KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the presentation of interim data from the Phase 1b/2 KEYNOTE-365 umbrella trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with various agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). These early findings show anti-tumor activity across three cohorts of the study, which investigated KEYTRUDA in combination with LYNPARZA (Cohort A, Abstract #145); docetaxel and prednisone (Cohort B, Abstract #170); and enzalutamide (Cohort C, Abstract #171) – with a safety profile consistent with each therapy alone. These results are being presented today at the 2019 Genitourinary Cancers Symposium (ASCO GU) in San Francisco. Based on the findings, Merck is initiating three new pivotal Phase 3 trials with KEYTRUDA in combination with LYNPARZA (KEYLYNK-010, NCT03834519), docetaxel and prednisone (KEYNOTE-921, NCT03834506) and enzalutamide (KEYNOTE-641, NCT03834493).
“At the core of our research program is a commitment to investigate the potential of KEYTRUDA – both as combination and monotherapy – to serve as a foundational treatment, especially for cancers where additional therapies are needed,” said Dr. Roy Baynes, senior vice president, head of global clinical development, and chief medical officer, Merck Research Laboratories. “These promising data presented at ASCO GU coupled with the significant unmet medical need in patients with metastatic castration-resistant prostate cancer, propelled us to initiate three new Phase 3 trials to further evaluate these KEYTRUDA combination regimens.”
Merck’s existing clinical development program in metastatic prostate cancer includes studies evaluating KEYTRUDA and LYNPARZA as monotherapy and in combination with other anti-cancer therapies with various mechanisms of action. Ongoing trials include the Phase 2 KEYNOTE-199 trial for KEYTRUDA monotherapy and, in collaboration with AstraZeneca, the Phase 3 trials PROfound evaluating LYNPARZA monotherapy and PROPEL evaluating LYNPARZA in combination with abiraterone as a first-line therapy in patients with mCRPC. With the initiation of KEYLYNK-010, KEYNOTE-921 and KEYNOTE-641, Merck now has the largest clinical program with an anti-PD-1 therapy in prostate cancer and the only program to evaluate overall survival (OS) as a co-primary endpoint across three Phase 3 trials.
Data from KEYNOTE-365 Presented at ASCO GU
KEYNOTE-365 (NCT02861573) is an ongoing global, open-label, non-randomized, multi-cohort, multi-center, Phase 1b/2 study evaluating the safety and efficacy of KEYTRUDA (200 mg fixed dose every three weeks) in combination with LYNPARZA (Cohort A), docetaxel and prednisone (Cohort B) and enzalutamide (Cohort C) for the treatment of patients with mCRPC. The primary endpoints are safety, prostatic specific antigen (PSA) response rate (measured by confirmed decrease in PSA of 50% or greater) and overall response rate (ORR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; secondary endpoints include disease control rate (DCR), radiographic progression-free survival (rPFS) and OS. The study is designed to enroll 400 patients across four cohorts, with outcome measures assessed individually for each cohort. Data at ASCO GU include interim efficacy and safety findings from three of the study cohorts (A, B and C).
Data and Safety from Cohort A (Abstract #145)
Cohort A is reported on 41 enrolled patients previously treated with docetaxel, and up to one other chemotherapy and up to two second-generation anti-hormone therapies. Patients in Cohort A received KEYTRUDA in combination with LYNPARZA (400 mg capsules orally twice daily).
The efficacy analysis from Cohort A presented at ASCO GU showed a PSA response rate of 12 percent in the total cohort population (n=5/41), 14 percent among patients with measurable disease (n=4/28) and 8 percent (n=1/13) among patients with non-measurable disease. The median time to PSA progression was 15.3 (95% CI, 9.3-27.1) and 18.1 (95% CI, 9.3-21.0) weeks for patients with measurable and non-measurable disease, respectively. Among patients with measurable disease, the ORR was 7 percent (95% CI, 1-23), with a partial response rate of 7 percent (n=2/28). The disease control rate (of 6 months or more) was 29 percent (95% CI, 16-45) in the total cohort population, 32 percent (95% CI, 16-52) among patients with measurable disease and 23 percent (95% CI, 5-54) among patients with non-measurable disease. In an analysis of rPFS and OS endpoints, the median rPFS was 4.7 months (95% CI, 4.0-7.7) and the six-month rPFS rate was 48 percent; the median OS was 13.5 months at the time of analysis (95% CI, 7.7-NR) and the six-month OS rate was 73 percent.
Analysis of the safety data showed that 49 percent of patients had a grade 3 or 4 treatment-related adverse event (TRAE), the most common (occurring in ≥10% of patients) of which was anemia (27%). Immune-mediated adverse events observed in this cohort were grade 1 or 2 and occurred in 49 percent of patients; the most commonly reported immune-mediated adverse event was hypothyroidism (5%). One patient died of a TRAE of unknown cause.
Data and Safety from Cohort B (Abstract #170)
Cohort B is reported on 72 enrolled patients previously treated with either abiraterone acetate or enzalutamide and who had not received chemotherapy. Patients in Cohort B received KEYTRUDA in combination with docetaxel (75 mg) plus prednisone (5 mg) orally twice daily.
The efficacy analysis from Cohort B presented at ASCO GU showed a PSA response rate of 31 percent in the total cohort population (n=22/72), 22 percent among patients with measurable disease (n=8/36) and 39 percent among patients with non-measurable disease (n=14/36). The median time to PSA progression was 24.1 (95% CI, 15.1-30) and 30.4 (95% CI, 15.0-36.3) weeks for patients with measurable and non-measurable disease, respectively. Among patients with measurable disease, the ORR was 14 percent (95% CI, 5-29), with a partial response rate of 14 percent (n=5/36). The disease control rate (of 6 months or more) was 57 percent (95% CI, 45-69) in the total cohort population, 50 percent (95% CI, 33-67) among patients with measurable disease and 64 percent (95% CI, 46-79) among patients with non-measurable disease. The median duration of response was 4.9 months (95% CI, 4.0-8.3+). In an analysis of rPFS and OS endpoints, the median rPFS was 8.3 months (95% CI, 7.5-10.2) and the six-month rPFS rate was 79 percent; the median OS had not been reached at the time of analysis (95% CI, 12.9-NR); the six-month OS rate was 96 percent.
Analysis of the safety data showed that 36 percent of patients had a grade 3-5 TRAE, the most common (occurring in ≥10% of patients) of which was febrile neutropenia (12%). Immune-mediated adverse events occurred in 33 percent of patients, the most common (occurring in ≥ 10% of patients) of which were infusion-related reactions (11%) and colitis (10%); two patients died due to TRAEs (pneumonitis).
