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ASCO 2019 Annual Meeting

ASCO 2019: Pembrolizumab plus Enzalutamide in Abiraterone Pretreated Patients with Metastatic Castrate Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study — Medical Oncologist Perspective

Chicago, IL (UroToday.com) KEYNOTE 365 is a large phase Ib/II study investigating different combinations of therapies in combination with pembrolizumab for patients with mCRPC. The four arms include:
  1. Pembrolizumab + Olaparib
  2. Pembrolizumab + Docetaxel + Prednisone
  3. Pembrolizumab + Enzalutamide 
  4. Pembrolizumab + Abiraterone. 
Combination therapy is important, as single agent pembrolizumab has shown very limited efficacy for most patients with mCRPC. KEYNOTE 199 previously described the efficacy of single-agent pembrolizumab for docetaxel refractory patients and found an objective response rate (ORR) of 5% for all patients.1 Peter Fong, MBBS, FRACP reports here the efficacy of pembrolizumab plus enzalutamide in patients who have progressed following abiraterone.

This abstract describes the outcomes of 69 patients who were treated with the combination of pembrolizumab and enzalutamide. All patients had progressed on abiraterone for mCRPC. Patients received pembrolizumab 200 mg daily in combination with enzalutamide 160 mg daily.  The median age of all patients was 69 and all patients had an ECOG of 0 or 1. The majority of patients were deemed PD-L1 negative (CPS<1) and 26% of patients had visceral disease.

For patients with measurable disease, the objective response rate (ORR) was 40% (10/25), and the ORR for the total evaluable population was 27% (18/67). The median radiographic progression-free survival (rPFS) was 6 months and the median overall survival has not yet been reached. Of the patients with objective responses, the median duration was 8.3 months with 75% of patients having a response greater than 6 months.
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25 patients had measurable disease and the ORR was 20% with 32% of patients had disease control, as defined by CR/PR/SD for 6 months or greater. The median rPFS was 6.1 months and median OS has not yet been reached. 
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The combination of therapy was well tolerated. The most common grade 3/4 adverse events were rash (10%), fatigue (4%), and asthenia (4%).
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Combination enzalutamide with pembrolizumab was well tolerated for post-abiraterone treated patients. Given that a subset of patients will respond to enzalutamide alone, it is not known based on this study if the addition of pembrolizumab is synergistic, additive, or neither. However, given that the median rPFS is 6.1 months, this suggests that pembrolizumab is likely contributing here as the typical PFS for patients on enzalutamide after abiraterone is less than 3 months.2 Correlative biomarker work is necessary to better identify which patients are most likely respond to this combination approach – NGS may be helpful in identifying these biomarkers (MSI status, biallelic CDK12 loss, etc). A randomized phase 3 study of enzalutamide with or without pembrolizumab for patients with mCRPC is open and enrolling.

Presented by: Peter C. Fong, MBBS, FRACP, Auckland Hospital, New Zealand 

Written by: Jason Zhu, MD, Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. De Bono JS, Goh JC, Ojamaa K, et al. KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). American Society of Clinical Oncology; 2018.
  2. Sandhu GS, Parikh RA, Appleman LJ, Friedland D. Enzalutamide after abiraterone in patients with metastatic castrate-resistant prostate cancer (mCRPC). American Society of Clinical Oncology; 2014.