nct04455750

Eligibility

Inclusion Criterea

• Histologic/cytologic documentation of prostate adenocarcinoma
• 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
• 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
• Measurable or non-measurable metastatic disease
• 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
• >= 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
• >= 4 weeks or 5 half-lives (whichever is longer) since any prior investigational therapy
• >= 4 weeks since a major surgery or radiation
• No prior therapy with enzalutamide, rucaparib or any other PARP inhibitor, or platinum chemotherapy
• Prior docetaxel and/or novel anti-androgen use is allowed only if given in the hormone-sensitive disease setting
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 10 g/dL
• Serum testosterone =< 50 ng/dl (=< 1.73 nmol/L)
• Serum creatinine =< 1.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate transaminase (AST)/alanine transferase (ALT) =< 2.5 x upper limit of normal (ULN)
• 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
• 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
• No blood product transfusion, granulocyte/granulocyte-macrophage-colony stimulating factor (G-CSF/GM-CSF), or erythropoietin/thrombopoietin use within 14 days of pre-registration
• 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
• 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
• 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
• No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or viral infection requiring treatment at the time of pre-registration
• No planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
• No untreated spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression
• No known or suspected contraindications or hypersensitivity to enzalutamide, rucaparib, or to any of the excipients
• No known or suspected gastrointestinal disorder affecting absorption of oral medications
• 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)
• 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
• Any concomitant medications that are substrates of CYP3A4, CYP2C9 and CYP2C8 cytochrome enzymes should be monitored closely per clinical judgement of the treating physician
• 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)

Exclusion Criterea

• Psychiatric illness which would prevent the patient from giving informed consent
• Medical condition such as uncontrolled infection (including human immunodeficiency virus [HIV]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
• Patients with a “currently active” second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for >= 3 years
• Patients who cannot swallow oral formulations of the agents