Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer

Background Checkpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response. Methods We evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens. Results Five (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression. Conclusions Pembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects. Trial registration number clinicaltrials.gov (NCT02312557).

Background Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial. Patients and methods PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N=872) versus placebo (N=845) in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary endpoints. Subgroup analysis of men aged ≥75 years (“elderly”) and men aged <75 years was prespecified for the coprimary endpoints and adverse events (AEs). Results Among 609 elderly patients (35%) who participated in PREVAIL, median treatment duration was 16.6 and 5.0 months in the enzalutamide and placebo arms, respectively. In the elderly subgroup, OS was greater with enzalutamide than with placebo (32.4 months [95% CI 27.7–not yet reached] versus 25.1 months [95% CI 22.6–28.0]; hazard ratio [HR]=0.61 [95% CI 0.47–0.79]; P=0.0001), as was rPFS (not yet reached [95% CI 12.3–not yet reached] versus 3.7 months [95% CI 3.6–5.3]; HR=0.17 [95% CI 0.12–0.24]; P<0.0001). Irrespective of treatment assignment, incidence of AEs was similar between the two age groups, except for an overall higher incidence of falls among elderly patients than younger patients (84/609 [13.8%] versus 62/1106 [5.6%]) and among elderly patients receiving enzalutamide than those receiving placebo (61/317 [19.2%] versus 23/292 [7.9%]). Conclusions Elderly men benefited from treatment with enzalutamide in terms of OS and rPFS. Enzalutamide was well tolerated in the elderly subgroup and those aged <75 years. Age and enzalutamide treatment were associated with a higher incidence of falls. Clinical trial identifier NCT01212991, ClinicalTrials.gov.

Immunotherapy encompasses a wide range of therapies to engage the immune system to target malignancies. In recent years, immunotherapy has made a major impact on treatment of metastatic cancer and has altered standard of care for many tumor types. However, predicting and understanding responses across tumor types has been challenging. While some metastatic cancers have shown dramatic responses to immunotherapy, such as melanoma, lung cancer, and renal cell carcinoma, prostate cancer has generally failed to show a significant response. However, small series of prostate cancer patients have shown impressive responses to cellular and immunotherapy. This review summarizes the current data for immunotherapy’s use in prostate cancer, as well as how currently available data might help predict patient responses to immunotherapy. Specifically, we will review vaccine-based therapies, immune checkpoint inhibitors, and future directions that are actively being explored.

Inhibition of poly(ADP-ribose) polymerase (PARP) after relapse on hormone therapy is well established for patients with prostate cancer with homologous recombination repair (HRR) gene alterations, but resistance often develops. We hypothesized that PARP inhibition within 6 months of starting androgen deprivation therapy for metastatic castration-sensitive prostate cancer (mCSPC) could be effective and improve radiographic progression-free survival when added to standard-of-care treatments. The double-blind AMPLITUDE trial evaluated combining niraparib, a potent and specific PARP inhibitor, with abiraterone acetate and prednisone (AAP) versus placebo and AAP in mCSPC with HRR gene alterations. Patients ( n = 696) were randomized in a 1:1 ratio (348 per group). Median age was 68 years; 56% had BRCA1 or BRCA2 alterations; 78% had high-volume metastases; and 16% had received docetaxel. The primary endpoint was met, with a significant improvement in radiographic progression-free survival observed first in the BRCA subgroup (median not reached at the time of analysis for the niraparib and AAP group versus 26 months for the AAP group; hazard ratio = 0.52; 95% confidence interval: 0.37–0.72; P < 0.0001) and then in the intention-to-treat population (hazard ratio = 0.63; 95% confidence interval: 0.49–0.80; P = 0.0001). The data for overall survival, a key secondary endpoint, are immature (193/389 events) but favor niraparib (hazard ratio = 0.79 (95% confidence interval: 0.59–1.04); BRCA subgroup: hazard ratio = 0.75 (95% confidence interval: 0.51–1.11)). Incidence of grade 3 or 4 adverse events was 75% in the niraparib and AAP group and 59% in the AAP group; most frequent in the niraparib and AAP group were anemia (29%), with 25% of patients requiring a blood transfusion, and hypertension (27%). There were 14 treatment-emergent adverse events leading to deaths in the niraparib group and seven in the placebo group. Combining niraparib with AAP significantly improved radiographic progression-free survival in patients with mCSPC harboring BRCA1/BRCA2 or other HRR gene alterations, suggesting clinical benefit with this combination for these patients. ClinicalTrials.gov identifier: NCT04497844 .

Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a genome-wide CRISPR interference (CRISPRi) screen and identified androgen receptor (AR) as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in Ar also demonstrated increased tumor immunogenicity and promoted T cell–mediated tumor control. Notably, the increase in MHCI expression upon AR blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape. Significance: Immunotherapy options for immune cold tumors, like prostate cancer, are limited. We show that AR downregulates MHCI expression/antigen presentation and that AR inhibition improves T-cell responses and tumor control. This suggests that treatments combining AR inhibitors and checkpoint blockade may improve tumor immune surveillance and antitumor immunity in patients.