ASCO 2018: Pembrolizumab plus Enzalutamide in mCRPC: Extended Follow Up

Chicago, IL (UroToday.com) While PD-1 inhibitors have made a marked impact on the survival of many patients with solid tumors, metastatic castration-resistant prostate cancer remains challenging to treat with checkpoint inhibitors and most patients are refractory to single-agent PD-1 inhibition on clinical trials. It has been reported that patients who progress on enzalutamide have increased PD-L1/2+ dendritic cells in blood compared to those patients who are responding to therapy1. Thus, it has been hypothesized that patients who progress on enzalutamide may have a primed tumor microenvironment which may sensitive them to PD-1 inhibition.

In this extended follow up of a single arm phase 2 study, patients who progressed on enzalutamide were given four cycles of standard dose pembrolizumab every three weeks in addition to enzalutamide. Inclusion criteria included any patient with biochemical or radiographic progression on enzalutamide. Prior therapy with sipuleucel-T and abiraterone was permitted. Patients were excluded if they had prior PD-1, PD-L1, or CTLA-4 antibodies or chemotherapy for mCRPC.

Cycles Pembrolizumab

The primary endpoint was a PSA reduction of 50%, and secondary endpoints were objective response, PSA PFS, time to subsequent treatment, and time to death. 

As of this abstract submission, 28 patients have been treated on protocol. 5/28 (18%) have had a PSA response ≥ 50% and 3/12 (25%) have had a partial radiographic response. The median overall survival of patients was 22.2 months and median PSA progression-free survival was 28 months. Two patients developed grade 3 colitis, and a number of other grade 3 adverse events occurred in single patients (myelitis, femoral fracture, humeral fracture, fatigue, anemia, hyponatremia, UTI).
pembro enza tumor size graph
Of the 5 patients who responded to pembrolizumab, 4 had prior abiraterone, and 3 had a response to enzalutamide. Only one of three responders who had genomic testing had a DNA repair defect (ATM). Of the non-responders, there were 4 patients with DNA repair defects (ATM, FANCC, CHK2, FANCA). 
Pembro Enza Subjects Chart

In conclusion, pembrolizumab in combination with enzalutamide after progression on enzalutamide may produce a durable response in certain patients. The number of patients in this trial was small so it is hard to generalize this data - it may be helpful to conduct a larger trial with more biomarker analysis to hopefully ascertain which factors are predictive of a durable response. Based on the available data, in an unselected population, most patients with mCRPC will not benefit from combination enzalutamide and pembrolizumab after progression on enzalutamide. 

References: 
1. Bishop JL, Sio A, Angeles A, et al. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget 2015; 6:234.

Presented By:  Julie Nicole Graff, MD, Oregon Health & Science University.


Written By: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA
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