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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: 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.

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: 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: 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.

Introduction & Objectives: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with castration-resistant prostate cancer. A clinical benefit of ENZA + ADT versus PBO + ADT for men with mHSPC has been shown in the ARCHES trial regardless of prior treatment, including prior docetaxel exposure, radical prostatectomy, and/or radiation therapy. The objective of this post hoc analysis was to evaluate the efficacy of ENZA + ADT in key clinical secondary endpoints in patients enrolled in the ARCHES trial by prior local and systemic treatment. Material(s) and Method(s): In ARCHES, a global, double-blind, PBO-controlled, Phase 3 study (NCT02677896), patients with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel therapy. Ethical Committee approval was obtained. The primary endpoint was radiographic progression-free survival (rPFS; scans assessed centrally). Secondary endpoints included prostate-specific antigen progression and radiographic responses. Analyses of clinical endpoints were completed by prior local and systemic treatment (including docetaxel exposure, radical prostatectomy, and/or radiation therapy) to further assess efficacy of ENZA. Treatment continued until disease progression or unacceptable toxicity. Result(s): 1150 men were randomized (ENZA + ADT, 574; PBO +ADT, 576). Baseline characteristics were balanced between groups. Median follow-up was 14.4 months. ENZA + ADT significantly improved rPFS (p<0.0001), with similar improvements reported in all subgroups (Table). Significant treatment benefits were observed with ENZA + ADT in several secondary clinical endpoints in the overall population and in prior local and systemic treatment subgroups (Table). Table presented Conclusion(s): This post hoc analysis demonstrates clinical benefit of ENZA + ADT versus PBO + ADT based on rPFS and secondary clinical endpoints in patients with mHSPC, which is maintained in most evaluated

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 in mHSPC patients (pts) randomized within the multinational, double-blind, 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. [Table presented] 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. Clinical trial identification: NCT02677896. Editorial acknowledgement: Beatrice Vetter-Ceriotti and Laure

Background: ENZA has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ARCHES assessed the efficacy of ENZA with ADT in men with mHSPC, including pre-specified subgroups based on prior therapy. Method(s): ARCHES, a multinational, double-blind, Phase 3 study (NCT02677896), randomized patients (pts) with mHSPC 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel (doce) use. Primary endpoint was radiographic progression-free survival (rPFS; centrally assessed radiographic progression or death within 24 weeks of treatment discontinuation). Secondary endpoints included time to initiation of new antineoplastic therapy 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). Overall, 63% had high-volume disease, 18% had prior doce, and 91% had prior ADT or orchiectomy (orch). Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); significant improvements in rPFS were also reported in prior treatment subgroups. Secondary endpoints improved with ENZA + ADT (Table), with no significant impact in time to deterioration in urinary symptoms. 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. Preliminary safety analysis appears consistent with the safety profile of ENZA in previous CRPC clinical trials. (Table Presented).

Background: Enzalutamide (ENZA), a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Method(s): ARCHES is a multinational, double-blind, Phase 3 study (NCT02677896). Patients with metastatic hormone-sensitive prostate cancer (mHSPC) were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (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 months. 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 (hazard ratios [HRs] 0.24-0.53). Secondary endpoints improved with ENZA + ADT (Table); overall survival data are immature. Grade 3-4 adverse events (AEs) were reported in 23.6% of ENZA patients versus 24.7% of PBO patients, with no unexpected AEs.(Table presented) Conclusion(s): ENZA + ADT significantly improved rPFS and other efficacy endpoints versus 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. Funding(s): Astellas Pharma Inc. and Medivation LLC, a Pfizer Company. Medical writing: Complete HealthVizion.

Topic: Primary results from the ARCHES trial of enzalutamide in mHSPC Background: ENZA has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Method(s): ARCHES is a global, double-blind, Phase 3 study (NCT02677896). Patients with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel. Primary endpoint: 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): A total of 1150 men were randomized to ENZA (n = 574) or PBO (n = 576); baseline characteristics were balanced. 67% had distant metastasis at initial diagnosis;63%high volume disease;18%prior docetaxel. Median follow-up: 14.4 months. ENZA+ADT significantly improved rPFS (Table); significant improvements in rPFS were seen in prespecified subgroups of disease volume, pattern of spread, geographical region, and prior docetaxel (hazard ratios [HRs] 0.24-0.53). Secondary endpoints improved with ENZA+ADT; OS data are immature. Grade 3-4 adverse events (AEs)were reported in 23.6% of ENZA versus 24.7% of PBO, with no unexpected AEs. Conclusion(s): ENZA+ADT significantly improved rPFS and other endpoints versus PBO+ADT in mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC trials (Table Presented).