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PurposeGermline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.MethodsA multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).ResultsLarge germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.ConclusionThis multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Background: In the global ARASENS study (NCT02799602), darolutamide plus androgen‐deprivation therapy (ADT) and docetaxel significantly reduced risk of death by 32.5% versus placebo plus ADT and docetaxel (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57–0.80; p < 0.0001), with a favorable safety profile in patients with metastatic hormone‐sensitive prostate cancer (mHSPC). We investigated outcomes in Japanese participants. Methods: Patients were randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, plus ADT and docetaxel. The primary endpoint was overall survival. Results: The Japanese subgroup comprised 148 patients (darolutamide 63, placebo 85). In the Japanese versus overall population, more patients were aged ≥75 years (darolutamide/placebo 35%/22% vs. 16%/17%) and had body mass index <25 kg/m2 (78%/79% vs. 46%/43%), The ECOG performance status 0 (92%/88% vs. 72%/71%), de novo mHSPC (95%/97% vs. 86%/87%), and Gleason score ≥8 (94%/92% vs. 78%/79%). Median treatment duration was 43.3/15.4 months for darolutamide/placebo. The overall survival HR for darolutamide versus placebo was 0.91 (95% CI 0.50–1.64), despite 85% of patients in the placebo group receiving subsequent life‐prolonging therapy. Darolutamide prolonged time to castration‐resistant prostate cancer (HR 0.31; 95% CI 0.17–0.55). Treatment‐emergent adverse event incidences were generally similar between groups. Adverse events known to be associated with docetaxel (e.g., neutropenia) were more frequent in the Japanese versus overall population. Conclusion: In conclusion, efficacy outcomes showed positive trends for darolutamide plus ADT and docetaxel in Japanese patients with mHSPC, consistent with the overall population, despite higher risk factors. The combination was well tolerated, with no new safety signals in Japanese patients. In Japanese patients with metastatic hormone‐sensitive prostate cancer (mHSPC) who participated in the global phase 3 ARASENS study, darolutamide in combination with androgen‐deprivation therapy (ADT) and docetaxel showed favorable trends in efficacy and tolerability over placebo plus ADT and docetaxel, with no new safety concerns. The outcomes were consistent with the findings in the overall study population and support the use of darolutamide in combination with ADT and docetaxel in Japanese patients with mHSPC as a new standard of care. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

BackgroundCastration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.MethodsMen with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.ResultsA total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P

PurposeFrequent prostate specific antigen testing for screening and monitoring prostate cancer has led to significant stage migration. We evaluated whether overall survival in hormone naïve patients with metastatic prostate cancer has improved during the era of prostate specific antigen use. We also assessed whether any patient subsets benefited differentially during this period.Materials and methodsWe compared overall survival in 3 sequential phase III trials of 3,096 men with hormone naïve, metastatic prostate cancer who received similar androgen deprivation therapy, including 2 trials performed before the prostate specific antigen era (S8494 and S8894) and the other done during this era (S9346). Overall survival was adjusted for patient and disease risk factors in the latter 2 trials. Subgroups were evaluated by interactions of risk factors with trial.ResultsMedian overall survival was 30 months in S8494, 33 months in S8894 and 49 months in S9346. Adjusting for risk factors, there was a 22% lower risk of death in S9346 than in S8894 (HR 0.78, 95% CI 0.70, 0.87, p

ContextSecondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer.ObjectiveTo determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men.Design, setting, and participantsA randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer.InterventionsOral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years.Main outcome measuresProstate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer.ResultsAs of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group.ConclusionSelenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.Trial registrationclinicaltrials.gov identifier: NCT00006392.

Purpose: Luteinizing hormoneereleasing hormone (LHRH) agonists are believed to have higher cardiovascular risk relative to gonadotropin-releasing hormone (GnRH) antagonists. However, previous studies have not consistently demonstrated this. We used real-world clinical practice data to evaluate differences in major adverse cardiovascular events (MACE) risk between LHRH agonists compared to a GnRH antagonist following androgen deprivation therapy (ADT) initiation. Materials and Methods: We performed a retrospective analysis of data in the Decision Resources Group (now Clarivate) Real World Evidence repository, which represents >300 million US patients from 1991 to 2020 across all US regions. Patients with prostate cancer who received at least 1 injection of ADT were included. The risks of MACE and all-cause mortality as independent endpoints were evaluated, Kaplan-Meier curves were constructed, and associations between MACE and all available confounding risk factors were evaluated by Cox regression analysis using Statistical Package for the Social Sciences. Results: A total of 45,059 men with prostate cancer treated with ADT were analyzed. Overall, the risks of MACE and all-cause mortality were slightly lower in the first year after ADT initiation compared to subsequent years. MACE risk was higher for the GnRH antagonist compared to LHRH agonists (HR[1.62; 95% CI 1.21-2.18, P = .001). The risk of all-cause mortality was also higher for the GnRH antagonist vs LHRH agonists (HR[1.87; 95% CI 1.39-2.51, P < .001). Conclusions: The adjusted incidence of MACE was higher for men treated with the GnRH antagonist compared to the LHRH agonists. The demographic and risk factors with the greatest impact on MACE risk were higher age, baseline metastasis, oncology (vs urology) setting, personal MACE history, antagonist (vs agonist), tobacco history, White (vs Black) race, and lower BMI. [ABSTRACT FROM AUTHOR]