Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study

Abstract

PURPOSE Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)–positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population. METHODS The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1–positive and PD-L1–negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety. RESULTS Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%. CONCLUSION Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

“…Furthermore, organisms and cancer cells alike must avoid predation to ensure their survival in any environment. Prostate cancer cells avoid the predation of the immune system in a number of ways, including 1) secretion of immunosuppressive molecules, such as TGF-β (Yang et al, 2010; Yoshimura and Muto, 2011) and soluble WNT ligands (Robinson et al, 2015), and 2) expression of cell surface or cellular immune checkpoint molecules (Antonarakis et al, 2020; Gao et al, 2017; Graff et al, 2016). For example, TGF-β has been identified as a potent immunosuppressive ligand, which can be regulated through Snail to mediate downregulation of HLA-I and promote immune escape (Chen et al, 2015).…”

Roles of N6‐methyladenosine (m6A) RNA modifications in urological cancers

“…64 Recent studies illustrated that PD-1/PD-L1-related immunotherapy was effective in urological cancers. [65][66][67][68] FTO is demonstrated to promote carcinogenesis and anti-PD-1 resistance in melanoma, suggesting that FTO could be a potential therapeutic target in immunotherapy, 69 As we mentioned before, both METTL3 and FTO play crucial roles in carcinogenesis in both bladder cancer and renal cell carcinoma. Taken together, these findings suggest that m 6 A regulators could be potential therapeutic targets for patients receiving chemoand radiotherapy.…”

Human Vaccines & Immunotherapeutics: news

“…Five percent of the men with end-stage prostate cancer reported tumor shrinkage or clearance following treatment with the anti-PD-1 MAb pembrolizumab (Merck) in a Phase 2 trial. 3 Notably, half of these patients were alive and tumor-free after 2 years of therapy. Nineteen percent showed some response with decrease in the cancerassociated prostate-specific antigen.…”