study of pembrolizumab (mk-3475) plus enzalutamide versus placebo plus enzalutamide in participants with metastatic castration-resistant prostate cancer (mcrpc) (mk-3475-641/keynote-641)

Conditions: Prostatic Neoplasms

Summary: the purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (mk-3475) and enzalutamide in the treatment of men with metastatic castration-resistant prostate cancer (mcrpc) who have not received chemotherapy for mcrpc, are abiraterone-naïve, or are intolerant to or progressed on abiraterone acetate. there are two primary study hypotheses. hypothesis 1: the combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to overall survival (os). hypothesis 2: the combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to radiographic progression-free survival (rpfs) per prostate cancer working group (pcwg)-modified response evaluation criteria in solid tumors version 1.1 (recist 1.1) as assessed by blinded independent central review.


Eligibility criteria:
the main inclusion and exclusion criteria include but are not limited to the following: inclusion criteria: * has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology * has prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months prior to randomization * has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by computed tomography/magnetic resonance imaging (ct/mri) * has met one of the following criteria with regard to abiraterone acetate exposure: (1) is abiraterone-naïve; (2) received prior abiraterone acetate for the treatment of mhspc or mcrpc, for a minimum of 4 weeks and not progressed while on treatment; or (3) received prior abiraterone acetate for the treatment of mhspc or mcrpc and progressed on treatment after a minimum of 8 weeks treatment (minimum 14 weeks for those with bone progression) * has ongoing androgen deprivation with serum testosterone \<50 ng/dl (\<2.0 nm) * participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization * participants must agree to the following during the study treatment period and for at least 90 days after the last dose of enzalutamide: refrain from donating sperm, plus either be abstinent or must agree to use male condom * has provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed). participants with bone only or bone predominant disease may provide a bone biopsy sample * has an eastern cooperative oncology group (ecog) performance status of 0 or 1 assessed within 7 days of randomization exclusion criteria: * has a known additional malignancy that is progressing or has required active treatment in the last 3 years * has an active autoimmune disease that has required systemic treatment in past 2 years * has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy * has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications * has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules * has an active infection (including tuberculosis) requiring systemic therapy * has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease * has known active human immunodeficiency virus (hiv), concurrent active hepatitis b virus (hbv) or known active hepatitis c virus (hcv) infection * has known active central nervous system (cns) metastases and/or carcinomatous meningitis * has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients * has a history of seizure or any condition that may predispose to seizure * has a history of loss of consciousness within 12 months of screening * has hypotension (systolic blood pressure \ 170 mmhg or diastolic blood pressure \>105 mmhg) at the screening visit * has bradycardia (heart rate of \<50 beats per minute) on the screening electrocardiogram (ecg) * has history of prostate cancer progression on ketoconazole * has had prior treatment with enzalutamide, apalutamide, darolutamide or cytochrome p450 (cyp) 17 inhibitor other than abiraterone acetate * has received prior therapy with an anti-programmed cell death-1 (anti-pd-1), anti-programmed cell death-ligand 1 (anti-pd-l1), or anti-pd-l2 agent or with an agent directed to another stimulatory or coinhibitory t-cell receptor * has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer * has received prior treatment with docetaxel or another chemotherapy agent for mcrpc * has had a prior anti-cancer monoclonal antibody (mab) prior to randomization * has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease psa levels (eg, saw palmetto) prior to randomization * has received a live or live attenuated vaccine within 30 days prior to randomization * is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * has a "superscan" bone scan * is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of enzalutamide * has had an allogenic tissue/solid organ transplant

Keywords: programmed cell death-1 (pd1, pd-1) programmed death-ligand 1 (pdl1, pd-l1)