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Item does not contain fulltext, 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 manage

Contains fulltext : 297160.pdf (Publisher’s version ) (Closed access), BACKGROUND: PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis. METHODS: This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0-1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system-interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 [two-sided]), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting. FINDINGS: Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1-40·3) for olaparib p

Introduction & Objectives: In the previously reported ARCHES trial (NCT02677896), ENZA + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT improved overall survival (OS) and clinical outcomes in men with mHSPC. This post hoc analysis assessed clinical endpoints in menwith mHSPC who reached undetectable PSA levels on ENZA+ADT or PBO+ADT and investigated predictors of such a PSA decline.Materials & Methods: Men with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO+ADT, stratified by disease volume and priordocetaxel. Post hoc analyses were based on reaching undetectable (<0.2 ng/mL) or detectable (>=0.2 ng/mL) PSA levels during study treatmentand included men with both detectable baseline PSA (>=0.2 ng/mL) and postbaseline PSA measurements (ENZA+ADT, n=507; PBO+ADT, n=504).Stepwise multivariate analysis was conducted on variables from a univariate logistic regression model to identify clinical factors that significantlycorrelated with PSA decline to undetectable levels. Result(s): PSA undetectable groups had fewer men with high-volume disease, Gleason scores >=8, and de novo mHSPC; both ENZA+ADT groupshad more men with these clinical factors. Men who reached undetectable PSA levels had improved clinical outcomes; e.g., delayed radiographicprogression and improved OS (Table). Men on ENZA+ADT (n=348 [68.6%]) were almost 4 times more likely to reach undetectable PSA than menon PBO+ADT (n=89 [17.7%]). Predictors of reaching undetectable PSA on ENZA+ADT were the absence of de novo disease (M0 vs M1: odds ratio[OR] 4.5; p=0.0003) and the presence of bone only (OR 2.0; p=0.0009) or soft tissue only (OR 2.4; p=0.0193) vs bone + soft tissue metastases. Menwho reached undetectable PSA on ENZA+ADT had more treatment-emergent adverse events (TEAEs) but fewer serious and grade 3-4 TEAEs vsthose with detectable PSA levels. Safety across treatment arms was similar to prior findings. Conclusion(s): Men with mHSPC in ARCHES who reached undetectable PSA levels had im

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 44.6 months), 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P < .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.

Background: Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is overexpressed on the surface of prostate cancer cells with low or no expression on normal tissue. AMG 509 is a bispecific XmAb 2+1 T-cell engager that simultaneously binds to STEAP1 on tumor cells and the CD3 complex on T cells resulting in T-cell mediated lysis of STEAP1-expressing cells. AMG 509 demonstrated significant antitumor activity in preclinical prostate cancer models. Method(s): This 4-part, first-in-human study will evaluate AMG 509 in pts with mCRPC previously treated with novel hormonal therapy (NHT) and will assess the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 to establish the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D). Part 1 is currently enrolling pts previously treated with NHT and up to 2 prior taxanes. As of 31 January 2022, 60 of up to 110 pts have been enrolled for treatment with intravenous (IV) AMG 509 with initial inpatient dosing followed by outpatient treatment. Part 2 will evaluate subcutaneous dosing of AMG 509 in the same patient population as in Part 1. Part 3 will explore AMG 509 IV dosing in chemotherapy-naive pts who have been treated previously with one NHT and will provide additional data on the safety, PK, efficacy, pharmacodynamics, and correlative biomarkers at the MTD or RP2D determined in Part 1. Part 4 will evaluate the combination of AMG 509 with abiraterone (Part 4A) or enzalutamide (Part 4B) in pts previously treated with one NHT and up to 1 prior taxane for castration-sensitive disease. Primary outcome measures include dose-limiting toxicities, treatment-emergent and treatment-related adverse events, and change in clinical and laboratory parameters. Key secondary outcome measures include PK, objective response per RECIST 1.1, prostate-specific antigen response, progression-free survival, and overall survival. Key inclusion criteria are men >=18 years of age with pathologically confirmed mCRPC

Background: While enzalutamide plus androgen deprivation therapy (ADT) significantly reduces the risk of radiographic progression-free survival (rPFS) and improves overall survival in metastatic hormone-sensitive prostate cancer (mHSPC), the efficacy in clinically relevant subgroups of patients based on prior local and systemic therapy, disease volume, and risk has not been analyzed to date. These post hoc analyses of the phase 3 ARCHES trial (NCT02677896) evaluated the efficacy of enzalutamide plus ADT according to prior local and systemic treatment, disease volume, and risk, assessed at trial baseline. Method(s): In ARCHES, a global, double-blind, placebo-controlled, phase 3 study, 1150 patients with mHSPC were randomized 1:1 to receive enzalutamide (160 mg/day) plus ADT or placebo plus ADT, stratified by prior docetaxel therapy and disease volume. Primary endpoint was rPFS. Secondary endpoints included time to prostate-specific antigen progression, symptomatic skeletal events, and prostate-specific antigen and radiographic responses. Analyses of clinical endpoints were completed by prior local therapy, prior docetaxel exposure, CHAARTED (NCT00309985)-defined disease volume, and LATITUDE (NCT01715285)-defined risk groups. Result(s): Patients were randomized to enzalutamide plus ADT (n = 574) and placebo plus ADT (n = 576). Enzalutamide plus ADT significantly improved rPFS (hazard ratio: 0.39; p < 0.0001), with similar improvements reported in all subgroups based on prior local and docetaxel treatment, disease volume, and risk. Treatment benefits were observed with enzalutamide plus ADT in multiple secondary clinical endpoints in the overall population and all subgroups. Conclusion(s): Enzalutamide plus ADT demonstrated clinical benefit across all patients with mHSPC, irrespective of prior local and systemic treatment, disease volume, and risk.Copyright © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

Background: Enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival versus ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in ARCHES (NCT02677896). While health-related quality of life (HRQoL) was generally maintained in the intent-to-treat population, we further analyzed patient-reported outcomes (PROs) in defined subgroups. Method(s): ARCHES was a randomized, double-blind, placebo-controlled, phase 3 study. Patients with mHSPC received enzalutamide (160 mg/day) plus ADT (n = 574) or placebo plus ADT (n = 576). Questionnaires, including the Functional Assessment of Cancer Therapy-Prostate, Brief Pain Inventory-Short Form, and EuroQol 5-Dimension, 5-Level (EQ-5D-5L), were completed at baseline, Week 13, and every 12 weeks until disease progression. PRO endpoints were time to first confirmed clinically meaningful deterioration (TTFCD) in HRQoL or pain. Subgroups included prognostic risk, pain/HRQoL, prior docetaxel, and local therapy (radical prostatectomy [RP] and/or radiotherapy [RT]). Result(s): There were several between-treatment differences in TTFCD for pain and functioning/HRQoL PROs. Enzalutamide plus ADT delayed TTFCD for worst pain in the prior RT group (not reached vs. 14.06 months; hazard ratio [HR]: 0.56 [95% confidence interval: 0.34-0.94]) and pain interference in low-baseline-HRQoL group (19.32 vs. 11.20 months; HR: 0.64 [0.44-0.94]) versus placebo plus ADT. In prior/no prior RP, prior RT, prior local therapy, no prior docetaxel, mild baseline pain, and low-risk subgroups, TTFCD was delayed for the EQ-5D-5L visual analog scale. Conclusion(s): Enzalutamide plus ADT provides clinical benefits in defined patient subgroups versus ADT alone, while maintaining lack of pain and high HRQoL, with delayed deterioration in several HRQoL measures.Copyright © 2022 The Authors. The Prostate published by Wiley Periodicals LLC.

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements.

Background: While enzalutamide plus androgen deprivation therapy (ADT) significantly reduces the risk of radiographic progression-free survival (rPFS) and improves overall survival in metastatic hormone-sensitive prostate cancer (mHSPC), the efficacy in clinically relevant subgroups of patients based on prior local and systemic therapy, disease volume, and risk has not been analyzed to date. These post hoc analyses of the phase 3 ARCHES trial (NCT02677896) evaluated the efficacy of enzalutamide plus ADT according to prior local and systemic treatment, disease volume, and risk, assessed at trial baseline. Method(s): In ARCHES, a global, double-blind, placebo-controlled, phase 3 study, 1150 patients with mHSPC were randomized 1:1 to receive enzalutamide (160 mg/day) plus ADT or placebo plus ADT, stratified by prior docetaxel therapy and disease volume. Primary endpoint was rPFS. Secondary endpoints included time to prostate-specific antigen progression, symptomatic skeletal events, and prostate-specific antigen and radiographic responses. Analyses of clinical endpoints were completed by prior local therapy, prior docetaxel exposure, CHAARTED (NCT00309985)-defined disease volume, and LATITUDE (NCT01715285)-defined risk groups. Result(s): Patients were randomized to enzalutamide plus ADT (n = 574) and placebo plus ADT (n = 576). Enzalutamide plus ADT significantly improved rPFS (hazard ratio: 0.39; p < 0.0001), with similar improvements reported in all subgroups based on prior local and docetaxel treatment, disease volume, and risk. Treatment benefits were observed with enzalutamide plus ADT in multiple secondary clinical endpoints in the overall population and all subgroups. Conclusion(s): Enzalutamide plus ADT demonstrated clinical benefit across all patients with mHSPC, irrespective of prior local and systemic treatment, disease volume, and risk.Copyright © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

Background: In ARCHES (NCT02677896) ENZA + ADT reduced the risk of radiographic progression-free survival (rPFS) events, primary endpoint, and improved key secondary endpoints vs PBO + ADT in men with mHSPC (also known as metastatic castration-sensitive PC). Given the progressive nature of PC, this exploratory analysis evaluated efficacy of ENZA + ADT in patients (pts) who progressed to M1 HSPC following initial diagnosis (M0) vs pts who presented with de novo mHSPC at diagnosis (M1). Method(s): mHSPC pts (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. In this post hoc analysis, pts previously centrally categorized as MX/unknown metastasis at initial diagnosis (n=213) were adjudicated as either M0 or M1 disease following review of their medical profiles; efficacy outcomes were compared according to M0 vs M1 disease at initial diagnosis. Result(s): In this analysis, 246 pts (ENZA n=117; PBO n=129) had M0 and 890 pts (ENZA n=448; PBO n=442) had M1 disease at initial diagnosis; metastatic status of 14 pts (ENZA n=9; PBO n=5) were unknown (data not shown). Baseline characteristics were generally comparable between treatment arms; however, a greater proportion of M1 pts had high disease volume (n=606; 68.1% vs n=116; 47.2% [M0]) and prior docetaxel (n=173, 19.4% vs n=29, 11.8% [M0]). ENZA + ADT improved rPFS vs PBO + ADT irrespective of M0 or M1 disease at diagnosis; similar improvements were observed for secondary endpoints including prostate-specific antigen (PSA) and objective responses, time to PSA progression, time to new antineoplastic therapy (Table). Safety profiles were generally similar between subgroups and the overall population; exceptions include higher fatigue in M0 ENZA and PBO treatment arms. Conclusion(s): This post hoc analysis demonstrates clinical benefit of ENZA + ADT vs PBO + ADT based on rPFS and secondary endpoints in men who progressed from M0 to M1 HSPC and those with d

PURPOSE: Enzalutamide plus androgen deprivation therapy has previously been shown to improve clinical outcomes in men with metastatic hormone-sensitive prostate cancer (ARCHES; NCT02677896). Here, we assessed if and how the pattern of metastatic spread impacts efficacy of enzalutamide plus androgen deprivation therapy in men enrolled in ARCHES. MATERIALS AND METHODS: Men with metastatic hormone-sensitive prostate cancer were randomized 1:1 to enzalutamide (160 mg/day) plus androgen deprivation therapy or placebo plus androgen deprivation therapy, stratified by disease volume and prior docetaxel treatment. The primary end point was radiographic progression-free survival. Secondary end points included time to prostate specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event and castration resistance. Post hoc analyses were performed by pattern of metastatic spread based on study entry imaging. RESULT(S): Of the overall population with metastases identified at enrollment (1,146), the largest patient subgroups were those with bone metastases only (513) and those with bone plus lymph node metastases (351); there were fewer men with lymph node metastases only (154) and men with visceral+/-bone or lymph node metastases (128). Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression vs placebo plus androgen deprivation therapy in men with bone metastases only (HR 0.33) and bone plus lymph node metastases (HR 0.31). Similar improvements in secondary end points were also observed in these subgroups. CONCLUSION(S): These findings indicate that treatment with enzalutamide plus androgen deprivation therapy provides improvements in men with bone and/or lymph node metastases but may be less effective in men with visceral patterns of spread.

Background: Enzalutamide plus androgen deprivation therapy (ADT) significantly reduced the risk of radiographic progression or death in men with metastatic hormone-sensitive prostate cancer (mHSPC), regardless of baseline prostate-specific antigen (PSA) levels (ARCHES; NCT02677896). Here, we further assess PSA-related outcomes in pa-tients enrolled in ARCHES by disease volume and prior docetaxel ther-apy at study entry. Method(s): Patients with mHSPC (n=1150) were randomised 1:1 to en-zalutamide (160 mg/day) plus ADT or placebo plus ADT. Primary end-point was radiographic progression-free survival. Secondary endpoints included time to PSA progression and PSA undetectable rate. Post hoc analyses were based on disease volume and prior docetaxel at study entry, which were stratification factors, as well as time to 50% PSA re-duction and time to undetectable (< 0.2 ng/mL) PSA. Result(s): Overall, 423 (36.8%) patients had low-volume disease and 205 (17.8%) patients reported prior docetaxel use. Enzalutamide plus ADT significantly improved PSA-related outcomes versus placebo plus ADT, regardless of disease volume or prior docetaxel use at study entry (Ta-ble). The proportion of patients with >=50% PSA reduction from baseline was 85-95% for enzalutamide plus ADT and 18-66% for placebo plus ADT across subgroups. Conclusion(s): Enzalutamide plus ADT improved all assessed PSA-related outcomes versus placebo plus ADT in patients with mHSPC, ir-respective of disease volume or prior docetaxel therapy. True baseline PSA is unknown for some patients due to prior ADT use in this popula-tion. (Figure Presented).

Background ENZA, a potent androgen receptor inhibitor, provides benefit in men with castration-resistant prostate cancer (CRPC). Objectives In post hoc analyses, the role of ENZA + ADT in mHSPC patients (pts) randomized within the multinational, double-blind, PBOcontrolled, Phase 3 ARCHES study (NCT02677896) was determined by disease volume and risk group stratification. Materials and methods mHSPC pts were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included prostate-specific antigen (PSA) progression and radiographic responses, overall survival (OS), and quality of life (QoL). Analyses were completed by CHAARTED-defined disease volume and LATITUDE-defined risk groups. Results and conclusion 1150 pts were randomized (ENZA + ADT, n = 574; PBO + ADT, n = 576). Median follow-up was 14.4 months. ENZA + ADT significantly improved rPFS (hazard ratio [95% CI] 0.39 [0.30, 0.50]; P < 0.0001). ENZA + ADT pts significantly benefited from prolonged rPFS in all subgroups (Table). Significant treatment benefits were observed with ENZA + ADT in several secondary clinical endpoints in the overall population and in both high and low disease volume and risk groups (Table). High QoL at baseline was maintained over time. OS data are immature. Adverse events (AEs) were reported in 85.1% of ENZA + ADT vs. 85.9% of PBO + ADT pts, with no unexpected AEs. ENZA + ADT treatment showed efficacy benefit across all mHSPC pts, irrespective of disease volume and risk group. Similar delays in rPFS, symptomatic skeletal events, PSA progression, castration resistance, and improvements in radiographic responses and PSA declines, with maintenance of high QoL over time, were observed. Preliminary safety analysis appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Funding This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-develop

Background: In ARCHES (NCT02677896), ENZA + ADT reduced risk of radiographic progression and improved secondary outcomes in men with mHSPC over PBO + ADT. Here we report the final OS (after 356 events), a key secondary endpoint in ARCHES and a critical benchmark of clinical efficacy, which was immature at the time of primary analysis. Method(s): Men with de novo or relapsed mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. At the time of data cut-off and unblinding, 180 (31.3%) patients treated with PBO + ADT crossed over to open-label ENZA + ADT. A stratified log-rank test was performed at a two-sided significance level of 0.04 for OS based on an O'Brien-Fleming boundary. Kaplan-Meier estimates of OS and time to subsequent antineoplastic therapy (TTNAnti) were reported and hazard ratios (HRs) were estimated from a stratified Cox proportional hazards model. Safety was assessed via treatment-emergent adverse events. Result(s): Baseline characteristics were similar between treatment arms. As of the data cut-off of May 28, 2021, 397 (34.5%) patients remained on treatment, with a median follow-up of 44.6 months). Median treatment duration was 40.2 months on ENZA + ADT, 13.8 months on PBO + ADT, and 23.9 months for crossover patients. ENZA + ADT extended survival vs PBO + ADT (HR 0.66; 95% confidence interval 0.53, 0.81; p<0.0001) [Table] with similar results in most prespecified subgroups. ENZA + ADT continued to prolong TTNAnti vs PBO + ADT. The safety profile of ENZA + ADT vs PBO + ADT was consistent with findings from the primary analysis. Conclusion(s): This final analysis demonstrates that ENZA + ADT significantly prolongs survival in men with mHSPC and, together with the acceptable safety profile, supports the clinical benefit of ENZA + ADT in men with mHSPC. [Formula presented] Clinical trial identification: NCT02677896. Editorial acknowledgement: This study was funded by Astellas Pha

Background: CheckMate 9KD is a phase II, multi-cohort trial of NIVO (anti-PD-1) combined with rucaparib, docetaxel, or enzalutamide for mCRPC. We report results for cohort A2, assessing NIVO + rucaparib for CT-naive mCRPC. Method(s): In cohort A2, unselected patients (pts) with CT-naive mCRPC, ongoing ADT, prior abiraterone and/or enzalutamide for mCRPC, and no prior PARP inhibitors received NIVO 480 mg Q4W + rucaparib 600 mg BID until disease progression/unacceptable toxicity (NIVO dosing <= 2 y). Coprimary endpoints were objective response rate (ORR) per PCWG3 criteria and prostate-specific antigen response rate (PSA-RR) in all treated pts and pts with homologous recombination deficiency positive (HRD+) tumors; HRD status was determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Result(s): Of 71 treated pts, median age 73 y (range, 51-87 y), 23.9% had visceral metastases and 54.9% had measurable disease. Median treatment duration was 4.6 mo for NIVO and 5.5 mo for rucaparib; median follow-up was 17.5 mo. The table summarizes efficacy results, and shows better outcomes for HRD+ vs HRD-/not evaluable tumors. Any-grade treatment-related AEs (TRAEs) occurred in 90.1% of pts, most commonly nausea (40.8%) and anemia (32.4%). Grade >= 3 TRAEs occurred in 50.7% of pts, most commonly anemia (14.1%) and increased ALT (12.7%). TRAEs led to discontinuation in...Copyright © 2021 European Society for Medical Oncology

Background: ENZA, a potent androgen receptor inhibitor, provides benefit in men with castration-resistant prostate cancer (CRPC). In post hoc analyses, the role of ENZA+ ADT inmHSPC patients (pts) randomized within the multinational, doubleblind, PBO-controlled, Phase 3 ARCHES study (NCT02677896) was determined by disease volume and risk group stratification. Method(s): mHSPC pts were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included prostate-specific antigen (PSA) progression and radiographic responses, overall survival (OS), and quality of life (QoL). Analyses were completed by CHAARTED-defined disease volume and LATITUDE-defined risk groups. Result(s): 1150 pts were randomized (ENZA +ADT, n=574; PBO +ADT, n=576). Median follow-up was 14.4 months. ENZA + ADT significantly improved rPFS (hazard ratio [95% CI] 0.39 [0.30, 0.50]; p<0.0001). ENZA+ ADT pts significantly benefited from prolonged rPFS in all subgroups (Table). Significant treatment benefits were observed with ENZA + ADT in several secondary clinical endpoints in the overall population and in both high and low disease volume and risk groups (Table). High QoL at baseline was maintained over time. OS data are immature. Adverse events (AEs) were reported in 85.1% of ENZA + ADT vs. 85.9% of PBO +ADT pts, with no unexpected AEs. Conclusion(s): ENZA+ ADT treatment showed efficacy benefit across all mHSPC pts, irrespective of disease volume and risk group. Similar delays in rPFS, symptomatic skeletal events, PSA progression, castration resistance, and improvements in radiographic responses and PSA declines, with maintenance of high QoL over time, were observed. Preliminary safety analysis appears consistent with the safety profile of ENZA in previous CRPC clinical trials.

PURPOSE Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). METHODS ARCHES (ClinicalTrials.gov identifier: NCT02677896) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival. RESULTS As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P, .001; median not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT (P, .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events. CONCLUSION Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems

Background: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Patients and Methods: ARCHES is a multinational, double-blind, phase 3 study (NCT02677896). Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel therapy. Primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Result(s): 1150 men were randomized to ENZA (n = 574) or PBO (n = 576); baseline characteristics were balanced between groups. Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, 18% had prior docetaxel. Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HRs 0.24-0.53). Secondary endpoints improved with ENZA + ADT (Table); OS data are immature. Grade 3-4 adverse events (AEs) were reported in 23.6% of ENZA pts vs 24.7% of PBO pts with no unexpected AEs. Conclusion(s): ENZA + ADT significantly improved rPFS and other efficacy endpoints vs PBO + ADT in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC clinical trials.

Background: The clinical benefit of ENZA + ADT versus PBO + ADT in reducing the risk of radiographic progression-free survival (rPFS) events has been shown in men with mHSPC, regardless of baseline PSA levels (> or <= median value) [ARCHES; NCT02677896]. Here, the aim was to further analyze efficacy outcomes by various baseline PSA categories. Method(s): Patients with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT. Prior ADT and up to six cycles of prior docetaxel were permitted before baseline assessment of PSA levels and study treatment initiation. Post hoc analyses of the primary endpoint (rPFS) and other secondary endpoints by different baseline PSA categories at time of randomization were conducted to assess the efficacy of ENZA + ADT. Result(s): In the overall population (N=1150), >90% received prior ADT and 18% had prior docetaxel treatment. Median duration (range) of prior ADT was 1.6 months (0.03-55.3) for ENZA + ADT patients versus 1.6 months (0.03-198.8) for PBO + ADT patients. Of the overall population with available baseline PSA values (n=1146), 135 patients had <=0.2 mug/L, 388 patients had >0.2-4 mug/L, and 623 patients had >4 mug/L PSA at baseline (Table). Across these subgroups, the beneficial effect of ENZA + ADT on rPFS was observed, irrespective of baseline PSA (Table); similar results were also observed with other endpoints such as time to PSA progression and time to castration resistance. [Formula presented] Conclusion(s): These post hoc analyses demonstrate the clinical benefit of ENZA + ADT versus PBO + ADT based on rPFS and secondary clinical endpoints in patients with mHSPC, irrespective of patients' baseline PSA values. Clinical trial identification: ARCHES; NCT02677896. Editorial acknowledgement: Medical writing and editorial assistance were provided by Beatrice Vetter-Ceriotti, PhD, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. Legal entity responsible for the study: Astellas Pharma Inc. an

Background: ENZA + ADT significantly reduced the risk of radiographic progression or death in men with mHSPC (NCT02677896). Here, we assess how pattern of metastatic spread impacts the efficacy of ENZA + ADT in patients enrolled in ARCHES. Method(s): Patients with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT, stratified by disease volume and prior docetaxel treatment. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included time to prostatespecific antigen (PSA) progression, time to first symptomatic skeletal event (SSE), time to castration resistance, and time to initiation of new antineoplastic therapy. Post hoc analyses were performed by pattern of metastatic spread at study entry. Result(s): Of the overall population with known metastases at screening (n=1146), the largest patient subgroups were those with bone metastases only (n=513) and those with bone and soft-tissue metastases only (n=351); there were fewer M0 patients or patients with soft-tissue metastases only (n=154) and patients with visceral +/- bone metastases (n=128). ENZA + ADT reduced the risk of rPFS and other secondary endpoint measures versus PBO + ADT across all subgroups, with greater relative efficacy observed in patients without visceral metastases (Table). Conclusion(s):ENZA + ADT provides improvements in rPFS and other secondary endpoints versus PBO + ADT in patients with mHSPC regardless of pattern of metastatic spread, particularly in patients without visceral metastases. These results highlight the importance of patient/physician discussion regarding the use of ENZA in the treatment of mHSPC.

Reef manta rays (Mobula alfredi) are capable of long-distance dispersal when habitat is continuous. In the Ningaloo Reef World Heritage Area located on Australia’s mid-west coast, M. alfredi is sighted year-round and is a focal species for ecotourism in the region. Despite value to local tourism and demographic vulnerability to exploitation, basic information regarding M. alfredi movements and area use in this region is lacking. Here we used satellite tags and a long-term photographic-identification database collected by researchers and citizen scientists to examine the species’ visitation patterns and regional space use. Tagged M. alfredi remained in coastal shelf waters, preferentially occupying shallow depths < 20 m (76% of depth observations). Comparison of real tracks against those produced by correlated random walk simulations revealed directional dispersal and connectivity between the Ningaloo and Shark Bay World Heritage Areas. The greatest linear distance an individual moved after tagging was ∼700 km. This movement range is comparable to seasonal M. alfredi migration observed at similar latitudes on Australia’s east coast. Photographic-identification of 1121 individual M. alfredi, from 5146 sighting events, revealed that some individuals exhibited long-term site affinity to locations within Ningaloo Marine Park, with the longest spanning 15.16 years (9.8% individuals > 10 years). Lagged Identification Rate analysis suggested site visitation was best described by a pattern of emigration and reimmigration. While our observations of movement and residency establishes basic information previously unknown for the species in this region, the overlap of core area use with existing UNESCO World Heritage Areas demonstrates the potential for well-positioned marine parks to provide protection of critical habitat for M. alfredi.

The known distribution of manta rays in Australian waters is patchy, with records primarily centred around tourism hotspots. We collated 11,614 records of Mobula alfredi from photo‐ID databases (n = 10,715), aerial surveys (n = 378) and online reports (n = 521). The study confirms an uninterrupted coastal distribution from north of 26°S and 31°S on the west and east coasts, respectively. More southerly M. alfredi records relate to warm‐water events with a southernmost extent at 34°S. Coastal sightings of Mobula birostris were rare (n = 32), likely reflecting a preference for offshore waters, but encompass a wider latitudinal extent than M. alfredi of 10–40°S.