Search

160 Background: Darolutamide is androgen-receptor (AR) inhibitor with low blood–brain barrier penetration and limited potential for clinically relevant drug–drug interactions. Darolutamide has been shown to increase overall survival in combination with androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone sensitive prostate cancer (PC) and, in combination with docetaxel, in men with non-metastatic castration resistant PC. This phase 2 study assessed the efficacy and safety of DARO as a monotherapy without ADT in patients with non-castrate testosterone (T) levels (≥230 ng/dL). Methods: This was a 24-wk, open-label, randomized study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages, with a max of 4 metastatic lesions) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 y. All patients received DARO 600 mg bid or commercially available LHRH analogue. The primary endpoint is PSA response defined as a ≥ 80% decline at week 24 relative to baseline, in the DARO study arm. The ADT arm is used as an internal control. Secondary endpoints included changes in T levels, safety/tolerability, and quality of life. Results: Among 61 men enrolled, the median (range) age was 72 y (53-86y); 49.2% had metastases; 14.8% and 62.3% had undergone prostatectomy or radiotherapy before study entry. The median (range) of PSA at baseline was 8.9 ng/mL (2.2-333.8). In the DARO arm, the evaluable population with available PSA values at baseline and week 24 consisted of 21 patients. The PSA response rate (>80% PSA decline at wk 24) was 100%, with a median (range) decrease of -99.6% (-94.3, -100) at wk 24 in the DARO arm. Serum T levels increased by a median (range) of 43.4% (5.7-144.0) at wk 24, compared with baseline. In the DARO arm, 45.2% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (19.4%), fatigue (12.9%), and hot flush (12.9%). 3.1% of men experienced SAEs, none of which were drug related. HR-QoL measures and ADT arm results will be presented as internal reference. Conclusions: DARO monotherapy (600 mg bid) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Testosterone level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT02972060 .

15 Background: In ARASENS (NCT02799602), DARO plus ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI: 0.57–0.80; P

20 Background: Metastatic castration-sensitive prostate cancer (mCSPC) primarily affects older men (OM). In this post-hoc analysis we investigated the safety and efficacy of abiraterone acetate + prednisone (AAP) in older (≥ 70 years) and younger (< 70 years) patients in PEACE-1. Methods: Men with de novo mCSPC were allocated to standard of care (SOC), SOC + AAP, SOC + radiotherapy (RXT), or SOC + AAP + RXT in this 2x2 design phase 3 trial. SOC was initially androgen deprivation therapy (ADT) alone, then from Oct 2015 onwards, the use of docetaxel (D) was authorized as part of SOC (at the investigator’s discretion until 2017, then, following the publication of LATITUDE and STAMPEDE trials, accrual was restricted to men receiving ADT+ D). Efficacy and safety in OM included in PEACE-1 were analyzed with the same methods used in the overall trial (Lancet 2022; 399: 1695-1707). Results: A total of 741 younger men (YM) (63%) and 431 OM (37%) were randomized. OM presented with more altered PS (ECOG 1-2) (36% vs 26% p=0.0003) and less frequent use of docetaxel (D) as part of SOC (66% vs 51% p

148 Background: In ARASENS (NCT02799602), DARO in combination with ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P2 q21d for 6 cycles). The effect of DARO on DOC PK was assessed by noncompartmental analysis from the first 25 patients with dense PK data and by population PK (PopPK) for all patients. DARO PK from ARASENS were compared with PK data from ARAMIS (NCT02200614; without DOC) to evaluate the impact of DOC on DARO PK. Results: Of 1306 randomized patients, 1305 were included in the full analysis set (DARO, n=651; PBO, n=654). The median treatment duration was longer with DARO vs PBO (41.0 vs 16.7 months) and more DARO-treated patients (45.9% vs 19.1%) were still receiving treatment at primary analysis cutoff (Oct 25, 2021). Almost all patients completed 6 cycles of DOC in both groups (DARO, 87.6%; PBO, 85.5%). The proportion of patients requiring DOC dose modification (interrupted/delayed or reduced) was similar between groups (DARO, 60.0%; PBO, 62.9%). TEAEs led to discontinuation/reduction of DOC in 8.0%/19.9% of DARO patients and 10.3%/19.5% of PBO patients. PopPK analysis indicated that DOC PK in ARASENS was generally consistent with that in the literature. A slight numeric increase in DOC exposure was observed in the DARO + DOC + ADT arm, with 15% higher maximum plasma concentration (geometric mean, 1.93 vs 1.68 µg/mL) and 6% higher area under the concentration-time curve (AUC0-tlast within an 8-hour sampling interval, 2.10 vs 1.99 µg·h/mL) vs PBO + DOC + ADT. This small numeric increase is likely not clinically relevant given the variability in DOC exposure (coefficient of variation, 23%–54%). PK meta-analysis of ARASENS and, which considered patients’ intrinsic characteristics as covariates (eg, age, body weight, region), indicated a 10% lower AUC0-12ss of DARO in patients receiving DOC vs those not receiving DOC, which is not considered clinically relevant. Conclusions: The combination of DARO + DOC + ADT increases overall survival with similar overall incidence of TEAEs and no observed drug-drug interactions between DARO and DOC. DARO can be effectively and safely administered with DOC in patients with mHSPC without clinically relevant changes in PK of DARO or DOC. Clinical trial information: NCT02799602 .

e18757 Background: Treatment options for patients with HSPC have broadened, and data regarding patient preferences for therapies can aid in therapeutic decision-making. This study evaluated the impact of attributes associated with therapies for US patients with locally advanced prostate cancer (LAPC) or metastatic HSPC (mHSPC) from the perspective of patient preferences. Methods: An online discrete choice experiment (DCE) was developed for patients with LAPC or mHSPC. The DCE included 12 questions designed to systematically require tradeoffs between treatment attributes of efficacy (5-year overall survival [OS]), tolerability (fatigue, skin rash, neurotoxicity, and common chemotherapy-related toxicity), and convenience (administration factors [route, frequency, and setting], concomitant use of steroids, and monitoring requirements). Respondents could choose androgen deprivation therapy (ADT) alone or with hypothetical therapies that improved 5-year OS but had additional adverse events (AEs). Attribute-specific importance weights measuring their relative impact on treatment choices were estimated using a mixed-logit model, which also controlled for heterogeneity in preferences. Results: From September 3 to October 14, 2021, 82 respondents (mean age 61 years) completed the survey (LAPC, n = 40; mHSPC, n = 42), with 61 (74.4%) receiving ADT at the time of the survey. Respondents reported treatment efficacy (36% [95% confidence interval (CI) 22, 49]) as the most important aspect of treatment choice, followed by changes in chemotherapy-related toxicity (13% [95% CI 3, 22]) and the need for concomitant steroid use (12% [95% CI 5, 19]). Respondents considered monitoring requirements (8% [95% CI 5, 19]) to be more important than fatigue (5% [95% CI 2, 13]). Administration factors were comparable in importance to therapy AEs (Table). Respondents preferred, by at least 10 percentage points, adding therapies to ADT that could improve 5-year OS, at the detriment of additional AEs. Conclusions: After efficacy, convenience was considered to impact treatment choices at a rate comparable to tolerability issues, potentially influenced by perceived COVID-19 exposure risks. Patients with LAPC and mHSPC prioritize efficacy despite the detriment of additional AEs.[Table: see text]

5041 Background: Ra-223 extends OS in pts with mCRPC. Predictive markers of response to Ra-223 are needed to help select pts who would benefit most from Ra-223 therapy. The ALSYMPCA study suggested a correlation between ALP decline and longer OS. Here, we evaluated whether ALP decline is associated with OS in the global real-world REASSURE study. Methods: Pts treated with Ra-223 were grouped by baseline ALP ≤147 U/L vs >147 U/L and any ALP decline vs no decline at week 12 from the first Ra-223 dose. The 147 U/L cut-off was selected based on the highest upper limit of normal for ALP from literature. Pts with a trend of decreasing ALP at closest value to week 12 between weeks 8 and 16 were included in the any decline group. Association of ALP decline with OS was assessed in the ≤147 U/L and >147 U/L groups separately. Median OS is provided with an unadjusted hazard ratio (HR) (95% confidence interval [CI]). Multivariate Cox models provided adjusted HRs (95% CI) for the association of ALP decline with OS. Some baseline covariates were not included in the models due to missing data. Results: 785 of 1465 pts had baseline ALP measurements, of whom 779 had week 12 ALP measurements: 443 had ≤147 U/L and 336 >147 U/L. In the ≤147 U/L group, median OS was 23.0 months (m) (95% CI 20.9–25.7) in pts with ALP decline (n=329) and 16.4 m (95% CI 14.1–20.4) in pts with no decline (n=114). In the >147 U/L group, median OS was 12.9 m (95% CI 11.7–14.3) in pts with ALP decline (n=295) and 8.1 m (95% CI 5.6–10.3) in pts with no decline (n=41). Comparison of unadjusted and adjusted HRs is shown in the Table. Conclusions: Pts with an ALP decline in first 12 weeks of Ra-223 treatment had longer OS. The effect of other baseline variables, including age, PSA, Hgb and prior treatments, provided adjustment but did not change this outcome. [Table: see text]

5078 Background: Reductions in PSA level have been associated with improved OS in patients (pts) with mHSPC. In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) in combination with docetaxel significantly reduced the risk of death by 32.5% (hazard ratio [HR] 0.675; 95% confidence interval [CI] 0.568–0.801; P< 0.0001) vs ADT + docetaxel in pts with mHSPC. We report the association between PSA response and OS from ARASENS. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or matching PBO + ADT and docetaxel. Serum PSA was measured at screening and every 12 weeks. Exploratory analyses included time to PSA progression (≥25% increase from PSA nadir [lowest or at study entry] and PSA increase ≥2 ng/mL ≥12 weeks from nadir [both confirmed by a second value ≥3 weeks later]) and undetectable PSA (< 0.2 ng/mL for 2 samples ≥3 weeks apart) at 24, 36, and 52 weeks and any time during treatment. Comparisons between treatment groups were performed using the Cochran-Mantel Haenszel test stratified by randomization stratification factors (metastatic spread according to TNM classification and alkaline phosphatase levels at study entry). Post hoc landmark analyses evaluated the association between undetectable PSA at weeks 24 and 36 and OS for the overall population. Results: Of 1306 randomized pts, 1305 were included in the full analysis set (DARO 651; PBO 654), both with ADT and docetaxel. Median (range) PSA levels at study entry were 30.3 (0.0–9219.0) and 24.2 (0.0–11,947.0) ng/mL, respectively. DARO significantly prolonged time to PSA progression (HR 0.255; 95% CI 0.208–0.313; P< 0.0001). Undetectable PSA was achieved in more pts receiving DARO (48.7%) vs PBO (23.9%) at 24 weeks, and the rate continued to increase at 36 and 52 weeks in the DARO group to 57.1% and 60.2%, respectively, vs minimal change in the PBO group (25.1% and 26.1%). Undetectable PSA levels at any time were achieved in 67.3% in the DARO group and 28.6% in the PBO group. A treatment difference in undetectable PSA based on non-overlapping 95% CIs was observed at all time points. For the overall population, OS was improved for pts who achieved undetectable PSA levels vs those who did not at 24 weeks (HR 0.398; 95% CI 0.321–0.493) and 36 weeks (HR 0.351; 95% CI 0.284–0.434). Additional baseline and safety data by PSA level will be reported. Conclusions: The combination of DARO + ADT and docetaxel significantly prolonged the time to PSA progression and more pts receiving DARO vs PBO achieved undetectable PSA levels, reflecting strong PSA response over time. In pts with mHSPC, achievement of undetectable PSA at 24 and 36 weeks was associated with improved OS, with risk of death reduced by 60% and 65%, respectively, vs those who did not achieve undetectable PSA at 24 and 36 weeks. Clinical trial information: NCT02799602.

5084 Background: Current management of HRLPC includes long-term ADT with primary RT. Despite definitive primary treatment, these pts have a high risk of metastasis and death. The phase 3 ATLAS study (NCT02531516) is investigating whether treatment intensification with the addition of APA to neoadjuvant and adjuvant treatment with gonadotropin-releasing hormone agonist (GnRHa) and external beam radiation therapy (EBRT) will improve metastasis-free survival (MFS) in high-risk pts. Here we describe (1) the distribution of baseline characteristics in this high-risk pt population and (2) the application of different RT regimens reflecting recent international guidelines and clinical practice changes for pts with HRLPC. Methods: Eligible HRLPC pts (Gleason score [GS] ≥ 8 or 7 and prostate-specific antigen [PSA] ≥ 20 ng/mL and stage ≥ cT2c), with ECOG PS 0/1 and Charlson Comorbidity Index (CCI) ≤ 3 are stratified by GS, pelvic nodal status, use of brachytherapy boost, and region; pts are randomized 1:1 to APA or PBO plus GnRHa for 30 (28-d) treatment cycles. Study treatment is applied neoadjuvant/concurrent to RT with APA 240 mg/d vs bicalutamide 50 mg/d for 4 cycles; another 26 cycles are completed adjuvantly after RT with APA 240 mg/d vs PBO. Primary end point is MFS (time from randomization to first distant metastasis on CT/MRI/bone scan by independent central review blinded to treatment or death from any cause). Imaging is conducted at baseline and q6m from biochemical failure until MFS. The protocol has been amended to include PET imaging (PSMA, fluciclovine, or choline). Results: Pts (N = 1503) were randomized at 266 sites in 24 countries in North America, Latin America, Europe, and Asia. The study is fully enrolled, but ongoing. Baseline characteristics for the total population: median age, 67 yrs; ECOG PS 0/1; 89%/11%; tumor classification at study entry: high-risk, 66%/very high–risk, 34%; median PSA, 6.3 ng/mL; cT2, 44%/cT3, 50%; cN1, 13%. In 90% of ATLAS pts, RT used was standard EBRT to prostate/pelvis over 6-8 weeks (cumulative 78-81 Gy); in 10%, recent hypofractionation schedules (per CHHiP or NRG/RTOG 0415) were applied (20x3 Gy/d or 28x2.5 Gy/d). 5.6% of pts had EBRT combined with brachytherapy (per ASCENDE-RT). Conclusions: Baseline characteristics of the ATLAS study population are reflective of pts with high- and very high–risk features and pelvic nodal involvement undergoing primary RT in clinical practice. The RT schedules applied reflect recent evidence and guideline changes for the use of hypofractionation in this pt population. ATLAS is an example of how RT can be included in phase 3 trials of HRLPC, in combination with next-generation androgen receptor inhibitors (eg, APA). Clinical trial information: NCT02531516.

13 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor that demonstrated improved overall survival (OS) and metastasis-free survival vs placebo (PBO) and a low incidence of treatment-emergent adverse events (TEAEs) in patients (pts) with nonmetastatic castration-resistant prostate cancer (CRPC). We investigated whether DARO in combination with standard androgen-deprivation therapy (ADT) + docetaxel would increase OS in pts with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study (NCT02799602). Methods: This international, double-blind, phase 3 study enrolled pts with mHSPC and ECOG PS 0/1 who were randomized 1:1 to DARO 600 mg twice daily or matching PBO in addition to ADT + docetaxel. Randomization was stratified by extent of disease according to TNM (M1a vs M1b vs M1c) and alkaline phosphatase levels ( < vs ≥ upper limit of normal). The primary endpoint was OS. Secondary efficacy endpoints included time to CRPC, time to pain progression, time to first symptomatic skeletal event (SSE), and time to initiation of subsequent systemic antineoplastic therapies. Safety was also assessed. Results: From Nov 2016 to June 2018, 1306 pts were randomized, 651 to DARO and 655 to PBO, in combination with ADT + docetaxel. Median age was 67 y in both arms. At the primary data cutoff (Oct 25, 2021), DARO significantly decreased the risk of death by 32.5% vs PBO (HR 0.675, 95% CI 0.568–0.801; P < 0.0001). The significant improvement in OS was observed even though substantially more pts received subsequent life-prolonging systemic antineoplastic therapy in the PBO arm (75.6%) vs the DARO arm (56.8%). The significant OS benefit was consistent across prespecified subgroups. In addition, DARO significantly delayed time to CRPC versus PBO (HR 0.357, 95% CI 0.302–0.421; P < 0.0001). Time to pain progression was also significantly longer with DARO vs PBO (HR, 0.792, 95% CI 0.660–0.950; P= 0.0058), as were time to first SSE and time to initiation of subsequent systemic antineoplastic therapy. TEAEs were similar between treatment arms, and the incidences of the most common TEAEs (≥10%) were highest during the overlapping docetaxel treatment period for both arms, with grade 3/4 TEAEs of 66.1% for DARO and 63.5%for PBO, mainly due to neutropenia (33.7% vs 34.2%, respectively). TEAEs led to treatment discontinuation in 13.5% of pts in the DARO arm and 10.6% of pts in the PBO arm. Conclusions: In pts with mHSPC, early treatment combining DARO with ADT + docetaxel significantly increased OS and improved key secondary endpoints vs ADT + docetaxel alone. The incidence of TEAEs was similar in the two treatment arms. Clinical trial information: NCT02799602.