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The use of finasteride to prevent prostate cancer reduced the risk of low-grade tumors by 43%, as compared with placebo. High-grade tumors were more common in the finasteride group, but long-term follow-up did not show a significant between-group difference in survival. With the advent of prostate-specific antigen (PSA) testing in the late 1980s, the rate of diagnosis of prostate cancer rose dramatically. Currently, a man in the United States has a 16.5% lifetime risk of receiving a diagnosis of prostate cancer. 1 The timing and magnitude of the 44% reduction in prostate-cancer mortality after the widespread adoption of PSA testing suggest that both screening and treatment improvements have contributed to this decline. 2 Unfortunately, treatments for prostate cancer (radiation and surgery) are associated with a substantial risk of side effects, including sexual, urinary, and bowel complications, that can dramatically affect quality of life. . . .

Despite theoretical benefits of intermittent as compared with continuous androgen-deprivation therapy in patients with metastatic prostate cancer, intermittent therapy did not result in longer survival or long-term improvement in quality of life. Prostate cancer is an androgen-dependent disease, and continuous androgen deprivation has been the standard therapy for metastatic hormone-sensitive disease. Despite a high response rate, resistance to androgen-deprivation therapy occurs in most patients, resulting in a median survival of 2.5 to 3 years. 1 , 2 There is evidence suggesting that progression to castration resistance is adaptive in part, and pathways involving the androgen receptor, as well as cell-survival pathways independent of the androgen receptor, have been implicated. 3 , 4 Data from an androgen-dependent tumor model have suggested that androgen withdrawal alters the ratio of putative stem cells in the tumor-cell population. 5 Initially, differentiated . . .

Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61–92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63–70] vs 63% [60–67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72–1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65–0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73–1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

ImportanceThe effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown.ObjectiveTo compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score >4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism.Design, setting, and participantsThis placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023.InterventionParticipants were randomized, with stratification for prior CVD, to topical 1.62% testosterone gel or placebo.Main outcomes and measuresThe primary prostate safety end point was the incidence of adjudicated high-grade prostate cancer. Secondary end points included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. Intervention effect was analyzed using a discrete-time proportional hazards model.ResultsA total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean (SD) treatment duration as 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2 596 [0.19%] in the TRT group vs 3 of 2 602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; p = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men.Conclusions and relevanceIn a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study’s findings may facilitate a more informed appraisal of the potential risks of TRT.Trial registrationClinicalTrials.gov Identifier: NCT03518034

The initial report on finasteride for prevention of prostate cancer documented a reduction in prostate cancers but a paradoxical increase in high-grade tumors. Prolonged follow-up and surveillance revealed that the number of deaths from prostate cancer was not increased by finasteride.

The role of the human gut microbiome in colorectal cancer (CRC) is unclear as most studies on the topic are unable to discern correlation from causation. We apply two-sample Mendelian randomization (MR) to estimate the causal relationship between the gut microbiome and CRC. We used summary-level data from independent genome-wide association studies to estimate the causal effect of 14 microbial traits (n = 3890 individuals) on overall CRC (55,168 cases, 65,160 controls) and site-specific CRC risk, conducting several sensitivity analyses to understand the nature of results. Initial MR analysis suggested that a higher abundance of Bifidobacterium and presence of an unclassified group of bacteria within the Bacteroidales order in the gut increased overall and site-specific CRC risk. However, sensitivity analyses suggested that instruments used to estimate relationships were likely complex and involved in many potential horizontal pleiotropic pathways, demonstrating that caution is needed when interpreting MR analyses with gut microbiome exposures. In assessing reverse causality, we did not find strong evidence that CRC causally affected these microbial traits. Whilst our study initially identified potential causal roles for two microbial traits in CRC, importantly, further exploration of these relationships highlighted that these were unlikely to reflect causality.

The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5–9·9) in the atrasentan group and 9·1 months (8·4–10·2) in the placebo group (hazard ratio 1·02, 0·89–1·16; p=0·81). Median overall survival was 17·8 months (16·4–19·8) in the atrasentan group versus 17·6 months (16·4–20·1) in the placebo group (1·04, 0·90–1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

Building accurate prediction models and identifying predictive biomarkers for treatment response in Muscle-Invasive Bladder Cancer (MIBC) are essential for improving patient survival but remain challenging due to tumor heterogeneity, despite numerous related studies. To address this unmet need, we developed an interpretable Graph-based Multimodal Late Fusion (GMLF) deep learning framework. Integrating histopathology and cell type data from standard H&E images with gene expression profiles derived from RNA sequencing from the SWOG S1314-COXEN clinical trial (ClinicalTrials.gov NCT02177695 2014-06-25), GMLF uncovered new histopathological, cellular, and molecular determinants of response to neoadjuvant chemotherapy. Specifically, we identified key gene signatures that drive the predictive power of our model, including alterations in TP63, CCL5, and DCN. Our discovery can optimize treatment strategies for patients with MIBC, e.g., improving clinical outcomes, avoiding unnecessary treatment, and ultimately, bladder preservation. Additionally, our approach could be used to uncover predictors for other cancers.

Three important studies published in the Journal during the past 3 years have addressed key issues related to prostate cancer. Two articles described large trials of prostate-specific antigen (PSA) screening and reached opposite conclusions regarding the impact of screening on the risk of death from prostate cancer. 1 , 2 In this issue of the Journal, Wilt and colleagues 3 report the results of a study that asked whether radical prostatectomy, as compared with observation, improved survival among men with prostate cancer. Collectively, these three studies suggest that a national focus on PSA screening and treatment for prostate cancer may have a marginal . . .