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
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
This randomized, placebo-controlled phase III trial is evaluating the benefit of rucaparib
 and enzalutamide combination therapy versus 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 testosterone-deprivation therapy (castration-resistant). Enzalutamide helps
 fight prostate cancer by blocking the use of testosterone by the tumor cells for growth. Poly
 adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as rucaparib, fight
 prostate cancer by prevent tumor cells from repairing their DNA. Giving enzalutamide and
 rucaparib may make patients live longer or prevent their cancer from growing or spreading for
 a longer time, or both. It may also help doctors learn if a mutation in any of the homologous
 recombination DNA repair genes is helpful to decide which treatment is best for the patient.
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:

 The mandatory PK substudy will enroll up to 18 patients. These patients receive a fixed dose
 of enzalutamide (160mg daily) and varying doses of rucaparib in cohorts of 3 to 6 patients to
 find the recommended dose for the phase 3 portion.

 In the randomized, placebo-controlled phase 3 portion, 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.
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 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 (>=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 and/or per Prostate Cancer Working Group 3
 (PCWG3) criteria for bone lesions

 -  Measurable or non-measurable 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 enrollment

 -  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 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