upper limit of normal (ULN)
20. No clinically suspected central nervous system (CNS) (leptomeningeal or parenchymal) metastases. Patients with a history of CNS metastasis(s) will be allowed as long (1) as the metastatic site(s) were adequately treated as demonstrated by clinical and radiographic improvement, AND (2) the patient has recovered from the intervention (no residual adverse events > Common Terminology Criteria for Adverse Events [CTCAE] grade 1), AND (3) the patient has remained without occurrence of new or worsening CNS symptoms for a period of 28 days prior to pre-registration
21. No known or suspected history of cytopenia (low white blood cell [WBC], hemoglobin or platelet count) of greater than 3 months duration with an unknown cause, myelodysplastic syndrome, or hematologic malignancies
22. No blood product transfusion, granulocyte/granulocyte-macrophage-colony stimulating factor (G-CSF/GM-CSF), or erythropoietin/thrombopoietin use within 14 days of pre-registration
23. No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, myocardial ischemia or infarction, severe or unstable angina, New York Heart Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within 3 months prior to pre-registration on A031902
24. No history of seizure or any condition that may increase the patient’s seizure risk (e.g., prior cortical stroke, significant brain trauma) within 2 years prior to pre-registration on A031902
25. No clinically active or chronic liver disease resulting in moderate/severe hepatic impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to liver dysfunction
26. No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or viral infection requiring treatment at the time of pre-registration
27. No planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
28. No untreated spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression
29. No known or suspected contraindications or hypersensitivity to enzalutamide, rucaparib, or to any of the excipients
30. No known or suspected gastrointestinal disorder affecting absorption of oral medications
31. No prior malignancy for which the last treatment was given within the past 2 years prior to pre-registration on A031902, or any active concurrent malignancy with the exception of non-melanomatous localized skin cancers (such as squamous or basal cell carcinoma of the skin)
32. Any concomitant medications that are strong inhibitors of CYP2C8 or inducers of CYP3A4 cytochrome enzymes must be discontinued prior to registration. Dose adjustments per Food and Drug Administration (FDA) label or clinical judgement should be considered for any concomitant medications that are moderate inhibitors of CYP2C8 or inducers of CYP3A4 cytochrome enzymes
33. Any concomitant medications that are substrates of CYP3A4, CYP2C9 and CYP2C8 cytochrome enzymes should be monitored closely per clinical judgement of the treating physician
34. Men of reproductive potential should agree to use an appropriate method of birth control and not donate semen while taking rucaparib/placebo and for 6 months following the last dose of rucaparib/placebo due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)