Pembrolizumab, an anti-PD-1 antibody, is an important agent that has had some important breakthroughs. It is the only pan-cancer agent approved by the FDA – and it is approved for all patients with solid malignancies and high MSI (microsatellite instability). Beyond that, it has been approved for advanced bladder cancer.
In this study, the authors combined Pembro with an established therapy, enzalutamide (Enza) in the metastatic castration-resistant prostate cancer (mCRPC) setting. The enrolled 28 patients to this open-label study. All patients had mCRPC, had never been treated with chemotherapy or ICIs; prior abiraterone or Provenge were allowed. Patients were then given Pembro (200 mg IV every 3 weeks for 4 doses), which could be repeated for the patients who had stable or responsive disease. All patients had been treated with enzalutamide and had demonstrated progression (biochemical or radiographic) prior to being enrolled.
The primary endpoint was prostate specific antigen (PSA) response (PSA decline of ≥ 50%). Secondary endpoints were radiographic objective response (RECIST 1.1), PSA progression free survival (PFS), time to subsequent treatment, and time to death from any cause.
In terms of additional evaluations, baseline tumor biopsies were done if there was a metastatic deposit amenable to biopsy. In this presentation, the authors present updated clinical outcomes and evaluation of samples for presence of Program Death-Ligand 1 (PD-L1), microsatellite instability (MSI) and DNA repair defects. Initial results were previously presented.
Baseline characteristics of the cohort were: 28 patients with 22.7 month median follow-up.
Median age 72, 27 (of 28) white, 17 (of 28) ECOG 1, 11 had prior RP while 8 had prior XRT, sites of metastases varied (13 bone only, 3 LN only, 9 both, 3 lung and/or liver), median PSA 26.61, prior treatment included docetaxol (4), abiraterone (10). Median time on enza prior to failure: 52 weeks (1 year).
In terms of response, 5 patients (18%) had a PSA decline of ≥ 50%. With regards to radiographic response, only 12 patients had measurable disease at baseline, and 3 (25%) achieved an objective response.
Looking specifically at the responders (R), one passed away from an unrelated cause without PSA recurrence after 14.2 mos, and one relapsed after 10 mos and did not respond to a second course of Pembro. The other 3 continue to be in response (range 21.9-33.8 mos). It would appear that similar to other studies, a small subset of patients benefit and potentially have a durable response.
For the entire cohort, the median follow up was 22.7 mos, and the median PSA-PFS time was 3.8 mos (95% CI: 2.8 – 9.9 mos). Time to subsequent treatment was 8.2 mos (95% CI: 5.1 – 12.8 mos). Median overall survival was 22.2 mos (95% CI: 14.7 – 28 .4 mos). Median radiographic PFS was 10.8 mos (5-22 mos).
Treatment was tolerated relatively well. There were 8 immune related adverse events in 7 unique patients (hypothyroid 3, hyperthyroid 1, myositis 2, colitis 2).
Seventeen patients had baseline biopsies of a metastatic deposit: 3 R, 14 non-responders (NR). Of the 3 R who had baseline biopsies, one had MSI and DNA repair defects. The other 2 had neither. Of the NR who had sequencing, 4 had a DNA repair defects, and none had MSI. None of the biopsies showed tumoral PD-L1 expression (Qualtek, 22C3).
As mentioned above, it would appear that Pembro has activity in a small subset of mCRPC patients when added to Enz, and these patients may have a durable response. Yet, biomarkers remain a challenge. Even MSI and DNA repair defects did not appear to be predictive.
Presented by: Julie Nicole Graff, MD
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA