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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/m 2 (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., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background and Objective: The use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) have been uncertain. RADICALS-HD compared adding no ("None"), 6-months ("Short"), or 24-mo ("Long") ADT to study efficacy in the long term., Methods: Participants with prostate cancer were indicated for postoperative RT and agreed randomisation between all durations. ADT was allocated for 0, 6, or 24 mo. The primary outcome measure (OM) was metastasis-free survival (MFS). The secondary OMs included freedom from distant metastasis, overall survival, and initiation of nonprotocol ADT. Sample size was determined by two-way comparisons. Analyses followed standard time-to-event approaches and intention-to-treat principles., Key Findings and Limitations: Between 2007 and 2015, 492 participants were randomised one of three groups: 166 None, 164 Short, and 162 Long. The median age at randomisation was 66 yr; Gleason scores at surgery were as follows: <7 = 64 (13%), 3+4 = 229 (47%), 4+3 = 127 (26%), and 8+ = 72 (15%); T3b was 112 (23%); and T4 was 5 (1%). The median follow-up was 9.0 yr and, with MFS events reported for 89 participants (32 None, 31 Short, and 26 Long), there was no evidence of difference in MFS overall (logrank p = 0.98), and, for Long versus None, hazard ratio = 0.948 (95% confidence interval 0.54-1.68). After 10 yr, 80% None, 77% Short, and 81% Long patients were alive without metastatic disease. The three-way randomisation was not powered to conventional levels for assessment, yet provides a fair comparison., Conclusions and Clinical Implications: Long-term outcomes after radical prostatectomy are usually favourable. In those indicated for postoperative RT and considered suitable for no, short-term, or long-term ADT, there was no evidence of improvement with addition of ADT. Future research should focus on patients at a higher risk of metastases in whom improvements are required more urgently., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Early PSA response has been found to be prognostic of outcomes in metastatic hormone sensitive prostate cancer. We performed a secondary analysis of the TITAN trial to determine if early PSA response was predictive of treatment efficacy in metastatic hormone sensitive prostate cancer patients., Materials and Methods: Early PSA response was defined as achieving a PSA level of ≤ 0.2 ng/mL by 6 months of random assignment. A Cox proportional hazard model was constructed in a landmark population with an interaction term between the treatment and early PSA response to determine differential treatment effect on overall survival (OS). We applied multivariable Cox proportional hazard regression model with time to early PSA response fitted with restricted cubic spline to determine the association of time to early PSA response with OS., Results: Approximately 24% (124/524) of patients in the androgen deprivation therapy (ADT) alone group and 61% (321/524) in the apalutamide group had PSA response ≤ 0.2 ng/mL by 6 months. Longer time to early PSA response was associated with significantly superior OS in the apalutamide group. There was a significant difference in treatment effect from apalutamide on OS ( P = .03 for interaction) among 6-month PSA responders (HR: 0.66; 95% CI: 0.44-1.00) vs nonresponders (HR: 1.14; 95% CI: 0.89-1.46). This difference in treatment effect was not statistically significant at 3 months ( P = .17 for interaction). Among 6-month PSA responders, 3-year confounder-adjusted OS was 84% (80%-88%) for the apalutamide group and 74% (66%-82%) for the ADT alone group. Among nonresponders, 3-year adjusted OS for the 2 treatment arms were 58% (52%-65%) and 56% (51%-60%), respectively., Conclusions: Early PSA response by 6 months was a predictor of treatment efficacy from ADT plus apalutamide on OS. Longer time to early PSA response was associated with superior OS in the apalutamide arm.

Background: This study aimed to examine clinicopathologic characteristics, treatment patterns, and survival rates in a contemporary population-based cohort of adult prostate sarcoma patients., Methods: In the Surveillance, Epidemiology, and End Results database (2004-2020), adult patients with prostate sarcoma were identified. Descriptive statistics, Kaplan-Meier analyses, smoothed cumulative incidence plots, and Cox regression models were used., Results: Of 125 patients, 45 (36%) harbored leiomyosarcoma, 17 (14%) had rhabdomyosarcoma, 15 (12%) had stromal sarcoma, 17 (14%) had sarcoma not otherwise specified (NOS), and 31 (25%) had other sarcoma subtypes. Metastatic stage was most common in the rhabdomyosarcoma patients (44%) and least common in the leiomyosarcoma (21%) and stromal sarcoma (20%) patients. Most of the rhabdomyosarcoma patients received the combination of systemic and radiation therapy with (24%) or without radical surgery (35%), whereas most of the leiomyosarcoma and stromal sarcoma patients underwent radical surgery with (22 and 13%) or without (22 and 47%) radiation. In the overall population, the median overall survival was 27 months. The 5-years overall versus cancer-specific versus other-cause mortality rates were respectively 71 versus 58 versus 13%. In the multivariable Cox regression models, the highest overall mortality was exhibited by the patients with metastatic disease (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.55-5.31; p < 0.001) or unknown disease stage (HR 2.94; 95% CI 2.20-7.21; p = 0.019). Conversely, of all the histologic subtypes, only stromal sarcoma distinguished itself by lower overall mortality (HR 0.41; 95% CI 0.18-0.96; p = 0.039)., Conclusions: Four major histologic subtypes were identified. Among most adult sarcoma patients, treatment patterns vary according to histology, from multimodal therapy to radical prostatectomy alone. These treatment differences reflect equally important heterogeneity in survival patterns., (© 2024. The Author(s).)

Background: Data regarding North-American incidental (cT1a/b) prostate cancer (PCa) patients is scarce. To address this, incidental PCa characteristics (age, PSA values at diagnosis, Gleason score [GS]), subsequent treatment and cancer-specific survival (CSS) rates were explored., Methods: Incidental PCa patients were identified within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2015). Descriptive statistics, annual percentage changes (EAPC), Kaplan-Meier estimates, as well as Cox regression models were used. Bootstrapping technique was used to generate 95% confidence intervals for CSS at 6 years., Results: Of all 344,031 newly diagnosed non metastatic PCa patients, 5155 harbored incidental PCa. Annual rates of incidental PCa increased from 1.9% (2004) to 2.5 % (2015; p = 0.02). PSA values at diagnosis were 0-4 ng/ml in 48% vs. 4-10 ng/ml in 31% vs. > 10 ng/ml in 21%. Of all incidental PCa patients, 64% harbored GS 6 vs. 25% GS 7 vs. 11% GS ≥ 8. Of all incidental PCa patients, 47% were aged < 70, 35% were between 70 and 79 and 18% were ≥ 80 years. Subsequently, 71% underwent no local treatment (NLT) vs. 16% radical prostatectomy (RP) vs. 14% radiotherapy (RT). Proportions of patients with NLT increased from 65 to 81% (p = 0.0001) over the study period (2004-2015). CSS at six years ranged from 58% in GS ≥ 8 patients with NLT to 100% in patients who harbored GS 6 and underwent either RP or RT., Conclusion: Incidental PCa in the United States is rare. Most incidental PCa patients are diagnosed in men aged less than 80 years of age. The majority of incidental PCa patients undergo NLT and enjoy excellent CSS., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In the HERO study, relugolix demonstrated sustained testosterone suppression superior to that of leuprolide acetate (97% vs 89%; difference 7.9% [95% confidence interval, 4.1-12%; p < 0.001])., Objective: To analyze testosterone recovery in a prespecified subset of men from the HERO study not indicated to continue androgen deprivation therapy., Design, Setting, and Participants: Men (N = 934) were randomized (2:1) to receive relugolix 120 mg orally daily or leuprolide acetate injections every 12 wk for 48 wk., Outcome Measurements and Statistical Analysis: Testosterone recovery was assessed in 184 men who completed 48 wk of treatment. During the 90-d recovery period, assessments included time to testosterone recovery (>280 ng/dl; ≥80% of baseline testosterone), serum levels of prostate-specific antigen and pituitary hormones, and adverse events., Results and Limitations: The cumulative incidence rate of testosterone recovery to >280 ng/dl at 90 d following drug discontinuation was significantly higher in the relugolix cohort (n = 137) than in the leuprolide acetate cohort (n = 47; 54% vs 3.2%; nominal p = 0.002). The median time to testosterone recovery was faster following relugolix treatment than with leuprolide acetate treatment (86.0 d vs 112.0 d). Compared with leuprolide acetate, more men treated with relugolix achieved ≥80% of baseline testosterone levels (39% vs 2.1%). Men ≤65 yr and those with baseline testosterone greater than the median had a higher incident rate of testosterone recovery. Adverse events were generally similar between treatment groups. One limitation is the short testosterone recovery follow-up period., Conclusions: Oral relugolix had faster and more complete recovery of testosterone to normal levels after treatment discontinuation than leuprolide acetate in a subset of men from the HERO study. The clinical implications of a faster testosterone recovery with relugolix may be significant for men being treated with androgen deprivation therapy and influence treatment decisions., Patient Summary: The male hormone testosterone is reduced during androgen deprivation therapy for prostate cancer. Reduced testosterone levels cause side effects, impacting patient quality of life. When treatment is stopped, the side effects lessen over time as the levels of testosterone come back to pretreatment range (testosterone recovery). In this study, we found that the time to testosterone recovery was faster with relugolix than with leuprolide acetate., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC., Methods: Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation., Key Findings and Limitations: Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51-1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92-1.42)., Conclusions and Clinical Implications: There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To identify low cancer-specific mortality (CSM) risk lymph node-positive (pN1) radical prostatectomy (RP) patients., Methods: Within Surveillance, Epidemiology and End Results database (2010-2015) pN1 RP patients were identified. Kaplan-Meier plots and multivariable Cox-regression (MCR) models were used. Pathological characteristics were used to identify patients at lowest CSM risk., Results: Overall, 2197 pN1 RP patients were identified. Overall, 5-year cancer-specific survival (CSS) rate was 93.3%. In MCR models ISUP GG1-2 (hazard ratio [HR]: 0.12, p < 0.001), GG3 (HR: 0.14, p < 0.001), GG4 (HR: 0.35, p = 0.002), pT2 (HR: 0.27, p = 0.012), pT3a (HR: 0.28, p = 0.003), pT3b (HR: 0.39, p = 0.009), and 1-2 positive lymph nodes (HR: 0.64, p = 0.04) independently predicted lower CSM. Pathological characteristics subgroups with the most protective hazard ratios were used to identify low-risk (ISUP GG1-3 and pT2-3a and 1-2 positive lymph nodes) patients versus others (ISUP GG4-5 or pT3b-4 or ≥3 positive lymph nodes). In Kaplan-Meier analyses, 5-year CSS rates were 99.3% for low-risk (n = 480, 21.8%) versus 91.8% (p < 0.001) for others (n = 1717, 78.2%)., Conclusions: Lymph node-positive RP patients exhibit variable CSS rates. Within this heterogeneous group, those at very low risk of CSM may be identified based on pathological characteristics, namely ISUP GG1-3, pT2-3a, and 1-2 positive lymph nodes. Such stratification scheme might be of value for individual patients counseling, as well as in design of clinical trials., (© 2024 Wiley Periodicals LLC.)

Importance: Metastatic hormone-sensitive prostate cancer is currently an incurable disease. Despite a high response rate to androgen-deprivation therapy, most cases progress to castration-resistant disease, the terminal phase. This review provides a summary of the most recent evidence for current and emerging management strategies, including treatment intensification with combinations of therapies. It also provides recommendations on applying the evidence in clinical practice to encourage appropriate treatment to improve survival outcomes among patients with metastatic hormone-sensitive prostate cancer., Observations: Androgen-deprivation therapy is the backbone of treatment for metastatic hormone-sensitive prostate cancer; however, it is insufficient alone to provide sustained disease control and long-term survival. Addition of an androgen receptor pathway inhibitor and/or docetaxel significantly improves survival, as demonstrated by several international phase 3 randomized clinical trials. Triplet therapy composed of androgen-deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel has been shown to improve overall survival over androgen-deprivation therapy plus docetaxel. In the ARASENS trial (darolutamide), the hazard ratios (HRs) were 0.68 (95% CI, 0.57-0.80) in the overall population; 0.71 (95% CI, 0.59-0.85) and 0.61 (95% CI, 0.35-1.05) in patients with de novo and recurrent disease, respectively; 0.69 (95% CI, 0.57-0.82) and 0.72 (95% CI, 0.41-1.13) in patients with high-volume and low-volume disease, respectively; and 0.71 (95% CI, 0.58-0.86) and 0.62 (95% CI, 0.42-0.90) in patients with high-risk and low-risk disease, respectively. In the PEACE-1 trial (abiraterone acetate + prednisone), the HRs were 0.75 (95% CI, 0.59-0.95; all de novo) in the overall population and 0.72 (95% CI, 0.55-0.95) and immature in the high-volume and low-volume subgroups, respectively. In the ENZAMET trial (enzalutamide), the HRs were 0.82 (95% CI, 0.63-1.06) in the overall population; 0.73 (95% CI, 0.55-0.99) and 1.10 (95% CI, 0.65-1.86) in the de novo and recurrent subgroups, respectively; and 0.87 (95% CI, 0.66-1.17) and 0.61 (95% CI, 0.33-1.10) in the high-volume and low-volume subgroups. Combination regimens are generally well tolerated, with adverse effects dependent on the profiles of the component drugs., Conclusions and Relevance: The findings of this review show compelling evidence from phase 3 randomized clinical trials in favor of initiating triplet combination therapy for patients with metastatic hormone-sensitive prostate cancer for the best overall survival. Patients who are eligible for chemotherapy should be offered androgen-deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel, particularly patients with high-volume, high-risk, or de novo metastatic disease.

Background: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear., Methods: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047., Findings: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths., Interpretation: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population., Funding: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society., Competing Interests: Declaration of interests AN reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck. ADC reports research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, and Clovis. ACT reports research grants to their institution from Elekta, Varian, and Accuracy; honoraria for talks from Elekta, Accuracy, and Janssen; travel assistance for radiotherapy conferences from Elekta; serving on the data safety board for two academic trials; and roles as the Chair of the MR-Linac Consortium and the genitourinary lead editor for the International Journal of Radiation Oncology, Biology, Physics. AC reports receiving grants or contracts from the National Institute for Health and Care Research, Manchester Biomedical Research Centre, Cancer Research UK, Medical Research Council (MRC) UK, Prostate Cancer UK, Bayer UK, and Elekta; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the American Society for Radiation Oncology, the American Society of Clinical Oncology, Cancer Research UK, Roche, AstraZeneca, and Bristol Myers Squibb (BMS). CNC reports support for the present manuscript from the Canadian Cancer Trials Group; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer Corp, Knight Therapeutics, and AbbVie. CLG reports participating in the independent data monitoring and steering committee for the BARCODE study at the Institute of Cancer Research in London (principal investigator Prof Ros Eeles). CCP reports consulting fees from AAA, ITM Radiopharma, Myovant, and Clarity Pharmaceuticals to his institution; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and Bayer to his institution. CM reports that they are employed by University College London (UCL) as Trial Manager for RADICALS. FS reports grants or contracts from Janssen, Bayer, Merck, Pfizer, Astellas, BMS, Novartis, Sanofi, and AstraZeneca to his institution; consulting fees from Janssen, Bayer, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer to him; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Bayer, Myovant, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer to him. LCB reports their previous Institute of Cancer role was funded in part by a Biomedical Research Centre grant which was paid to the institution; the role was not connected to the RADICALS trial. MRS reports research grants and biomarker testing costs, all to their institution and all active in the past 36 months but on research outside of this research, from Astellas, Clovis Oncology, Janssen, Novartis, and Sanofi-Aventis; consulting fees from Eli Lilly; speaker fees at a clinical trial statistics training meeting for clinicians (no discussion of particular drugs) from Lilly Oncology, Janssen, and Eisai; and is an independent member of many independent data monitoring committees but all for academic sponsors and unpaid. NWC reports honoraria for lectures, advisory boards, and symposia from AstraZeneca, Janssen, Bayer, and Pfizer; support for travel to and attendance at a European meeting from Bayer; participation on the independent data monitoring committee for the Probio trial (Karolinska), and the trial steering committee for the Capi 28 trial (AstraZeneca) and the STAMPEDE trial (MRC); and is the Joint National Clinical Lead for the National Prostate Cancer Audit. PWMC reports grants or contracts from the Canadian Association of Radiation Oncology ACURA program and the Canadian Institute of Health Research; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer and EMD Serono; and participation on a data safety monitoring board or advisory board from TerSera, AbbVie, Tolmar, and Knight Therapeutics. PMP reports participation on a data safety monitoring board or advisory board for AAA Nordic, MSD, and Pfizer Denmark. SCM reports honoraria from Janssen, Astellas, Knight Therapeutics, AMGEN Pharmaceutical, AstraZeneca, AbbVie, and Bayer; and support for attending meetings or travel from TerSera and Sanofi. VK reports a Cancer Research UK grant for the CORE trial to his institution; honoraria from Accuracy, Astellas, Bayer, and Boston Scientific; meeting attendance support from Accuray, Astellas, AstraZeneca, Bayer, BMS, Boston Scientific, Janssen, Merck Sharp & Dohme, and Norvatis; is an unpaid member of the independent data monitoring committee for the EPIC trial and the advisory board for Bayer and Janssen; and is the unpaid Chair of National Cancer Research Institute Penile subgroup of the Bladder and Renal Clinical Studies Group. WRC reports consulting fees from Bayer and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Janssen, AAA Novartis, and Myriad Genetics; and support for attending meetings or travel from Janssen, AAA Novartis, and Bayer. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In incidental prostate cancer (IPCa), elevated other-cause mortality (OCM) may obviate the need for active treatment. We tested OCM rates in IPCa according to treatment type and cancer grade and we hypothesized that OCM is significantly higher in not-actively-treated patients., Methods: Within the Surveillance, Epidemiology, and End Results database (2004-2015), IPCa patients were identified. Smoothed cumulative incidence plots as well as multivariable competing risks regression models were fitted to address OCM after adjustment for cancer-specific mortality (CSM)., Results: Of 5121 IPCa patients, 3655 (71%) were not-actively-treated while 1466 (29%) were actively-treated. Incidental PCa not-actively-treated patients were older and exhibited higher proportion of Gleason sum (GS) 6 and clinical T1a stage. In smoothed cumulative incidence plots, 5-year OCM was 20% for not-actively-treated versus 8% for actively-treated patients. Conversely, 5-year CSM was 5% for not-actively-treated versus 4% for actively-treated patients. No active treatment was associated with 1.4-fold higher OCM, even after adjustment for age, cancer characteristics, and CSM. According to GS, OCM reached 16%, 27%, and 35% in GS 6, 7, and 8-10 not-actively-treated IPCa patients, respectively and exceeded CSM recorded for the same three groups (2%, 6%, and 28%, respectively)., Conclusion: Our results quantified OCM rates, confirming that in not-actively-treated IPCa patients OCM is indeed significantly higher than in their actively-treated counterparts (HR: 1.4). These observations validate the use of no active treatment in IPCa patients, in whom OCM greatly surpasses CSM (20% vs. 5%)., (© 2024 Wiley Periodicals LLC.)

Background: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain., Methods: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047., Findings: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths., Interpretation: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy., Funding: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society., Competing Interests: Declaration of interests AN reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck. ADC reports research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, and Clovis. CMH is an executive committee member for the British Uro-Oncology Group. CNC reports support for the present manuscript from the Canadian Cancer Trials Group; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer Corp, Knight Therapeutics, and AbbVie. CLG reports that they participate in the independent data monitoring and steering committee for the BARCODE study at the Institute of Cancer Research in London (principal investigator Ros Eeles). CB reports stock or stock options from GSK; and has been an employee at GSK since August, 2023. CCP reports consulting fees from AAA, ITM Radiopharma, Myovant, and Clarity Pharmaceuticals to his institution; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and Bayer to his institution. FS reports grants or contracts from Janssen, Bayer, Merck, Pfizer, Astellas, Bristol Myers Squibb (BMS), Novartis, Sanofi, and AstraZeneca to his institution; consulting fees from Janssen, Bayer, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer to him; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Bayer, Myovant, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer to him. LCB reports that their previous Institute of Cancer role was funded in part by a Biomedical Research Centre grant which was paid to the institution; the role was not connected to the RADICALS trial. MRS reports research grants and biomarker testing costs, all to institution and all active in past 36 months but on research outside of this research, from Astellas, Clovis Oncology, Janssen, Novartis, and Sanofi-Aventis; consulting fees from Eli Lilly; speaker fees at a clinical trial statistics training meeting for clinicians (no discussion of particular drugs) from Lilly Oncology, Janssen, and Eisai; and is an independent member of many independent data monitoring committees but all for academic sponsors and unpaid. NDJ is a Senior Investigator for the National Institute for Health and Care Research. NWC reports honoraria for lectures, advisory boards, and symposia from AstraZeneca, Janssen, Bayer, and Pfizer; support for travel to and attendance at a European meeting from Bayer; participation on an independent data monitoring committee for the Probio trial (Karolinska), and the trial steering committee for the Capi 28 Trial (AstraZeneca) and the STAMPEDE Trial (Medical Research Council [MRC]); and is the Joint National Clinical Lead for National Prostate Cancer Audit. PW reports an educational event payment from Astellas; conference and travel cost support from AstraZeneca and Aventis; and participation on the advisory board for Ferring and Roche. PWMC reports grants or contracts from CARO-ACURA and the Canadian Institutes of Health Research; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer and EMD Serono; and participation on a data safety monitoring board or advisory board for TerSera, AbbVie, Tolmar, and Knight Therapeutics. PMP reports participation on a data safety monitoring board or advisory board for AAA Nordic, MSD, and Pfizer Denmark. SCM reports honoraria from Janssen, Astellas, Knight Therapeutics, Amgen Pharmaceutical, AstraZeneca, AbbVie, and Bayer; and support for attending meetings or travel from TerSera and Sanofi. WRC reports consulting fees from Bayer and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Janssen, AAA Novartis, and Myriad Genetics; and support for attending meetings or travel from Janssen, AAA Novartis, and Bayer. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Pelvic radiation therapy may lead to decreased bone mineral density (BMD) and increased risk of fracture that could be of particular concern in patients with prostate cancer who also receive androgen deprivation therapy (ADT). We performed an exploratory analysis of a randomized, double-masked, placebo-controlled trial to determine whether exposure to prior pelvic external beam radiation therapy (XRT) affects BMD and risk of fracture in patients with prostate cancer treated with ADT., Methods and Materials: Patients with nonmetastatic prostate cancer aged ≥70 years or <70 years with low BMD (T-score < -1) or osteoporotic fracture who had been receiving ADT for ≥12 months were randomly assigned to receive densoumab or placebo every 6 months for 3 years. BMD was measured at baseline and at months 1, 3, 6, 12, 24, and 36. We applied multivariable linear mixed-effects models with an interaction term between the treatment arm and exposure to prior pelvic XRT to evaluate differential XRT effect on percent BMD change between the 2 treatment arms., Results: Among 1407 eligible patients, 31% (n = 447) received prior pelvic XRT. There was no significant difference in any clinical fractures among patients with (5.8%, 26 of 447) or without (5.2%, 50 of 960) prior pelvic XRT (P = .42). Prior pelvic XRT was associated with a significant (0.54%) improvement in BMD (95% CI, 0.05-1.02) in the placebo group and a nonsignificant (0.04%) decline in BMD (95% CI, -0.47 to -0.35) in the denosumab group (interaction P = .007). There was no significant difference in pelvic XRT effect on percent BMD change in the lumbar spine (P = .65) or total hip (P = .39) between the 2 treatment groups., Conclusions: We did not find sufficient evidence to suggest any detrimental effect of pelvic XRT on the treatment effect from denosumab on percent BMD change, with only an approximately 5% incidence of clinical fractures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The cT1a vs. cT1b substratification was introduced in 1992 but never formally tested since. We tested the discriminative ability of cT1a vs. cT1b substaging on cancer-specific survival (CSS) in contemporary incidental prostate cancer (PCa) patients., Design, Setting and Participants: Incidental (cT1a/cT1b) PCa patients were identified within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2015)., Outcome Measurements and Statistical Analysis: Kaplan-Meier estimates, as well as uni- and multivariable Cox regression models predicted CSS at five years. Subgroup analyses addressed CSS at five years according to active vs. no local treatment (NLT) as well as Gleason score sum (GS; 6 vs. 7 vs. ≥ 8)., Results and Limitation: We identified a total of 5,155 incidental prostate cancer patients of which 3,035 (59%) were stage cT1a vs. 2,120 (41%) were stage cT1b. In all incidental PCa patients, CSS at five years was 95% (95% CI 0.94-0.96). In cT1a patients, CSS at five years was 98 vs. 90% in cT1b patients (p < 0.001). In multivariable Cox regression analyses, cT1b independently predicted 2.8-fold higher CSM than cT1a (HR 2.5, 95% CI 1.8-3.6, p < 0.001) for incidental PCa patients who underwent NLT. In subgroup analyses, cT1b represented an independent predictor of higher CSM in GS ≥ 8 (HR 3.0, 95% CI 1.4-6.2, p = 0.003), and GS 7 (HR 3.9, 95% CI 1.6-9.7 p = 0.002) patients who underwent NLT. For actively treated patients, cT1b was not independently associated with worse CSM., Conclusion: The historical subclassification of cT1a vs. cT1b in incidental PCa patients displayed a strong ability to discriminate CSS in contemporary GS 7 and GS ≥ 8 patients who underwent NLT. However, no statistically significant difference was recorded in actively treated patients. In consequence, the importance of the current substage stratification predominantly applies to GS ≥ 8 patients who undergo a non-active treatment approach., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To evaluate the International Society of Urological Pathology (ISUP) 5-tier grade grouping (GG) system of prostate cancers as well as previously proposed optimizations., Patients and Methods: The PROCURE biobank is a prospective cohort study of patients with localized prostate cancer who underwent radical prostatectomy in Quebec province between 2005 and 2013. Surgical specimens were graded by experienced genitourinary pathologists using 2019 ISUP criteria. Follow-up was conducted until November 2021. The current 5-tier and a proposed 6-tier GG system were evaluated, the latter having two changes: 1) Gleason 3 + 4 and 4 + 3 tumors with minor/tertiary Gleason 5 patterns were upgraded to GG 3 and 4, respectively; and 2) patients in GG5 were separated based on primary Gleason pattern (4 or 5). Cox proportional hazards models and Harrell's concordance (C) indices were used for statistical analyses., Results: 2003 patients were included (median follow-up: 8.7 years). The current 5-tier GG system predicted time to recurrence (hazard ratio [HR] 2.12, 95% confidence interval [95%CI] 1.99-2.25, C 0.717), androgen-deprivation therapy (HR 2.58, 95%CI 2.38-2.80, C 0.790), metastasis (HR 2.48, 95%CI 2.17-2.83, C 0.806), castration-resistant prostate cancer (HR 2.67, 95%CI 2.28-3.13, C 0.829), and cancer-specific mortality (HR 2.80, 95%CI 2.27-3.44, C 0.835). Goodness-of-fit further improved with the proposed 6-tier GG system, with Harrell's C of 0.733, 0.807, 0.827, 0.853, and 0.853, respectively., Conclusions: The 5-tier GG system predicted short- and long-term outcomes for patients with localized prostate cancer, and the proposed 6-tier GG system further improved its accuracy., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Androgen deprivation therapy for prostate cancer was pioneered by Charles Huggins, laureate of the Nobel Prize in Medicine in 1966. The authors tried to understand the scientific context and how previous findings paved Huggins way to his discoveries. With the help of summary or review articles on androgen deprivation therapy, the authors identified key publications and used his Nobel Prize speech as a basis to understand his discoveries. Furthermore, they used a recording of the laboratory-talk interview he gave about his findings to guide them to relevant publications. The authors found that the basis for Huggins' discoveries was the isolation of testosterone in 1935, not long before Huggins' 1941 hallmark publication. Huggins' work follows major experiments in the 19th century in orchiectomy done as a treatment for prostate hypertrophy. Researching the etiology of idiopathic hydrocele, Huggins analyzed the composition of prostate fluid. Further research led to the discovery of the influence of castration, testosterone, and estrogen on acid phosphatase. Recently developed methods facilitated the measurement of the phosphatases. He, therefore, had a biomarker for metastatic prostate cancer to measure treatment response. Very early on, he reported clinical improvements after castration in metastatic patients. Although the effect of orchiectomy on prostate hypertrophy was already known, Huggins was the first to show that testosterone stimulated and estrogen decreased the activity of prostate cancer. Huggins also established phosphatases as a tumor marker to measure disease response., (© 2023 American Cancer Society.)

Introduction: It is unknown whether specific locations of visceral metastatic sites affect overall survival (OS) of metastatic prostate cancer (mPCa) patients. We tested the association between specific locations of visceral metastatic sites and OS in mPCa patients., Materials and Methods: Within Surveillance, Epidemiology and End Results database (2010-2016), survival analyses relied on specific locations of visceral metastases: lung only vs. liver only vs. brain only vs. ≥2 visceral sites. Kaplan-Meier plots and Cox regression models were fitted., Results: Of 1827 patients, 1044 (57%) harbored lung only visceral metastases vs. 457 (25%) liver only vs. 131 (7%) brain only vs. 195 (11%) ≥2 visceral sites. Median OS was 22 months in all patients vs. 33 months in lung only vs. 15 months in liver only vs. 16 months in brain only vs. 15 months in patients with ≥2 visceral sites. Highest OS was recorded in lung only visceral metastases patients, especially when concomitant nonvisceral metastases were located in lymph nodes only (median OS 57 months) vs. bone only (26 months) vs. lymph nodes and bone (28 months). Liver only, brain only or ≥2 visceral sites exhibited poor OS, regardless of concomitant nonvisceral metastases type (median OS from 13 to 19 months)., Conclusion: In mPCa patients, lung only visceral metastases, especially when associated with lymph node only nonvisceral metastases, portend the best prognosis. Conversely, visceral metastatic sites other than lung portend poor prognosis, regardless of concomitant nonvisceral metastases type., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS., Patients and Methods: Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety., Results: In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%)., Conclusion: In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population., (© The Author(s) 2023. Published by Oxford University Press.)

Purpose: It is unclear whether exposure to commonly prescribed medications influences survival and treatment response in patients with de novo high-risk metastatic prostate cancer (mPCa) treated with androgen receptor pathway inhibitors (ARPIs)., Methods: We performed a secondary analysis of the LATITUDE trial to determine whether receipt of concomitant medications influenced the effect of abiraterone acetate and prednisone, in addition to androgen deprivation therapy (ADT), on overall survival (OS) and prostate cancer-specific mortality (PCSM) in patients with de novo mPCa. We focused on 7 commonly prescribed classes of medications: metformin, statins, proton pump inhibitors (PPIs), cyclooxygenase 2 (COX-2) inhibitors, aspirin, acetaminophen, and NSAIDs (nonselective COX inhibitors). To account for multiple testing, a two-sided p < 0.0024 was set as the threshold for statistical significance., Results: Overall, 1135 patients were eligible. There was some evidence of a differential treatment effect from abiraterone among patients who received concomitant NSAIDs (hazard ratio [HR] for OS: 0.54; 95% CI: 0.42-0.70) versus those who did not (HR: 0.74; 95% CI: 0.60-0.91), though this did not reach significance (interaction p = 0.05). A similar non-significant finding of heterogeneity of effect from abiraterone was noted among patients who received concomitant aspirin (HR for OS: 0.93 [0.63-1.36]) versus those who did not (HR: 0.61 [0.51-0.73]) (interaction p = 0.04). Receipt of NSAIDs was independently associated with a significantly inferior OS (HR: 1.37 [1.15-1.62]; p < 0.001) and higher relative incidence of PCSM (sHR: 1.47 [1.21-1.78]; p < 0.001)., Conclusions: This exploratory analysis did not find statistically significant evidence of differences in treatment effects from ADT plus abiraterone in de novo high-risk mPCa based on the receipt of concurrent medications. The receipt of NSAIDs was independently associated with increased PCSM and inferior OS., Competing Interests: Declaration of Competing Interest Outside of this work, Dr. Roy reports research grant from Swim Across America. Dr. Spratt reports personal fees from Blue Earth, personal fees from Janssen, personal fees from AstraZeneca, Gammatile, Varian, and Boston Scientific, outside the submitted work. Outside of this work, Dr. Morgan reports personal fees from Astellas, Bayer, Janssen, and TerSera. Dr. Saad reports grants, personal fees, and non-financial support from Janssen, during the conduct of the study; grants, personal fees, and non-financial support from Astellas, grants, personal fees, and non-financial support from Bayer, outside the submitted work. Dr. Wallis has received honoraria from Bayer, EMD Serono, Knight Therapeutics, Haymarket Media, Science & Medicine Canada, TerSera Canada, and Tolmar Pharmaceuticals Canada; reports consulting fees from Janssen Oncology SESEN Bio, and Precision Point Specialty LLC; and has received research funding from Knight Therapeutics outside the submitted work. Dr. Malone has received honoraria from Astellas, Bayer, Janssen, and Sanofi; and travel and accommodations support from TerSera and Sanofi. There are no other conflicts of interest among the other authors., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

What Is This Summary About?: This is a summary of a paper that describes the results of the SPARTAN and TITAN studies, which looked at whether a treatment called apalutamide can help treat individuals with advanced prostate cancer.The SPARTAN study included 1207 participants with nonmetastatic castration-resistant prostate cancer (or nmCRPC). The TITAN study included 1052 participants with metastatic castration-sensitive prostate cancer (or mCSPC). Treatment with apalutamide was compared with treatment with placebo. In both studies, all participants were also given androgen deprivation therapy (or ADT), which has been used for many years for the treatment of prostate cancer.The results showed that treatment with apalutamide plus ADT increased participants' survival time while their health-related quality of life stayed the same, compared with placebo plus ADT. Also, apalutamide plus ADT increased the length of time that the cancer did not spread to other parts of the body (metastasize) or did not continue to grow. In both studies, treatment with apalutamide plus ADT was associated with a deep decline in blood prostate-specific antigen (or PSA) levels (called a deep PSA decline). This additional analysis of the SPARTAN and TITAN studies was performed to understand whether the deep PSA decline in participants who received apalutamide plus ADT was linked to their overall health-related quality of life., What Were the Results of the Additional Analysis?: In participants who received apalutamide plus ADT, those who achieved a deep PSA decline after the start of treatment had a greater chance that their health-related quality of life would remain stable. When participants achieved a deep PSA decline at 3 months after the start of treatment, the benefit to their health-related quality of life, including physical wellbeing, was even greater., What Do These Results Mean for Individuals With Advanced Prostate Cancer?: For individuals with advanced prostate cancer, it is important to monitor both PSA decline and any impacts on health-related quality of life. These results will help doctors and other healthcare professionals have a better understanding of patients' cancer experience and the impact of their treatment. Clinical Trial Registration: NCT01946204 (SPARTAN) and, NCT02489318 (TITAN) (ClinicalTrials.gov).

Purpose: To test cancer-specific mortality (CSM) differences in specimen-confined (pT2) prostate cancer (PCa) at radical prostatectomy (RP) with lymph node dissection (LND) according to lymph node invasion (LNI)., Methods: RP + LND pT2 PCa patients were identified (surveillance, epidemiology, and end results 2010-2015). CSM-FS rates were tested in Kaplan-Meier plots and multivariable Cox-regression (MCR) models. Sensitivity analyses respectively addressing patients with 6 or more lymph nodes analyzed and pT2 pN1 patients were performed., Results: Overall, 32,258 patients with pT2 PCa at RP + LND were identified. Of these, 448 (1.4%) patients harbored LNI. Five-year CSM-free estimates were 99.6% for pN0 vs. 96.4% for pN1 (P < .001). In MCR models, pN1 (HR: 3.4, P < .001) independently predicted higher CSM. In sensitivity analyses addressing patients with 6 or more lymph nodes analyzed (n = 15,437), 328 (2.1%) pN1 patients were identified. In this subgroup, 5-year CSM-free estimates were 99.6% for pN0 vs. 96.3% for pN1 (P < .001) and, in MCR models, pN1 independently predicted higher CSM (HR: 4.4, P < .001). In sensitivity analyses addressing pT2 pN1 patients, 5-year CSM-free estimates were 99.3, 100 and 84.8% for ISUP GG 1-3 vs. 4 vs. 5, respectively (P < .001)., Conclusions: In patients with pT2 PCa a small proportion harbor LNI (1.4%-2.1%). In such patients, CSM rate is higher (HR 3.4-4.4, P < .001). This higher CSM risk seems to virtually exclusively apply to ISUP GG5 patients (84.8% 5-year CSM-free rate)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and use CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study., Methods: In HERO, 930 men with advanced prostate cancer (APC) were randomized 2:1 and treated with relugolix (120 mg orally once daily; after single 360 mg loading dose) or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies (LMAs), as well as the most common drug classes (> 10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks and safety., Results: Antihypertensives, antithrombotics, and LMAs were utilized by 52.7%, 39.1%, and 39.6% of men in HERO, respectively. In the main subgroups, point estimates for sustained castration rates were generally consistent with overall estimates of relugolix and leuprolide observed in the overall population. Sustained castration rates were also mostly consistent for men taking the most common drug classes and individual agents in each class (losartan [n = 103]: relugolix, 95.4% vs leuprolide, 80.6%; amlodipine [n = 229]: 97.2% vs 85.5%; metoprolol [n = 88]: 95.7% vs 86.9%; acetylsalicylic acid [n = 259]: 97.0% vs 92.1%; clopidogrel [n = 43]: 96.4% vs 86.7%; simvastatin [n = 78]: 98.0% vs 87.3%). Incidence and types of adverse events (AEs) among men who received these medications were mostly consistent with overall population results, with some increases in grade ≥ 3 and fatal AEs., Conclusion: Relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents., Trial Registration: Clinical Trial ID NCT03085095., Prior Presentation: Data presented at 15th Annual Genitourinary Cancers Symposium; February 17-19, 2022, San Francisco, CA, USA [Abstract 101, Poster board E11]. The published abstract from this presentation can be found at https://ascopubs.org/doi/10.1200/JCO.2022.40.6&#95;suppl.101 ., (© 2023. The Author(s).)

Purpose: Emerging data indicate comparable disease control and toxicity of normal postoperative fractionation and moderate hypofractionation radiation therapy (RT) in prostate cancer. In RADICALS-RT, patients were planned for treatment with either 66 Gy in 33 fractions (f) over 6.5 weeks or 52.5 Gy in 20f over 4 weeks. This non-randomized, exploratory analysis explored the toxicity of these 2 schedules in patients who had adjuvant RT., Methods and Materials: Information on RT dose was collected in all patients. The Radiation Therapy Oncology Group toxicity score was recorded every 4 months for 2 years, every 6 months until 5 years, then annually until 15 years. Patient-reported data were collected at baseline and at 1, 5, and 10 years using standard measures, including the Vaizey fecal incontinence score (bowel) and the International Continence Society Male Short-Form questionnaire (urinary incontinence). The highest event grade was recorded within the first 2 years and beyond 2 years and compared between treatment groups using the χ² test., Results: Of 634 patients, 217 (34%) were planned for 52.5 Gy/20f and 417 (66%) for 66 Gy/33f. In the first 2 years, grade 1 to 2 cystitis was reported more frequently among the 66 Gy/33f group (52.5 Gy/20f: 20% vs 66 Gy/33f: 30%; P = .04). After 2 years, grade 1 to 2 cystitis was reported in 16% in the 66-Gy group and 9% in the 52.5-Gy group (P = .08). Other toxic effects were similar in the 2 groups, and very few patients had any grade 3 to 4 toxic effects. Patients reported slightly higher urinary and fecal incontinence scores at 1 year than at baseline, but no clinically meaningful differences were reported between the 52.5 Gy/20f and 66 Gy/33f groups. Patient-reported health was similar at baseline and at 1 year and similar between the 52.5 Gy/20f and 66 Gy/33f groups., Conclusions: Severe toxic effects were rare after prostate bed radiation therapy with either 52.5 Gy/20f or 66 Gy/33f. Only modest differences were recorded in toxic effects or in patient-reported outcomes between these 2 schedules., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

A prominent toxicity of androgen suppression in patients with prostate cancer (PCa) is loss of skeletal muscle. Exercise may induce tumor suppression through the endocrinal function of skeletal muscle; however, this is currently unknown. In this review, we summarize our work demonstrating the acute and chronic myokine response to exercise and the tumor-suppressive effect of circulatory milieu alteration in PCa patients., (Copyright © 2023 by the American College of Sports Medicine.)

Purpose: Prostate-specific membrane antigen (PSMA) ligand positron emission tomography (PET) is increasingly integrated in prostate cancer management because of its diagnostic performance. We sought to evaluate the effect of PSMA-PET/computed tomography (CT)-guided intensification of radiation therapy (PSMAgRT) on patient outcomes. Here, we report secondary trial endpoints including the rate of new lesion detection, effect on prostate cancer management, and treatment-related toxicities., Methods and Materials: In this phase 2 cohort multiple randomized controlled trial across 2 institutions, men with prostate cancer planned for RT were randomly selected for PSMAgRT across 4 strata: oligometastatic, high risk (Cancer of the Prostate Risk Assessment ≥6 or cN1), salvage post-RT, and salvage postprostatectomy (RP). Primary endpoint was failure-free survival at 5 years, with analysis pending further follow-up. Secondary endpoints included new lesion detection yield of PSMA-PET/CT, acute and delayed toxicities, effect on prostate cancer management, and health-related quality-of-life outcomes. This trial is registered with ClinicalTrials.gov, identifier NCT03525288, companion to registry NCT03378856., Results: Between May 2018 and February 2021, 262 patients were enrolled and randomized. Nine patients were later excluded (5 control, 4 PSMAgRT), leaving 253 patients for analysis (23 oligometastatic, 86 high risk, 16 salvage post-RT, and 128 salvage post-RP). New lesions were detected in 45.5% of oligometastatic, 39.5% of high risk, 14.3% of salvage post-RT, and 51.6% of salvage post-RP. Overall, PSMA-PET/CT led to intensification of RT in over half of patients (52.0%), with minimal intensification of systemic therapy (4.0%). With a median follow-up of 12.9 months, this intensification was associated with 3 attributable grade 3+ events (2.5% of patients undergoing PSMAgRT) but no difference in the rate of grade 2+ events attributable to RT compared with controls (43%, both arms)., Conclusions: In this randomized trial, PSMA-PET/CT led to intensification of RT in more than half of patients. Longer follow-up is required to determine whether this intensification translates to effect on cancer control and long-term toxicity and health-related quality-of-life outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk., Methods: Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases., Results: Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel., Conclusion: In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population.[Media: see text].

Background: To characterize the impact of concomitant prostate cancer treatments with the use of relugolix, the oral GnRH receptor antagonist, in advanced prostate cancer, a subgroup and pharmacokinetic/pharmacodynamic analyses of the HERO study was undertaken., Patients and Methods: Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide or docetaxel 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant enzalutamide or docetaxel. A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Pharmacokinetic/pharmacodynamic analyses of 20 participants in the relugolix treatment group assessed the net effect of enzalutamide on exposure to relugolix., Results: Overall, 125 patients (13.4%) took concomitant therapies that could impact testosterone levels. Enzalutamide (n = 23) was the most frequently used therapy in the relugolix (2.7%) and leuprolide groups (1.9%). Docetaxel (n = 13) was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in <1% of population. Sensitivity analysis showed concomitant therapy did not impact the testosterone levels. Castration rates were similar with and without concomitant use of enzalutamide or docetaxel. No clinically relevant differences in adverse events were observed between subgroups in either treatment group. No differences in relugolix C trough or testosterone concentrations were observed, suggesting that any induction or inhibition properties of enzalutamide on relugolix metabolism result in a neutral net effect on relugolix exposure and testosterone suppression., Conclusion: Treatment with relugolix was associated with similar efficacy and safety profiles with and without concomitant enzalutamide or docetaxel. Standard-of-care use of relugolix in combination with these agents is supported by these data., Competing Interests: Disclosure DJG: grants from Acerta Pharmaceuticals, other from American Association for Cancer Research, grants and personal fees from Astellas, personal fees from Astrazeneca, personal fees from Axess Oncology, grants, personal fees and nonfinancial support from Bayer H/C Pharmaceuticals, grants and personal fees from BMS, grants from Calithera, grants and personal fees from Capio Biosciences, personal fees from EMD Serona, grants, personal fees and nonfinancial support from Exelixis, Inc, personal fees from Flatiron, personal fees from Ipsen, grants and personal fees from Janssen Pharmaceuticals, personal fees from Merck, Sharp & Dohme, personal fees from Michael J Hennessey Assoc, personal fees from Millennium Medical Publishing, personal fees from Modra Pharmaceuticals B.V., personal fees from Myovant Sciences, Inc, personal fees from NCI Genitourinary, personal fees from Nektar Therapeutics, grants and personal fees from Novartis, personal fees from Physician Education Resource, grants and personal fees from Pfizer, grants, personal fees and nonfinancial support from Sanofi, personal fees from UroGPO, personal fees and nonfinancial support from UroToday, personal fees from Vizuri Health Sciences, personal fees from Platform Q. FS: Advisory roles for Astellas Pharma, AstraZeneca/ MedImmune, Bayer, Janssen Oncology, and Sanofi; has received honoraria from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Janssen Oncology, and Sanofi; and has received research funding grants provided to the institution from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Pfizer, and Sanofi. MSC: Honoraria: Merck, Janssen Biotech, Bayer, Astellas Pharma, Myovant Sciences Consulting or Advisory Role: Merck, Janssen Biotech, MDxHealth, Bayer, Astellas Pharma, Myovant Sciences, TesoRx Pharma, Genomic Health, Ferring Pharmaceuticals, Precision Biopsy. DRS: No relevant conflicts. RT: No relevant conflicts. AB: No relevant conflicts. BT: grants from Myovant, during the conduct of the study; grants and personal fees from Astellas, grants and personal fees from Bayer, grants and personal fees from Janssen, grants and personal fees from Ferring, grants and personal fees from Sanofi. NDS: Consulting or Advisory Role: Bayer, Janssen Scientific Affairs, Dendreon, Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, AstraZeneca, Genentech, Myovant Sciences Speakers' Bureau: Janssen, Bayer, Dendreon. BB, BS, SL, AND DB: employees of Myovant Sciences, Inc., (Copyright © 2023. Published by Elsevier Inc.)

Background: To assess the association between of type and number of D'Amico high-risk criteria (DHRCs) with rates of cancer-specific mortality (CSM) in prostate cancer (PCa) patients treated with external beam radiotherapy (RT)., Methods: In the Surveillance, Epidemiology, and End Results database (2004-2016), we identified 34,908 RT patients with at least one DHRCs, namely prostate-specific antigen (PSA) >20 ng/dL (hrPSA), biopsy Grade Group (hrGG) 4-5, clinical T stage (hrcT) ≥T2c. Multivariable Cox regression models (CRM), as well as competing risks regression (CRR) model, which further adjust for other cause mortality, tested the association between DHRCs and 5-year CSM., Results: Of 34,908 patients, 14,777 (42%) exclusively harbored hrGG, 5641 (16%) hrPSA, 4390 (13%) had hrcT. Only 8238 (23.7%) harbored any combination of two DHRCs and 1862 (5.3%) had all three DHRCs. Five-year CSM rates ranged from 2.4% to 5.0% when any individual DHRC was present (hrcT, hrPSA, hrGG, in that order), versus 5.2% to 10.5% when two DHRCs were present (hrPSA+hrcT, hrcT+hrGG, hrPSA+hrGG, in that order) versus 14.4% when all three DHRCs were identified. In multivariable CRM hazard ratios relative to hrcT ranged from 1.07 to 1.76 for one DHRC, 2.20 to 3.83 for combinations of two DHRCs, and 5.11 for all three DHRCs. Multivariable CRR yielded to virtually the same results., Conclusions: Our study indicates a stimulus-response effect according to the type and number of DHRCs. This indicates potential for risk-stratification within HR PCa patients that could be applied in clinical decision making to increase or reduce treatment intensity., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Purpose: To test the effect of race/ethnicity on Social Security Administration (SSA) life tables' life expectancy (LE) predictions in localized prostate cancer (PCa) patients treated with either radical prostatectomy (RP) or external beam radiotherapy (EBRT). We hypothesized that LE will be affected by race/ethnicity., Patients and Methods: We relied on the 2004-2006 Surveillance, Epidemiology, and End Results database to identify D'Amico intermediate- and high-risk PCa patients treated with either RP or EBRT. SSA life tables were used to compute 10-year LE predictions and were compared to OS. Stratification was performed according to treatment type (RP/EBRT) and race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic/Latino, and Asian)., Results: Of 55,383 assessable patients, 40,490 were non-Hispanic White (RP 49.3% vs. EBRT 50.7%), 7194 non-Hispanic Black (RP 41.3% vs. EBRT 50.7%), 4716 Hispanic/Latino (RP 51.0% vs. EBRT 49.0%) and 2983 were Asian (RP 41.6% vs. EBRT 58.4%). In both RP and EBRT patients, OS exceeded life tables' LE predictions, except for non-Hispanic Blacks. However, in RP patients, the magnitude of the difference was greater than in EBRT. Moreover, in RP patients, OS of non-Hispanic Blacks virtually perfectly followed predicted LE. Conversely, in EBRT patients, the OS of non-Hispanic Black patients was worse than predicted LE., Conclusions: When comparing SEER-derived observed OS with SSA life table-derived predicted life expectancy, we recorded a survival disadvantage in non-Hispanic Black RP and EBRT patients, which was not the case in the three other races/ethnicities (non-Hispanic Whites, Hispanic/Latinos, and Asians). This discrepancy should ideally be confirmed within different registries, countries, and tumor entities. Furthermore, the source of these discrepant survival outcomes should be investigated and addressed by health care politics., (© 2022. The Author(s).)

Background: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management., Objective: To present consensus voting results for select questions from APCCC 2022., Design, Setting, and Participants: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3., Outcome Measurements and Statistical Analysis: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement., Results and Limitations: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis., Conclusions: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pain is an important dimension of quality-of-life in patients with metastatic castrate-sensitive prostate cancer (mCSPC). However, it is unclear if dynamic change in pain over time can predict for overall survival (OS) or progression-free survival (PFS) in these patients., Methods: This is an exploratory analysis of LATITUDE, a phase III randomized study, in which men with de novo mCSPC were randomized to receive either ADT plus abiraterone versus ADT alone. Information was collected on patient-reported worst pain score (WPS) and pain-interference score (PIS) from the Brief Pain Inventory-Short Form. A Bayesian joint modelling approach was used determine the association of dynamic change in WPS and PIS with OS and PFS., Results: Overall, 1125 patients with at least 3 measurements on pain scores were eligible. On Cox multivariable regression, increase in baseline WPS was associated with inferior OS (hazard ratio [HR] 1.049 [95% confidence intervals [CI] 1.015-1.085]; time dependent area under curve [tAUC] 0.64) and PFS (HR 1.045 [1.011-1.080]; tAUC: 0.64). Increase in baseline PIS was associated with inferior OS (HR 1.062 [1.020-1.105]; tAUC: 0.63) but not with PFS (HR 1.038 [0.996-1.08]). On independent joint models, an increase in the current value of WPS by 1-unit was associated with inferior OS (HR 1.316 [1.258-1.376]; tAUC 0.74) and PFS (HR 1.319 [1.260-1.382]; tAUC 0.70). Similar association was seen for increase in the current value of PIS with OS (HR 1.319 [1.261-1.381]; tAUC 0.73) and PFS (HR 1.282 [1.224-1.344]; tAUC 0.73)., Conclusions: The above findings highlight the potential dynamic interplay between patient-reported pain with OS and PFS in mCSPC. Compared to baseline pain, such dynamic assessment of pain was found to have superior predictive ability and thus has the potential to tailor subsequent treatment based on response to initial therapy beyond its role as a very important dimension of quality-of-life., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Metastatic castrate sensitive prostate cancer (mCSPC) is a heterogeneous disease state with variable prognosis. Although several life-prolonging systemic agents are available, there is no robust multivariable model to predict prognosis and improve risk stratification in mCSPC. The objective of this study was to build and validate a multivariable prognostic model to predict overall survival (OS) in mCSPC., Methods: We used data from LATITUDE, a phase III randomized controlled trial in which men with de novo mCSPC were randomly allocated to either ADT plus abiraterone or ADT with placebo. Patients with non-missing data (n = 1,058) were randomly split in a 70:30 ratio to training (n = 743) and testing (n = 315) sets. Elastic net regression was used for variable selection. A multivariable Cox regression model for OS was then fitted using the selected variables. The predictive accuracy of the model was assessed on the testing set using the time-dependent area under curve (tAUC) with bootstrapped confidence intervals [CI] primarily for OS and secondarily for radiographic progression-free survival (rPFS)., Results: The 11 prognostic variables in the final model were performance status, number of skeletal metastases, Gleason score, presence of liver metastasis, worst pain score, albumin, lactate dehydrogenase, prostate-specific antigen, hemoglobin, and treatment regimen. The tAUC for predicting OS at 2- and 3-years was 0.74 (95% CI, 0.67-0.80) and 0.72 (95% CI, 0.65-0.77), respectively. The tAUC for rPFS at 2- and 3-years was 0.72 (95% CI, 0.65-0.77) and 0.77 (95% CI, 0.70-0.82), respectively., Conclusions: A prognostic model for men with de novo mCSPC was developed and validated in an independent testing set. Our model had high accuracy for predicting OS and rPFS. The model includes commonly used clinical and laboratory parameters and can guide risk stratification of these patients for participation in future trials., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of 11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized prostate cancer., Materials and Methods: We studied 1,793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors in the prospective PROCURE cohort, for which preoperative plasma samples were obtained prior to radical prostatectomy. Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7), were quantified using liquid chromatography-tandem mass spectrometry. Circulating levels were evaluated in relation to prognostic factors, disease-free survival, and metastasis-free survival using multivariable Cox proportional hazards models., Results: At a median follow-up of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease, and 168 deceased. Higher levels of 11-hydroxytestosterone and 11-ketotestosterone were observed in men with PSA >20 ng/mL and positive nodal status ( P < .05). In multivariable analyses, no significant association between 11-oxygenated androgens and disease-free survival was observed. Adrenal 11β-hydroxyandrostenedione, the predominant androgenic 11-ketotestosterone, and its metabolite 11-ketoandrosterone, modeled as quartiles, were associated with metastasis-free survival ( P = .06, P = .03, and P = .008, respectively). Significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in patients on 5α-reductase inhibitors ( P < .001)., Conclusions: Preoperative circulating 11-oxygenated androgen levels are associated with metastasis-free survival in men with localized prostate cancer undergoing radical prostatectomy and are affected by 5α-reductase inhibitor treatment.

Background: The effect of positive surgical margins (PSM) on cancer specific mortality (CSM) in high/very high-risk (HR/VHR) prostate cancer (PCa) with aggressive Gleason Grade Group (GGG) is unknown. We tested PSM effect on CSM in this setting, in addition to testing of radiotherapy (RT) benefit in PSM patients., Methods: We relied on Surveillance, Epidemiology, and End Results database (2010-2015), focusing on HR/VHR patients with exclusive GGG 4-5 at radical prostatectomy (RP). Kaplan-Meier plots and multivariable Cox regression models tested the relationship between PSM and CSM. Moreover, the effect of RT on CSM was explored in PSM patients., Results: Of 3383 HR/VHR patients, 15.1% (n = 511) exhibited PSM. Patients with PSM harbored higher rates of GGG 5 (60.1% vs. 50.9%, p < 0.001), pathologic tumor stage T3a (69.1% vs. 45.2%, p < 0.001) and lymph node involvement (14.1% vs. 9.4%, p < 0.001), relative to patients without PSM. PSM rates decreased over time (2010-2015) from 16.0% to 13.6%. Seven-year CSM-free survival rates were 91.6% versus 95.7% in patients with and without PSM, respectively. In multivariable Cox regression models, PSM was an independent predictor of CSM (hazard ratio = 1.6, p = 0.040) even after adjustment for age, prostate specific antigen, pathologic tumor stage and lymph node status. Finally, in PSM patients, RT delivery did not reduce CSM in either univariable or multivariable Cox regression models., Conclusions: In HR/VHR PCa patients with exclusive GGG 4-5, PSM at RP adversely affect survival. Moreover, RT has no protective effect on CSM. In consequence, lowest possible PSM rates are crucial in such patients., (© 2022 Wiley Periodicals LLC.)

The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28. In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Naturally occurring germline gene deletions (KO) represent a unique setting to interrogate gene functions. Complete deletions and differential expression of the human glycosyltransferase UGT2B17 and UGT2B28 genes are linked to prostate cancer (PCa) risk and progression, leukaemia, autoimmune and other diseases., Methods: The systemic metabolic consequences of UGT deficiencies were examined using untargeted and targeted mass spectrometry-based metabolomics profiling of carefully matched, treatment-naive PCa cases., Results: Each UGT KO differentially affected over 5% of the 1545 measured metabolites, with divergent metabolic perturbations influencing the same pathways. Several of the perturbed metabolites are known to promote PCa growth, invasion and metastasis, including steroids, ceramides and kynurenine. In UGT2B17 KO, reduced levels of inactive steroid-glucuronides were compensated by sulfated derivatives that constitute circulating steroid reservoirs. UGT2B28 KO presented remarkably lower levels of oxylipins paralleled by reduced inflammatory mediators, but higher ceramides unveiled as substrates of the enzyme in PCa cells., Conclusion: The distinctive and broad metabolic rewiring caused by UGT KO reinforces the need to examine their unique and divergent functions in PCa biology., (© 2022. The Author(s).)

Background: Detection of skeletal metastases in patients with prostate cancer or breast cancer remains a major clinical challenge. We aimed to compare the diagnostic performance of 99m Tc-methylene diphosphonate ( 99m Tc-MDP) single-photon emission CT (SPECT) and 18 F-sodium fluoride ( 18 F-NaF) PET-CT for the detection of osseous metastases in patients with high-risk prostate or breast cancer., Methods: MITNEC-A1 was a prospective, multicentre, single-cohort, phase 3 trial conducted in ten hospitals across Canada. Patients aged 18 years or older with breast or prostate cancer with a WHO performance status of 0-2 and with high risk or clinical suspicion for bone metastasis, but without previously documented bone involvement, were eligible. 18 F-NaF PET-CT and 99m Tc-MDP SPECT were done within 14 days of each other for each participant. Two independent reviewers interpreted each modality without knowledge of other imaging findings. The primary endpoint was the overall accuracy of 99m Tc-MDP SPECT and 18 F-NaF PET-CT scans for the detection of bone metastases in the per-protocol population. A combination of histopathological, clinical, and imaging follow-up for up to 24 months was used as the reference standard to assess the imaging results. Safety was assessed in all enrolled participants. This study is registered with ClinicalTrials.gov, NCT01930812, and is complete., Findings: Between July 11, 2014, and March 3, 2017, 290 patients were screened, 288 of whom were enrolled (64 participants with breast cancer and 224 with prostate cancer). 261 participants underwent both 18 F-NaF PET-CT and 99m Tc-MDP SPECT and completed the required follow-up for statistical analysis. Median follow-up was 735 days (IQR 727-750). Based on the reference methods used, 109 (42%) of 261 patients had bone metastases. In the patient-based analysis, 18 F-NaF PET-CT was more accurate than 99m Tc-MDP SPECT (84·3% [95% CI 79·9-88·7] vs 77·4% [72·3-82·5], difference 6·9% [95% CI 1·3-12·5]; p=0·016). No adverse events were reported for the 288 patients recruited., Interpretation: 18 F-NaF has the potential to displace 99m Tc-MDP as the bone imaging radiopharmaceutical of choice in patients with high-risk prostate or breast cancer., Funding: Canadian Institutes of Health Research., Competing Interests: Declaration of interests FB is co-founder, director, consultant, and shareholder of Alpha-9 Theranostics, a radiopharmaceutical company, outside the submitted work. UM reports consulting fees from POINT Biopharma, outside the submitted work. KZ reports grants or contracts from Canadian Cancer Society, Ontario Institute for Cancer Research, Invicro, General Electric, Fusion Pharmaceuticals, and Centre for Probe Development and Commercialization; payment or honoraria for lectures from Jubilant Draximage and Canadian Urological Association; and leadership or fiduciary role in the Society of Nuclear Medicine and Molecular Imaging (SNMMI), American College of Nuclear Medicine, and Intersocietal Accreditation Commission, all outside the submitted work. GA reports a leadership role in the SNMMI, outside the submitted work. FS reports grants or contracts from Astellas, AstraZeneca, Bayer, Janssen, Merck, Myovant, Pfizer, and Sanofi; consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Myovant, Pfizer, Sanofi, Tolmar, and Abbvie; and payment or honoraria for lectures from Astellas, AstraZeneca, Bayer, Janssen, Merck, Myovant, Pfizer, Sanofi, Tolmar, and Abbvie, all outside the submitted work. BJE reports consulting fees from Seagen Canada, Pfizer, Merck, EMD Serono, and Bayer; payment or honoraria for lectures from Pfizer, EMD Serono, and Merck; and support for attending meetings from EMD Serono, all outside the submitted work. PB reports participation in advisory boards of Janssen, Merck, Roche/Genentech, BMS, Urogen, Asieris, EMD Serono, Bayer, Astellas, AbbVie, AstraZeneca, Ferring, Fergene, Sanofi, H3-Biomedicine, Nonagen, miR Scientific, Stimit, Prokarium, Tolmar, Protara Therapeutics, Verity, Sesen Biosciences; consulting fees from NanOlogy; and payment or honoraria for lectures from Janssen, Bayer, TerSera, Ferring, Pfizer, H3-Biomedicine, and Biosyent, all outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Upgrading and/or upstaging in low-risk prostate cancer (PCa) patients may represent an indication for active treatment instead of active surveillance (AS). We addressed contemporary upgrading and/or upstaging rates in a large population based-cohort of low-risk PCa patients., Materials and Methods: Whitin the SEER database (2010-2015), NCCN low-risk PCa patients were identified across management modalities: radical prostatectomy (RP), radiotherapy (RT) and non-local treatment (NLT). In RP patients, upgrading and/or upstaging rates were assessed in logistic regression models., Results: Overall, of 27,901 low-risk PCa patients, 38% underwent RP vs 28% RT vs 34% NLT. RP patients were the youngest and harbored the highest percentage of positive cores and a higher rate of cT2a than NLT. At RP, 46.2% were upgraded to GGG ≥ 2, 6.0% to GGG ≥ 3 and 10.5% harbored nonorgan-confined stage (NOC, pT3-4 or pN1). Of NOC patients, 1.6% harbored GGG ≥ 3, 6.3% harbored GGG2 and 2.6% harbored GGG1. Of pT2 patients, 4.4% harbored GGG ≥ 3, 33.9% harbored GGG2 and 51.3% harbored GGG1. Age, PSA, percentage of positive cores and number of positive cores independently predicted the presence of NOC and/or GGG ≥ 3, but with low accuracy (63.9%)., Conclusions: In low-risk PCa, critical changes between tumor grade and stage at biopsy vs RP may be expected in very few patients: NOC with GGG ≥ 3 in 1.6% and NOC with GGG2 in 6.3%. Other patients with upgrading and/or upstaging combinations will invariably harbor either pT2 or GGG1 that far less critically affect PCa prognosis., (© 2022. The Author(s).)

Purpose: To investigate pathological stage at radical prostatectomy (RP) using the "Partin tables" approach in NCCN high-risk (HR) prostate cancer (PCa) patients., Materials and Methods: Within the SEER 2010 to 2016 database, we identified 7,718 NCCN HR PCa patients. Cross-tabulation was used to illustrate the distribution of organ confined disease (OC, pT2), extra-prostatic extension (EPE, pT3a), seminal vesicles invasion (SVI, pT3b), lymph node invasion (LNI, pT2N1), extra-prostatic and lymph node invasion (EPE + LNI, pT3aN1), and seminal vescicale and lymph node invasion (SVI + LNI, pT3bN1), according to preoperative criteria, which consisted in PSA, clinical T stage, biopsy Gleason Score (GS). Binomial 95%CI was constructed for the reported proportions., Results: Median (IQR) PSA levels was 9 (6-20) ng/ml. The majority of patient harbored cT1c (51%) followed by cT2 (35%) and cT3 (14%) stage. Most patients exhibited GS 4+4 (43%). Overall, 87 vs. 15 vs. 2% of patients harbored only 1 vs. 2 vs. all 3 HR criteria. At RP, OC, EPE, SVI, and LNI rates were respectively 36%, 27%, 17%, and 19%. Highest levels of OC were recorded for cT1c, PSA <10 ng/mL and biopsy GS4+4. Conversely, EPE, SVI and LNI were the highest in patients with cT3, PSA ≥20 ng/mL and GS 5+5. After stratification according to clinical stages, OC rates decreased with increasing PSA levels and GS. Conversely, EPE, SVI and LNI rates increased with increasing PSA and GS., Conclusion: We provide a lookup table to illustrate the relationship between clinical and pathological characteristics in NCCN HR PCa patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Intermediate risk prostate cancer (IR PCa) may exhibit a wide array of phenotypes, from favorable to unfavorable. NCCN criteria help distinguishing between favorable versus unfavorable subgroups. We studied and attempted to improve this classification., Methods: Within the SEER database 2010-2016, we identified 19,193 IR PCa patients treated with radical prostatectomy. A multivariable logistic regression model predicting unfavorable IR PCa was developed and externally validated, in addition to a head-to-head comparison with NCCN IR PCa stratification., Results: Model development (development cohort N.=13,436: 3585 unfavorable versus 9851 favorable) rested on age, PSA, clinical T stage, biopsy Gleason Grade Group (GGG) and percentage of positive cores. All were independent predictors of unfavorable IR PCa. In external validation cohort (N.=5757: 1652 unfavorable versus 4105 favorable), NCCN stratification was 61.8% accurate in discriminating between favorable versus unfavorable, compared to 67.6% for nomogram, which exhibited excellent calibration, less pronounced departures from ideal prediction and greater net-benefit in decision curve analyses (DCA) than NCCN stratification. The optimal nomogram cutoff misclassified 312 of 1976 patients (15.8%) versus 598 of 2877 (20.8%) for NCCN stratification. Of NCCN misclassified patients, 90.0% harbored pT3-4 stages versus 84.6% of nomogram., Conclusions: The newly developed, externally validated nomogram discriminates better between favorable versus unfavorable IR PCa, according to overall accuracy, calibration, DCA, and actual numbers and stage distribution of misclassified patients.

Context: Randomized controlled trials (RCTs) have shown that addition of docetaxel or androgen receptor axis-targeted therapy (ARAT) to androgen deprivation therapy (ADT) or addition of ARAT to ADT and docetaxel improves overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC). However, it is unknown whether docetaxel, when given as part of triplet therapy, has an independent OS benefit., Objective: To compare the efficacy of ADT plus ARAT with the triplet of ADT, ARAT, and docetaxel through a network meta-analysis (NMA) of RCTs in mHSPC., Evidence Acquisition: Bibliographic databases and conference proceedings were searched in March 2022 for RCTs that evaluated the addition of docetaxel, ARAT, or both to ADT in mHSPC. The primary endpoint was OS. Standard random-effect NMA and Bayesian analyses were performed to compare ADT plus ARAT with triplet therapy., Evidence Synthesis: Eleven RCTs (n = 11 546) were eligible. Compared with ADT plus ARAT, the triplet had a nonsignificant OS benefit (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.68-1.16), while ADT plus docetaxel (HR 1.16 [0.94-1.43]) and ADT alone (HR 1.46 [1.30-1.64]) had an increased risk of death. By P-score ordering, the triplet was the most effective treatment strategy (P score = 0.936) followed by ADT plus ARAT (P score = 0.704). The triplet had a 77% likelihood of being the best treatment strategy compared with a 23% likelihood for ADT plus ARAT., Conclusions: The triplet of ADT, ARAT, and docetaxel was the highest ranked treatment strategy, but it did not confer a statistically significant OS benefit over ADT plus ARAT. This NMA provides the highest-level comparative evidence for these treatment approaches in the initial management of mHSPC., Patient Summary: We synthesized the available evidence from clinical trials conducted in newly diagnosed metastatic prostate cancer to compare the survival of patients receiving triplet therapy (androgen receptor axis-targeted therapy [ARAT], androgen deprivation therapy [ADT], and docetaxel) with those receiving only ARAT and ADT. We conclude that the triplet is a somewhat more effective treatment approach., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The numbers needed to image to identify pelvic lymph node and/or distant metastases in newly diagnosed prostate cancer (PCa) patients according to risk level are unknown., Methods: Relying on Surveillance, Epidemiology, and End Results (2010-2016), we tabulated rates and proportions of patients with (a) lymph node or (b) distant metastases according to National Comprehensive Cancer Network (NCCN) risk level and calculated the number needed to image (NNI) for both endpoints. Multivariable logistic regression analyses were performed., Results: Of 145,939 newly diagnosed PCa patients assessable for analyses of pelvic lymph node metastases (cN1), 4559 (3.1%) harbored cN1 stage: 13 (0.02%), 18 (0.08%), 63 (0.3%), 512 (2.8%), and 3954 (14.9%) in low, intermediate favorable, intermediate unfavorable, high, and very high-risk levels. These resulted in NNI of 4619, 1182, 319, 35, and 7, respectively. Of 181,109 newly diagnosed PCa patients assessable for analyses of distant metastases (M1 a-c ), 8920 (4.9%) harbored M1 a-c stage: 50 (0.07%), 45 (0.1%), 161 (0.5%), 1290 (5.1%), and 7374 (22.0%) in low, intermediate favorable, intermediate unfavorable, high, and very high-risk. These resulted in NNI of 1347, 602, 174, 20, and 5, respectively., Conclusions: Our observations perfectly validated the NCCN recommendations for imaging in newly diagnosed high and very high-risk PCa patients. However, in unfavorable intermediate-risk PCa patients, in whom bone and soft tissue imaging is recommended, the NNI might be somewhat elevated to support routine imaging in clinical practice., (© 2022 Wiley Periodicals LLC.)

Objective: Not infrequently patients are diagnosed with clinically localized prostate based on a single positive biopsy core exhibiting Gleason grade group 1 (GGG1) with variable prostate-specific antigen (PSA) levels. We investigated treatment patterns and hypothesized that regardless of PSA in cT1- to cT2-stage patients, presence of GGG3/GGG4/GGG5 and/or non-organ confined stage will rarely be identified., Materials and Methods: Within the Surveillance, Epidemiology, and End Results database (2010-2015), clinically localized prostate cancer (CaP) patients with PSA ≤ 50 ng/ml and a single positive GGG1 biopsy core were identified. Overall treatment rates were examined, estimated annual percentage changes and logistic regression analyses were fitted to test for no-local treatment. Subsequently, rates of upgrading (GGG3/GGG4/GGG5) and/or upstaging (≥pT3 and/or pN1) were investigated in radical prostatectomy patients., Results: 13,342 clinically localized CaP patients harbored single GGG1 positive biopsy core at diagnosis. No local treatment was recorded in 5,235 (53.0%) cT1-stage vs. in 1,039 (49.0%) cT2-stage patients. No local treatment rates increased over time from 35.0% to 67.0% vs. 34.0% to 63.0% in cT1 vs. cT2 patients, observations were confirmed in logistic regression analyses (cT1: multivariable odds ratio [mOR]: 1.39; cT2: mOR: 1.33). In radical prostatectomy treated cT1-patients (n = 2,293) and cT2-patients (n = 659), upgrading vs. upstaging vs. upgrading/upstaging combined was 6.1%, 6.5%, 11.0% and 6.2%, 5.0%, 9.9% respectively., Conclusions: In single GGG1 positive biopsy core CaP patients, the combined proportion of upgrading and upstaging should be expected in one tenth. In consequence, the overwhelming majority harbors favorable grade and stage that is compatible with no local treatment., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Some high-risk prostate cancer (PCa) patients may show more favorable Gleason pattern at radical prostatectomy (RP) than at biopsy., Objective: To test whether downgrading could be predicted accurately., Design, Setting, and Participants: Within the Surveillance, Epidemiology and End Results database (2010-2016), 6690 National Comprehensive Cancer Network (NCCN) high-risk PCa patients were identified., Outcome Measurements and Statistical Analyses: We randomly split the overall cohort between development and validation cohorts (both n = 3345, 50%). Multivariable logistic regression models used biopsy Gleason, prostate-specific antigen, number of positive prostate biopsy cores, and cT stage to predict downgrading. Accuracy, calibration, and decision curve analysis (DCA) tested the model in the external validation cohort., Results and Limitations: Of 6690 patients, 50.3% were downgraded at RP, and of 2315 patients with any biopsy pattern 5, 44.1% were downgraded to RP Gleason pattern ≤4 + 4. Downgrading rates were highest in biopsy Gleason pattern 5 + 5 (84.1%) and lowest in 3 + 4 (4.0%). In the validation cohort, the logistic regression model-derived nomogram predicted downgrading with 71.0% accuracy, with marginal departures (±3.3%) from ideal predictions in calibration. In DCA, a net benefit throughout all threshold probabilities was recorded, relative to treat-all or treat-none strategies and an algorithm based on an average downgrading rate of 50.3%. All steps were repeated in the subgroup with any biopsy Gleason pattern 5, to predict RP Gleason pattern ≤4 + 4. Here, a second nomogram (n = 2315) yielded 68.0% accuracy, maximal departures from ideal prediction of ±5.7%, and virtually the same DCA pattern as the main nomogram., Conclusions: Downgrading affects half of all high-risk PCa patients. Its presence may be predicted accurately and may help with better treatment planning., Patient Summary: Downgrading occurs in every second high-risk prostate cancer patients. The nomograms developed by us can predict these probabilities accurately., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence., Objective: To present the voting results from APCCC 2021., Design, Setting, and Participants: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions., Outcome Measurements and Statistical Analysis: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process., Results and Limitations: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material., Conclusions: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: Several recent randomised trials have evaluated the role of combination systemic treatment using androgen deprivation therapy (ADT) plus chemotherapy or an androgen receptor signaling inhibitor (ARSI) in patients with high-risk and/or unfavourable nonmetastatic prostate cancer (nmPC)., Objective: To assess the outcomes associated with adding combination systemic treatment to primary definitive local therapy in patients with high-risk and/or unfavourable nmPC., Evidence Acquisition: We queried the PubMed, Web of Science, and Scopus databases and conference abstracts to identify prospective randomised trials examining the value of adding chemotherapy or an ARSI to ADT and primary local therapy with curative intent for nmPC. The primary endpoints were overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS), and failure-free survival (FFS). Secondary endpoints included adverse events (AEs) and pathologic outcomes., Evidence Synthesis: We identified 15 randomised studies, of which nine evaluated chemohormonal and six investigated ARSI-based treatment strategies. In both radical prostatectomy (RP) and radiation therapy (RT) settings, addition of docetaxel to ADT was associated with significantly better CSS (pooled hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49-0.95; p = 0.025), MFS (pooled HR 0.82, 95% CI 0.71-0.95; p = 0.008), and FFS (pooled HR 0.70, 95% CI 0.62-0.79; p < 0.001); the difference did not meet the conventional level of statistical significance for OS (pooled HR 0.86, 95% CI 0.73-1.01; p = 0.072). For patients treated with RT alone, docetaxel-based combination treatment did not meet the significance threshold set for OS (p = 0.3), CSS (p = 0.072), or MFS (p = 0.079), but the difference for FFS was statistically significant (pooled HR 0.72, 95% CI 0.63-0.84; p < 0.001). On network meta-analyses including RT studies, ARSI + ADT outperformed docetaxel + ADT for survival endpoints and had a more favourable AE profile., Conclusions: Intensification of systemic therapy with docetaxel or an ARSI in addition to ADT improves oncologic endpoints in high-risk and/or unfavourable nmPC treated with local definitive therapy. The highest efficacy was achieved with ARSI + ADT, specifically in patients treated with RT., Patient Summary: Our findings highlight that selected patients with high-risk nonmetastatic prostate cancer benefit from intensification of systemic therapy beyond hormonal treatment., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

What Is This Summary About?: This is a summary of a publication about the ARASENS trial, which was published in the New England Journal of Medicine in February 2022. The trial includes 1,306 men with a type of prostate cancer called metastatic, hormone-sensitive prostate cancer (also called mHSPC). In the trial, researchers wanted to learn if combining a treatment called darolutamide (also known by the brand name Nubeqa ® ) with two other medicines called androgen deprivation therapy (also called ADT) and docetaxel (brand name Taxotere ® ) could help treat patients with mHSPC better than placebo plus ADT and docetaxel. ADT with docetaxel is a treatment used for patients with mHSPC. Darolutamide is an approved treatment for a different type of prostate cancer called non-metastatic, castration-resistant prostate cancer (also called nmCRPC)., What Were the Results?: The trial results showed that combining darolutamide with ADT and docetaxel increased the chance of survival and lowered the risk of death by 32.5% compared to combining ADT and docetaxel with placebo instead. Compared to patients who received the placebo, patients who received darolutamide had a delay in: their cancer becoming castration-resistant worsening pain having cancer-related bone fractures or related symptoms needing additional therapies for cancer The percentage of trial patients who had medical problems during the trial, also called adverse events, was similar between trial patients who received darolutamide and those who received the placebo., What Do the Results of the Study Mean?: Combining darolutamide with ADT and docetaxel helped treat trial patients with mHSPC better than placebo with ADT and docetaxel. Darolutamide in combination with ADT and docetaxel could be a treatment option for patients with mHSPC. Patients should always talk to their doctors and nurses before making any decisions about their treatment. This summary also includes perspectives on the ARASENS trial and prostate cancer from 3 members of the patient community. ClinicalTrials.gov NCT number: NCT02799602.