No abstract

Background: In men with castration-sensitive prostate cancer (CSPC), the HSD3B1 c.1245A>C variant has been reported to be associated with shorter responses to first-line androgen-deprivation therapy (ADT). Here, we evaluated the association between the inherited HSD3B1 c.1245A>C variant and outcomes from metastatic castration-resistant prostate cancer (mCRPC) after first-line treatment with abiraterone (Abi) or enzalutamide (Enza). Patients and methods: Patients with mCRPC (n ¼ 266) were enrolled from two centers at the time of starting first-line Abi/Enza. Outcomes after Abi/Enza included best prostate-specific antigen (PSA) response, treatment duration, and overall survival (OS). Outcomes after first-line ADT were determined retrospectively, and included treatment duration and OS. As was prespecified, we compared patients with the homozygous variant HSD3B1 genotype (CC genotype) versus the combined group with the heterozygous (AC) and homozygous wild-type (AA) genotypes. Results: Among the 266 patients, 22 (8.3%) were homozygous for the HSD3B1 variant (CC). The CC genotype had no association with PSA response rate; the median Abi/Enza treatment duration was 7.1 months for the CC group and 10.3 months for the AA/AC group (log rank P ¼ 0.34). Patients with the CC genotype had significantly worse OS, with median survival at 23.6 months for the CC group and 30.7 months for the AA/AC group (log rank P ¼ 0.02). In multivariable analysis adjusting for age, Gleason score, PSA, prior chemotherapy, and M1 disease, the association between the CC genotype and OS remained significant (hazard ratio 1.78, 95% confidence interval 1.03e3.07, P ¼ 0.04). Poor outcome after first-line ADT in the CC group was also observed when evaluating retrospective ADT duration data for the same combined cohort. Conclusions: In this large two-center study evaluating the HSD3B1 c.1245 genotype and outcomes after first-line Abi/Enza, homozygous variant (CC) HSD3B1 genotype was associated with worse outcomes. Novel therapeutic strategies are needed to enable treatment selection based on this genetic marker.

Background. Genomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer. Methods. To enrich for response to anti-PD1 therapy, we assembled a multi-center cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden (FSB) and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently utilized data from a clinical trial of pembrolizumab in patients with non-prostatic dMMR cancers of various histologies as a biomarker validation cohort. Results. Nineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy and demonstrated a PSA 50 response rate of 65% and a median progression-free survival (PFS) of 24 (95%CI, 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment, and with density of CD8+ tumor infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort. Conclusions. Tumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers, and may represent a new biomarker of immune checkpoint inhibitor sensitivity. The Oncologist 2020;9999:• • Implications for Practice: Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, we assembled a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer as these patients are enriched for responses to ICI. We observed a high response rate to anti-PD1 therapy in these patients, however these responses were not durable in most patients. Notably, we identified tumor frameshift mutation proportion (FSP) as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.