A Clinical Study Evaluating The Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant To Testosterone-Deprivation Therapy

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. (PK substudy) To evaluate the safety and tolerability of rucaparib and enzalutamide combination III. (Quality of life substudy) 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 the 12-month time point (primary QOL timepoint).

SECONDARY OBJECTIVES:

I. To compare rPFS and OS with enzalutamide and rucaparib versus enzalutamide alone within homologous-recombination repair (HRR) aberrant 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.

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; and trial discontinuation for treatment emergent toxicities.

IX. To compare performance of plasma-based and tissue-based genomic profiling in detection of homologous-recombination repair mutation (HRRm) in metastatic castration-resistant prostate cancer (mCRPC).

OUTLINE:

In the randomized, placebo-controlled phase III study, patients will be randomized to 1 of 2 arms:

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

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

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

• Enzalutamide (Drug): Given PO
• Rucaparib camsylate (Drug): Given PO
• Placebo (Drug): Given PO
• Leuprolide Acetate (Drug): Given IM
• Goserelin Acetate (Drug): Given SC
• Degarelix (Drug): Given SC
• Quality-of-Life Assessment (Other): Ancillary studies
• Questionnaire Administration (Other): Ancillary studies

Primary outcomes

• Radiographic progression-free survival (rPFS) [Up to 5 years post treatment]: Radiographic progression-free survival (rPFS) is defined as the time from randomization to date of disease progression or death due to any cause. rPFS time will be compared between the treatment arms using a log-rank test. Median times per treatment arms will be reported.
• Overall survival (OS) [Up to 5 years post treatment]: Overall survival is defined as the time from randomization to death due to any cause. Overall survival time will be compared between the treatment arms using a log-rank test. Median times per treatment arms will be reported.

Secondary outcomes

• Radiographic progression-free survival (rPFS) within HRRm status [Up to 5 years post treatment]: Defined as the time from randomization to date of disease progression or death due to any cause. rPFS time will be compared between the treatment arms using a log-rank test. Median times per treatment arms will be reported.
• Time to unequivocal clinical progression [Up to 5 years post treatment]: Defined as deterioration in clinical status clearly attributable to prostate cancer progression with occurrence of cancer pain requiring initiation of chronic administration of opiate analgesia, or an immediate need to re-initiate cytotoxic chemotherapy, radiation therapy or surgical intervention for disease-progression related events; or deterioration of Eastern Cooperative Oncology Group (ECOG) performance status to 3 or greater. Time to unequivocal clinical progression will be compared between the treatment arms using a log-rank test. Median times per treatment arms will be reported.
• Overall survival by HRRm status [Up to 5 years post treatment]: Defined as the time from randomization to death due to any cause.Overall survival time will be compared between the treatment arms using a stratified (by HRRm status) log-rank test. Median times per treatment arms/HRRm status will be reported.
• Overall response rate [Up to 1 year after completion of treatment]: Defined as confirmed radiographic complete response or partial response. The proportion of patients with confirmed radiographic response or partial response will be compared between the treatment arms with a chi-square test (or Fisher's exact test if more appropriate).
• Duration of overall response [Up to 1 year after completion of treatment]: Defined as the time from documentation of a radiographic response to disease progression. Duration of response time will be compared between the treatment arms using a log-rank test. Median times per treatment arms will be reported.
• Prostate specific antigen (PSA) response rate [Up to 1 year after completion of treatment]: Defined as >= 50% reduction in PSA from baseline. The proportion of patients with PSA response will be compared between the treatment arms with a chi-square test (or Fisher's exact test if more appropriate).
• Best response by serum prostate specific antigen (PSA) [At 7 and 13 months from the start of treatment]: Defined as best percentage PSA decline from baseline to 7 and 13 months. The percent PSA decline will be compared between treatment arms with a Wilcoxon rank sum test.
• Time to first symptomatic skeletal event (SSE) [Up to 5 years after completion of treatment]: Defined as the time to first use of external-beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic vertebral or nonvertebral bone fractures, spinal cord compression, or tumor-related orthopedic surgical intervention. Time to first SSE will be compared between the treatment arms using a log-rank test. Median times per treatment arms will be reported.
• Incidence of adverse events [Up to 1 year after completion of treatment]: Frequency as measured by National Cancer Institute (NCI) Common Toxicity Criteria. The proportion of patients experiencing at least one grade 3+ adverse event will be compared between the treatment arms with a chi-square test (or Fisher's exact test if more appropriate).
• Discontinuation for treatment emergent toxicities [Up to 1 year after completion of treatment]: The proportion of patients who discontinued treatment for emergent toxicities will be compared between the treatment arms with a chi-square test (or Fisher's exact test if more appropriate).

Other outcomes

• Quality of life [12 months]: Measured by change from baseline to 12 months of the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) patient-reported outcome questionnaire.
• Quality of life [12 months]: Measured by change from baseline to 12 months of the Utility Score of the European Quality of Life Five Dimension Five Level (EQ-5D-5L) patient-reported outcome questionnaire.
• Laboratory correlative science [Up to 1 year after completion of treatment]: Area under curve for plasma-based and tissue-based genomic profiling in detection of HRRm in mCRPC.
• Laboratory correlative science [Up to 1 year after completion of treatment]: The proportion of patients with homologous-recombination repair (HRR) alterations at baseline who develop HRR reversion/function restoring alterations after initiation of treatment in each arm with a chi-square test (or Fisher's exact test if more appropriate).

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* 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 pre-registration 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 (>=4 weeks since last flutamide, bicalutamide or nilutamide, apalutamide or darolutamide)
  * 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
* 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 registration
* >= 2 weeks or 5 half-lives (whichever is shorter) 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 shorter) 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 non-metastatic or metastatic, or castration-resistant non-metastatic 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 the past 3 months
* 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
* 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 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, 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 CYP2C19 cytochrome enzymes should be monitored closely per clinical judgement of the treating physician

314 more sites not listed.

• Arpit Rao, MD, Study chair, Baylor College of Medicine

NIH grants: U10CA180821