CASPAR - A Phase III Trial of Enzalutamide and Rucaparib as a Novel Therapy in First-Line Metastatic Castration-Resistant Prostate Cancer
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 61
- 试验地点
- 414
- 主要终点
- Radiographic progression-free survival (rPFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- 未提供
研究组 & 干预措施
Arm I (enzalutamide, rucaparib)
Patients receive enzalutamide PO QD and rucaparib PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Enzalutamide (Drug)
Arm I (enzalutamide, rucaparib)
Patients receive enzalutamide PO QD and rucaparib PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Rucaparib camsylate (Drug)
Arm I (enzalutamide, rucaparib)
Patients receive enzalutamide PO QD and rucaparib PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Leuprolide Acetate (Drug)
Arm I (enzalutamide, rucaparib)
Patients receive enzalutamide PO QD and rucaparib PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Goserelin Acetate (Drug)
Arm I (enzalutamide, rucaparib)
Patients receive enzalutamide PO QD and rucaparib PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Degarelix (Drug)
Arm I (enzalutamide, rucaparib)
Patients receive enzalutamide PO QD and rucaparib PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Arm I (enzalutamide, rucaparib)
Patients receive enzalutamide PO QD and rucaparib PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Arm II (enzalutamide, placebo)
Patients receive enzalutamide PO QD and placebo PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Enzalutamide (Drug)
Arm II (enzalutamide, placebo)
Patients receive enzalutamide PO QD and placebo PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Placebo (Drug)
Arm II (enzalutamide, placebo)
Patients receive enzalutamide PO QD and placebo PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Leuprolide Acetate (Drug)
Arm II (enzalutamide, placebo)
Patients receive enzalutamide PO QD and placebo PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Goserelin Acetate (Drug)
Arm II (enzalutamide, placebo)
Patients receive enzalutamide PO QD and placebo PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Arm II (enzalutamide, placebo)
Patients receive enzalutamide PO QD and placebo PO BID. Patients who did not undergo bilateral orchiectomy also receive ADT consisting of leuprolide acetate IM, goserelin acetate SC every 12 weeks or degarelix SC. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
结局指标
主要结局
Radiographic progression-free survival (rPFS)
时间窗: 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)
时间窗: 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.
次要结局
- Radiographic progression-free survival (rPFS) within HRRm status(Up to 5 years post treatment)
- Overall survival by HRRm status(Up to 5 years post treatment)
- Time to unequivocal clinical progression(Up to 5 years post treatment)
- Duration of overall response(Up to 1 year after completion of treatment)
- Best response by serum prostate specific antigen (PSA)(At 7 and 13 months from the start of treatment)
- Incidence of adverse events(Up to 1 year after completion of treatment)
- Discontinuation for treatment emergent toxicities(Up to 1 year after completion of treatment)
- Overall response rate(Up to 1 year after completion of treatment)
- Prostate specific antigen (PSA) response rate(Up to 1 year after completion of treatment)
- Time to first symptomatic skeletal event (SSE)(Up to 5 years after completion of treatment)