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.
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
