Enzalutamide and Niraparib in the Treatment of Metastatic Castrate-Resistant Prostate Cancer (CRPC)

OUTLINE: This is a multi-center trial.

INVESTIGATIONAL TREATMENT:

Each eligible subject will begin treatment with a 28-day enzalutamide 160 mg/day lead-in
cycle. If a subject is able to tolerate the lead-in enzalutamide cycle without Grade 2 or
Grade 2-4 drug-related toxicity, dose reduction, or missed doses due to toxicity, cycle 1 of
combined enzalutamide and niraparib will commence. Enzalutamide will continue at 160 mg
daily.

Niraparib will be dosed daily starting at 100mg (dose level 1). Six subjects will be enrolled
per dose level. If less than 33% of the subjects experience a dose-limiting toxicity (DLT) at
the beginning of cycle 2, then the daily dose of niraparib will escalate to 200mg (dose level
2). If dose level 2 is similarly tolerated, then the daily dose of niraparib escalate to
300mg (dose level 3).

The following required laboratory values must be obtained within 14 days prior to
registration for protocol therapy:

Hematopoietic:

- White blood cell count (WBC) ≥ 1500/mm3

- Hemoglobin (Hgb) ≥ 9 g/dL

- Platelets ≥ 150,000/µL

- Absolute neutrophil count (ANC) ≥ 1500/mm3

Renal:

- Calculated creatinine clearance of ≥ 40 cc/min using the Cockcroft-Gault formula

Hepatic:

- Bilirubin ≤ 1.5 × upper limit of normal (ULN)

- Aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN

Inclusion Criteria:

- Written informed consent and Health Insurance Portability and Accountability Act
(HIPAA) authorization for release of personal health information. NOTE: HIPAA
authorization may be included in the informed consent or obtained separately.

- Age ≥ 18 years at the time of consent.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 14 days
prior to registration.

- Men who are not surgically sterile (vasectomy) must agree to use an acceptable method
of contraception. Male subjects with female sexual partners who are pregnant, possibly
pregnant, or who could become pregnant during the study must agree to use condoms from
the first dose of study drug through at least 120 days after the last dose of study
drug. Total abstinence for the same study period is an acceptable alternative.

- Documented histologically or cytologically confirmed adenocarcinoma of the prostate.

- Ongoing androgen deprivation therapy with a Gonadotropin Releasing Hormone (GnRH)
analogue or bilateral orchiectomy. Subjects who have not undergone orchiectomy must
plan to continue GnRH analogue therapy for the duration of the trial.

- All subjects on oral anti-androgen therapy must have been off therapy for at least 4
weeks prior to registration (6 weeks for bicalutamide) to exclude an anti-androgen
withdrawal response. Patients who received secondary anti-androgen therapy and did not
exhibit a >50% PSA decline, or subjects with any rise in PSA, objective or symptomatic
progression following anti-androgen withdrawal will not be required to meet this
withdrawal requirement.

- Documented metastatic disease with prostate-specific antigen (PSA) progression,
radiographic progression, or both, despite receiving luteinizing hormone releasing
hormone (LHRH) analogue therapy or orchiectomy with a serum testosterone level of 50
ng/dL or less.

- PSA progression is defined as three successive rising PSA values with an interval
of at least one week between determinations.

- Radiographic progression is defined by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 criteria or at least two new lesions on bone scan.

- At screening the serum testosterone must be 50 ng/dL or less and the PSA must be
greater or equal to 2 ng/mL.

- Estimated life expectancy > 6 months

- Prior treatment of CRPC, including docetaxel, cabazitaxel, sipuleucel-T, or Radium-223
is allowed.

- Prior therapy with abiraterone allowed for a maximum of 9 subjects.

- Prior chemotherapy must be completed at least 28 days prior to registration and the
participant subject must have recovered from the acute toxic effects.

Exclusion Criteria:

- Prior enzalutamide or other next-generation androgen receptor- (AR) targeting therapy.

- Prior PARP-inhibitor therapy.

- History of or active central nervous system (CNS) metastases. Subjects with
neurological symptoms must undergo a head computed tomography (CT) scan or brain
magnetic resonance imaging (MRI) to exclude brain metastasis.

- Radioisotope or external beam radiation exposure in the last 4 weeks. Exposure to
strontium, regardless of when exposure occurred.

- Prior radiation to 25% or more of the bone marrow.

- Treatment with any investigational agent within 28 days prior to registration.

- Known significant immunodeficiency as determined by the site investigator.

- Prior malignancy except for adequately treated basal cell or squamous cell skin
cancer, or other cancer for which the subject has been disease-free or stable for at
least one year.

- Prolonged QTc over 470 ms.

- History of seizure.

- Clinically significant active infections on systemic therapy as judged by the site
investigator.