Summary Background HSD3B1(1245A>C) has been mechanistically linked to castration-resistant prostate cancer by encoding an altered enzyme that augments dihydrotestosterone synthesis. We hypothesized that men inheriting the HSD3B1(1245C) allele would exhibit resistance to androgen deprivation therapy (ADT). Methods We determined HSD3B1 genotype retrospectively in men treated with ADT for post-prostatectomy biochemical failure and correlated genotype with long-term clinical outcomes. Patients who received postoperative adjuvant or salvage radiotherapy were eligible, provided they had residual active disease as reflected by continued increase in their PSA after treatment. We analyzed progression-free survival (PFS; primary endpoint), distant metastasis-free survival (DMFS), and overall survival (OS) according to HSD3B1 genotype. Multivariable analyses were performed to assess the independent predictive value of HSD3B1 genotype on outcomes. Results were externally validated in two additional cohorts, including a second post-prostatectomy biochemical failure cohort as well as a metastatic cohort. There was no age limit for eligibility in the primary or validation cohorts. Findings The study included 443 patients: 118 in the primary cohort, 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary study cohort, median PFS diminished as a function of the number of variant alleles inherited: 6.6 years in homozygous wild-type men (95% CI, 3.8 to not reached); 4.1 years in heterozygotes (95% CI, 3.0 to 5.5); and 2.5 years in homozygous variant men (95% CI, 0.7 to not reached); P=0.011. Median DMFS likewise decreased according to the number of variant alleles inherited: 9.1 years (95% CI, 7.4 to not reached); 6.8 years (95% CI, 4.3 to 7.4); and 3.6 years (95% CI, 1.0 to 7.3), respectively; P=0.014. Finally, OS diminished with the number of variant alleles inherited: 5-year and 10-year OS 82% (95% CI, 69 to 94) and 55% (95% CI, 35 to 75) in homozygous wild-type men; 74% (95% CI, 62 to 85) and 35% (95% CI, 21 to 49) in heterozygotes; and 58% (95% CI, 30 to 86) and 0% in homozygous variant men; P=0.0064. On multivariable analysis, the hazard ratio (HR) for progression was 1.6 for men with at least one variant allele (95% CI, 1.0 to 2.7; P=0.074), which compared favorably with Gleason score (HR 1.3 for Gleason score 8–10 vs. 6–7; 95% CI 0.8 to 2.0; P=0.31), though neither factor reached statistical significance with the small sample size. The impact of homozygous variant genotype on metastasis (HR 2.8; 95% CI, 1.1 to 6.7; P=0.025) and death (HR 3.5; 95% CI 1.3 to 9.5; P=0.013) was maintained on multivariable analysis. Findings in the external cohorts independently validated the impact of HSD3B1(1245C) on outcomes. Interpretation Inheritance of the HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to ADT. Our findings nominate HSD3B1 as a powerful genetic biomarker capable of distinguishing men who are a priori ...

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The adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC).OBJECTIVE To examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data. DESIGN, SETTING, AND PARTICIPANTSThe E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018.INTERVENTIONS Men were randomized to castration plus docetaxel, 75 mg/m 2 , every 3 weeks for 6 cycles or castration alone.MAIN OUTCOMES AND MEASURES Two-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype. RESULTSOf 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (Ն1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years.Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel.CONCLUSIONS AND RELEVANCE Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.

In this study, the HSD3B1 (1245C) allele was associated with more rapid development of metastases in men treated with ADT for biochemical recurrence after primary radiation therapy for prostate cancer. Notably, 105 of 213 men (49%) had received prior ADT, and 119 of 213 (56%) received an androgen receptor antagonist during salvage treatment, both of which may attenuate the effect of the variant allele.

Inheritance of the HSD3B1 (1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.

Background Among men with localized high‐risk prostate cancer (PCa), patients who meet very high‐risk (VHR) criteria have been shown to experience worse outcomes after radical prostatectomy (RP) in a previous study. Variations of VHR criteria have been suggested to be prognostic in other single‐center cohorts, but multicenter outcomes validating VHR criteria have not been described. This study was designed to validate VHR criteria for identifying which PCa patients are at greatest risk for cancer progression. Methods Patients with high‐risk PCa undergoing RP (2005‐2015) at 3 tertiary centers were pooled. The outcomes of men with VHR PCa were compared with the outcomes of those who did not meet VHR criteria. The high‐risk criteria were a clinical stage of T3 to T4, a prostate‐specific antigen level > 20 ng/mL, or a biopsy Gleason grade sum of 8 to 10. The VHR criteria were multiple high‐risk features, >4 biopsy cores with a Gleason grade sum of 8 to 10, or primary Gleason grade pattern 5. Biochemical recurrence, metastasis (METS), and cancer‐specific mortality (CSM) were assessed with competing risks regressions. Overall mortality was assessed with Cox survival models. Results Among 1981 patients with high‐risk PCa, men with VHR PCa (n = 602) had adverse pathologic outcomes: 37% versus 25% for positive margins and 37% versus 15% for positive lymph nodes (P <  .001 for both comparisons). Patients with VHR PCa also had higher adjusted hazard ratios for METS (2.78; 95% confidence interval [CI], 2.08‐3.72), CSM (6.77; 95% CI, 2.91‐15.7), and overall mortality (2.44; 95% CI, 1.56‐3.80; P <  .001 for all comparisons). Conclusions In a validation study of patients who underwent treatment for high‐risk PCa, VHR criteria were strongly associated with adverse pathologic and oncologic outcomes.

Introduction: Neoadjuvant chemotherapy (NAC) prior to radical or partial cystectomy is considered the standard of care for eligible patients with muscle-invasive urothelial carcinoma. Despite guideline recommendations, adoption of NAC has historically been low, although prior studies have suggested that use is increasing. In this contemporary study, we examine trends in the use of NAC and explore factors associated with its receipt. Methods: We identified patients in the National Cancer Database who underwent radical or partial cystectomy for cT2-cT4N0M0 urothelial carcinoma from 2006-2014. The proportion of patients receiving NAC during each year was examined. Logistic regression models were used to evaluate clinical and socioeconomic factors associated with the receipt of NAC. Results: A total of 18 188 patients were identified who underwent radical or partial cystectomy for muscle-invasive bladder cancer. Overall, 3940 (21.7%) received NAC. We noted a significant increase in the use of NAC over time, from 9.7% in 2006 to 32.2% in 2014. Factors associated with lower use of NAC include older age, higher comorbidity score, lower cT stage, lower hospital radical cystectomy volume, treatment at a non-academic facility, lower patient income, and receipt of partial cystectomy (all p<0.001). Interestingly, neither sex nor race were associated with receipt of NAC. Conclusions: Use of NAC has increased significantly over time to a modest rate of 32%. However, disparities still exist in the receipt of NAC and future efforts aimed at mitigating these disparities are warranted.

Objective To compare radical prostatectomy (RP) vs radiotherapy (RT) with androgen‐deprivation therapy (ADT) in the setting of patients with high‐risk and very high‐risk (VHR) prostate cancer who were deemed eligible for either therapy and made a treatment choice after consultation in a multidisciplinary prostate cancer clinic (MDPCC), and to compare the MDPCC patients’ outcomes to a matched Surveillance, Epidemiology and End Results (SEER) cohort. Patients and methods Prospectively collected, retrospective study comparing patients who underwent RP (231 patients) vs RT+ADT (73) from 2004 to 2013. Biochemical recurrence (BCR), local recurrence, distant metastasis failure, and overall survival (OS) were calculated for each treatment group overall and according to National Comprehensive Cancer Network risk strata. A propensity score matched comparison with a SEER cohort was performed for OS. Results There was no difference in local recurrence (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.0–7.9; P = 0.06), distant metastasis failure (HR 2.5, 95% CI 0.8–7.8; P = 0.1) and OS (HR 1.35, 95% CI 0.4–4.8; P = 0.6) between patients undergoing RP vs RT+ADT. Patients treated via the MDPCC survived on average 16.9 months (95% CI 13.1–20.8) longer than those in the matched SEER cohort. Conclusions Long‐term outcomes appear similar amongst patients with high‐risk and VHR prostate cancer deemed eligible for either RP or RT, and treated after consultation in a MDPCC. Outcomes of the MDPCC patients were superior to those of the matched SEER cohort.