Phase II study of pembrolizumab with enzalutamide (Enz) in metastatic, castration-resistant prostate cancer (mCRPC): 30 patient expansion with examination of tumour-infiltrating immune cells and fecal microbiota

Abstract Background PD-1 inhibition (α-PD-1) can lead to deep, durable responses in mCRPC, but only in a minority of patients (pts). We previously reported 5 (18%) responders among 28 pts. No marker has been shown to universally predict response. Analysis of fecal microbiota from pts with epithelial cancers showed an association between elevated Akkermansia muciniphila (A. muc) levels and response to α-PD-1. To evaluate predictive markers, we treated an additional 30 pts obtaining tumor biopsies, blood, and fecal specimens collected for analysis. Methods 30 pts with mCRPC progressing on Enz received α-PD-1 pembrolizumab 200 mg IV every 3 weeks for 4 doses with continued Enz. Prior chemotherapy for mCRPC was prohibited. The primary endpoint was the proportion of pts with a prostate-specific antigen (PSA) decline ≥ 50%. The secondary endpoints were objective response, PSA progression-free survival (PFS), radiographic PFS, overall survival (OS) and correlative studies. Results Four of 30 (13%) achieved a PSA reduction ≥ 50%. Six of 24 (25%) pts with measurable disease responded radiographically. After median follow up of 17.4 months (mos), median PSA PFS was 5.57 mos (95%CI: 3.48-8.06). Median OS was 17.25 mos (95% CI: 7.71-17.68). Of 27 pts evaluable for radiographic PFS, 17 (63%) have progressed; median radiographic PFS was 5.26 mos (95% CI: 2.6-11.2). Eight pts had immune related adverse events. Single cell analysis revealed that immune cells represent an average 0.5% of cells in tumor biopsies. Single cell transcriptomic analysis prior to α-PD-1 in 12 pts revealed enrichment in a CD8+ exhausted T cell population (p Conclusions Using single cell RNA sequencing, we reveal a T-cell signature associated with response, an observation not possible at the bulk transcriptome level. Responders had lower levels of fecal A. muc than non-responders, suggesting markers of α-PD-1 response in mCRPC may be different than in other cancer types. Clinical trial identification NCT02312557. Legal entity responsible for the study Julie N Graff. Funding Merck Sharp & Dohme. Disclosure J.N. Graff: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas/Pfizer. A.E. Moran: Research grant / Funding (institution): Merck Sharp & Dohme. J.J. Alumkal: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Janssen Biotech; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Zenith Epigenetics Ltd; Research grant / Funding (institution): Gilead Sciences Inc. R.C. Bergan: Leadership role, Licensing / Royalties, Full / Part-time employment: Third Coast Therapeutics. T.M. Beer: Research grant / Funding (institution): Alliance Foundation Trials; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Corcept Therapeutics; Research grant / Funding (institution): Endocyte Inc; Research grant / Funding (institution): Janssen Research & Development; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): OncoGenex; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Theraclone Sciences/OncoResponse; Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Janssen Biotech; Honoraria (self), Advisory / Consultancy: Janssen Japan; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.