ASCO 2019: Pembrolizumab Plus Docetaxel and Prednisone in Abiraterone or Enzalutamide Pretreated Patients with mCRPC: KEYNOTE-365 Study

Chicago, IL ( Docetaxel was the first systematic therapy that showed a survival improvement in patients with metastatic castrate-resistant prostate cancer (mCRPC). Currently, it is a recommended treatment option after enzalutamide or abiraterone.1,2

Pembrolizumab is a highly selective humanized monoclonal antibody that blocks the interaction between PD-1 and its ligand, PD-L1, and PD-L2. It has shown activity in patients with heavily pretreated, PD-L1 positive advanced prostate cancer.3,4 Pembrolizumab combined with chemotherapy, has shown clinical benefit in patients with other types of solid tumors.5,6 

In this presented study, data from cohort B (pembrolizumab + docetaxel/prednisone) of KEYNOTE-365 (NCT02861573) was presented. KEYNOTE-365 is a phase 1b/2 non-randomized, multicenter, multicohort, open-label umbrella study to test various pembrolizumab combinations in mCRPC patients (Figure 1). 

Figure 1 – Study design:

The aims of the presented study were to evaluate the efficacy, safety, and tolerability of pembrolizumab combined with docetaxel and prednisone in patients with abiraterone or enzalutamide pretreated mCRPC. The primary endpoints of this study were safety and prostate specific antigen (PSA) response rate (defined as a PSA decrease of more than 50%). The key secondary endpoints were investigator-determined objective response rates (ORR) (according to the RECIST v1.1 criteria), disease control rate (defined as complete response + partial response + stable disease for more than 6 months), time to PSA progression, radiographic progression-free survival (rPFS), and overall survival (OS). Patients eligible for this trial were those who progressed on or became intolerant to more than four weeks of abiraterone or enzalutamide in the pre-chemotherapy mCRPC state and progressed within six months before screening. 

The patient disposition is shown in Figure 2 and the baseline characteristics are demonstrated in Table 1. A total of 72 patients were analyzed (median age of 68 years; with 36% having a visceral disease, and 50% harboring measurable disease). All patients began pembrolizumab + docetaxel. Median (95% CI) follow-up was 10 (8-12) months. 

Figure 2 – Patient disposition:

Table 1 – Baseline characteristics:

Treatment-related adverse events occurred in 69 (96%) patients. Those occurring in more than a third of the patients included: alopecia (43%), fatigue (40%), and diarrhea (39%) (Table 2). Grade 3-5 treatment-related adverse events occurred in 27 (38%) patients, including two deaths from treatment-related adverse events (pneumonitis).  The immune-mediated adverse events and infusion reactions are shown in table 3. The most commonly reported immune-mediated adverse events were infusion-related reactions (11%) and colitis (10%).

The PSA response rates are shown in Figure 3, stratified by whether they were RECIST measurable or not. Figure 4 demonstrates the time to PSA progression. A summary of the confirmed best objective response by investigator assessment per RECIST criteria v1.1 is shown in table 4, with a 31% response rate in the total population. 

Table 2 – Treatment-related adverse events of all grade (>10% of the population) and corresponding grade 3-5 adverse events:

Table 3 – Immune-mediated adverse events and infusion reactions:

Figure 3: Confirmed PSA response rate:

Figure 4 – Time to PSA progression:

Table 4 – Confirmed
best objective response by investigator assessment per RECIST v1.1:

The authors concluded that pembrolizumab + docetaxel/prednisone has activity in patients with mCRPC who previously progressed on second-generation hormone therapy. Importantly, the adverse events were considered mild for the treatment combination and were well-tolerated. The confirmed PSA response rate was 31% in the total population and 22% among patients with RECIST-measurable disease. 

Further evaluation of the combination of docetaxel and prednisone with or without pembrolizumab in mCRPC patients, previously treated with abiraterone or enzalutamide, is warranted. 

An ongoing randomized phase 3 study of docetaxel and prednisone with or without pembrolizumab in mCRPC patients, who are chemotherapy naïve and were previously treated with enzalutamide or abiraterone, is open to enrollment (KEYNOTE-921, NCT03834506).

Presented by: Christophe Massard, MD, Gustave Roussy Cancer Campus and University Paris-Sud, Orsay, France 

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

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