Darolutamide Research Articles

Abstract C162: Prespecified interim analysis of the DARolutamide ObservationaL (DAROL) study in Black/African American patients with nonmetastatic castration-resistant prostate cancer (nmCRPC)

Abstract Introduction: Black/African American (B/AA) men are disproportionately affected by prostate cancer, having higher incidence and mortality rates compared with other ethnic/racial populations. Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor with low blood–brain barrier penetration and limited potential for drug–drug interactions. In ARAMIS (NCT02200614; phase 3), DARO significantly improved metastasis- free survival (MFS) by ∼2 years and reduced the risk of death by 31% vs placebo in patients with nmCRPC, with favorable tolerability. The DAROL study (NCT04122976) is assessing the real- world safety and effectiveness of DARO in patients with nmCRPC. Here we report a subgroup analysis of B/AA patients from the prespecified third interim analysis (IA3). Methods: DAROL is an ongoing, global, open-label, single-arm, non-interventional study in patients aged ≥18 years with nmCRPC for whom the decision to be treated with DARO was decided pre-enrollment. The primary endpoint is safety, including incidence and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints include MFS, overall survival (OS), prostate-specific antigen (PSA) progression, and PSA response. IA3 was conducted when 550 patients completed ≥6 months of treatment (data cut-off July 17, 2023). Results: Of 550 patients, 199 (36%)/191 (35%)/152 (28%)/8 (2%) were from Europe/North America/Asia Pacific/Latin America, respectively. All 23 B/AA patients were from North America and represented 12% of this cohort. At baseline, PSA levels (median 4.2 ng/mL vs 4.0 ng/mL) and PSA doubling time (median 5.9 months vs 5.3 months) were similar in the B/AA and overall DAROL population, whereas B/AA patients were generally younger than the overall population (median 74 [range 49–94] vs 79 [range 29–98] years, respectively) with proportionately fewer patients aged ≥75 yrs (12 [52%] vs 387 [70%]), fewer B/AA patients (33%) had a Gleason score ≥8 vs the overall population (53%), and proportionally more B/AA patients (94%) had ECOG PS 0 vs the overall population (64%). Consistent with the DAROL IA3 overall population, DARO showed a favorable safety profile in the B/AA subgroup, and TEAEs were mostly grade 1/2. In the DAROL IA3 overall population, the proportion of patients who achieved a 90% reduction in PSA from baseline was 54%, while MFS and OS rates at 2 years were 78% and 88%, respectively. Effectiveness and safety outcomes for the B/AA subgroup will be presented. Conclusion: Findings from the DAROL IA3 B/AA subgroup were similar to the overall population and consistent with the favorable efficacy and safety profile of DARO observed in the ARAMIS B/AA subgroup and overall population. Citation Format: Evan Y. Yu, Christopher Pieczonka, Hiroyoshi Suzuki, Alberto Briganti, Murilo Luz, Declan Murphy, Patrick Adorjan, Mercedeh Ghadessi, Frank Verholen, Andrew J. Armstrong. Prespecified interim analysis of the DARolutamide ObservationaL (DAROL) study in Black/African American patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C162.

Clinical Outcomes and Prognostic Factors in Nonmetastatic Castration-Resistant Prostate Cancer Treated with Androgen Receptor Signaling Inhibitors Therapy.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen-progression-free survival (PSA-PFS) from ARSI initiation were assessed using the Kaplan-Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA-PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥ 3.67 ng/mL at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS.

Real-world retrospective study of prostate-specific antigen and safety assessment with darolutamide plus androgen deprivation therapy for metastasis hormone-sensitive prostate cancer.

ARASENS has demonstrated the efficacy and safety for darolutamide (DARO) with androgen deprivation therapy (ADT) plus docetaxel in metastasis hormone-sensitive prostate cancer (mHSPC). There is a lack of reports for DARO with ADT in mHSPC though the regimen is used in clinical from time to time. Moreover, recent studies have supported the importance of early and rapid prostate-specific antigen (PSA) reduction, which correlates with reduced disease progression and improved survival in patients with mHSPC. This study aims to evaluate PSA reduction as a primary endpoint for DARO with ADT in the treatment of mHSPC and to evaluate the real-world short-term PSA control of DARO with ADT from two leading medical centers in China. We retrospectively reviewed the clinical records of patients with mHSPC receiving ADT and DARO (600 mg, b.i.d.). The collection of data spanned from March 1, 2022, to July 31, 2023. The main observation indicators were PSA level and drug-related adverse events (AE) after medication. PSA levels were closely monitored prior to treatment initiation and at 2-week intervals, as well as at 1, 3, and 6 months after the initiation of treatment. We also conducted an analysis to determine the proportion of patients achieving a PSA reduction of 50% or more (PSA50) and 90% or more (PSA90) as well as the percentage of patients with a notable decrease in PSA level to 0.2 ng/mL and PSA nadir of ≤0.02 ng/mL. Fifty-one patients were included in the study, with a median age of 73 years. At diagnosis of HSPC, the majority of patients had a Gleason score ≥8 (n=40, 78.40%) and a median baseline PSA level of 88 ng/mL. Approximately 45.1% (n=23) of patients had a Charlson Comorbidity Index over 1 and were receiving one or more nontumor-related treatments. The median follow-up time was 9.3 months (range, 1.16-15.8 months). The median reductions in PSA levels compared to baseline were 84.37%, 91.48%, 94.67% and 99.81% at 2 weeks, 1 month, 3 months and 6 months after administration of DARO with ADT, respectively. The median time to PSA50, PSA90, significant PSA reduction (PSA <0.2 ng/mL), and PSA nadir (PSA <0.02 ng/mL) was 0.97, 1.27, 1.98, and 2.08 months, respectively. AE mainly included fatigue (two patients) and arm pain (one patient), all of which were grade I or II AE. No grade III or AE were observed. For treating prostate cancer, DARO with ADT has good early efficacy, demonstrating prompt and substantial control of PSA levels, with a favorable safety profile.

Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy.

166 Background: Darolutamide (DARO) + ADT + docetaxel (DOC) is approved for metastatic hormone-sensitive prostate cancer (mHSPC) based on the phase 3 ARASENS study (NCT02799602). To address the impact of informative intercurrent events (eg, use of subsequent therapy) in censored patients (pts), as defined by the European Medicines Agency, we performed a post hoc sensitivity analysis of OS. Methods: Pts with mHSPC were randomized 1:1 to oral DARO 600 mg twice daily or placebo (PBO) + ADT + DOC. The primary endpoint was OS using a log-rank test, with HR (95% CI) calculated by Cox model, stratified by extent of disease (EoD; nonregional lymph node vs bone ± lymph node vs visceral ± lymph node/bone metastases) and alkaline phosphatase (&lt; vs ≥ upper limit of normal). Pts with no documented death were censored at last known alive or data cut-off date, whichever was earlier. The post hoc sensitivity analysis counted initiation of subsequent systemic antineoplastic therapy as an event in censored pts still alive at end of follow-up. In addition planned sensitivity analyses used an unstratified log-rank test/Cox model, a log-rank test/Cox model with stratification factors from electronic case report forms, and a log-rank test/Cox model with EoD stratification factors from central imaging review. Results: In the primary analysis DARO + ADT + DOC significantly improved OS ( P&lt;0.0001; Table), despite a high percentage of pts who entered follow-up in the PBO group receiving subsequent life-prolonging systemic therapies (374/495, 76%). Time to first subsequent systemic antineoplastic therapy (a key secondary endpoint) was significantly longer with DARO + ADT + DOC vs PBO + ADT + DOC (HR 0.39, 95% CI 0.33–0.46, P&lt;0.001). Findings from the post hoc sensitivity analysis counting initiation of subsequent systemic antineoplastic therapy as an event in censored pts (pts with events: DARO 300/651, 46.1%; PBO 476/654, 72.8%) and the planned sensitivity analyses were consistent and supported the primary OS analysis (Table). Treatment-emergent adverse events (TEAEs) were similar between groups. TEAEs led to DARO/PBO discontinuation in 13.5%/10.6% of pts. Conclusions: The results of the post hoc and planned sensitivity analyses were consistent with and supportive of the ARASENS primary OS analysis. These data reinforce DARO + ADT + DOC as an effective and well tolerated new standard of care for early treatment intensification in pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]

A cost-effectiveness analysis assessing systemic treatments in metastatic castration-sensitive prostate cancer (mCSPC) by volume of disease.

93 Background: The treatment paradigm for mCSPC patients has rapidly evolved over the last few years with the emergence of triplet therapy and prognostication by volume of disease. However, the health economic implications of triplet therapy by disease volume remain unclear. Methods: A Markov model where patients transitioned between the progression-free, progression and death states was developed. State utilities were derived from the LATITUDE trial. Point probabilities for overall survival, progression-free survival, grade ≥ 3 and 5 toxicities were obtained from the eligible mCSPC phase III clinical trials. Medicare Advantage and commercial total paid amounts (2022 US$) of treatments were obtained from OptumLabs Data Warehouse. Costs and disutilities of adverse events were derived from published literature. Half-cycle corrected costs and utilities were accrued monthly over a 20-year lifetime horizon and were discounted at 3%. Monte Carlo simulation was used to calculate incremental cost-effectiveness ratios (ICERs). A willingness-to-pay (WTP) threshold of US$100,000 was used. Results: In terms of Medicare Advantage payer’s perspective (Table), docetaxel (D)+ADT was observed to provide additional 0.068 QALYs compared to ADT at an ICER of US$16,544 per QALY in high volume disease. Compared to D+ADT, abiraterone (AAP) triplet provided additional 1.03 QALYs at US$56,641 per QALY. Compared to AAP triplet, apalutamide (APA)+ADT provided additional 0.048 QALYs at US$5,846,248 per QALY in high volume disease. In low volume disease, D+ADT provided 0.45 more QALYs at US$20,690 per QALY compared to ADT alone. Compared to D+ADT, AAP triplet provided an additional 1.51 QALYS at US$44,267 per QALY. In terms of total paid commercial costs, AAP triplet provided an additional 1.19 QALYs compared to ADT at US$91,952 per QALY in high volume disease. In low volume, D+ADT provided additional 0.38 QALYs at US$22,058 per QALY compared to ADT. Compared to D+ADT, AAP triplet provided a 0.97 QALY gain at US$105,958 per QALY. Compared to AAP triplet, darolutamide (DARO) triplet provided a 0.47 QALY at US$689,196 per QALY. Compared to DARO triplet, APA+ADT provided an additional 0.49 QALYs at an ICER of US$971,389 per QALY. All other treatments (not reported here) were dominated. Conclusions: At the selected WTP of US$100,000 per QALY, AAP triplet therapy was most likely the cost-effective strategy in overall mCSPC population particularly in patients with high volume disease. However, these results should be interpreted with careful accounting for timing of metastases. [Table: see text]

ARAMON: A phase 2, randomized, open-label study comparing darolutamide (DARO) vs enzalutamide (ENZA) monotherapy on serum testosterone levels in patients (pts) with castration-sensitive prostate cancer (CSPC) after biochemical recurrence (BCR).

TPS243 Background: DARO, a structurally distinct and highly potent androgen receptor inhibitor, has low blood–brain barrier (BBB) penetration and limited potential for drug–drug interactions. In phase 3 trials, DARO showed significant efficacy and a favorable safety profile. In ARAMIS (NCT02200614), DARO and androgen-deprivation therapy (ADT) significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT in pts with nonmetastatic castration-resistant prostate cancer. In ARASENS (NCT02799602), DARO + ADT + docetaxel significantly improved OS in pts with metastatic hormone-sensitive prostate cancer vs placebo + ADT + docetaxel. In both studies, the incidence of adverse events (AEs) was similar between treatment groups. Currently, the ARASTEP study (NCT05794906) is evaluating DARO and ADT in pts with high-risk BCR following primary therapy who have prostate-specific membrane antigen PET/CT-positive lesions. Based on a neuroimaging study of healthy volunteers, cerebral blood flow was not altered with DARO but was significantly reduced in brain areas related to cognition with ENZA. It is postulated that the low BBB penetration of DARO may result in lower serum testosterone elevations than those seen with ENZA, which may reduce the frequency of AEs. The ARAMON study (NCT05526248) will compare the effect of DARO and ENZA monotherapy on post-treatment testosterone levels in pts with CSPC who developed a BCR after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of pts with histologically or cytologically confirmed adenocarcinoma of the prostate who experienced BCR after radical primary prostatectomy (RP) or radiation therapy (RT), with &lt;5 asymptomatic oligometastatic disease sites. Key inclusion criteria are prostate-specific antigen (PSA) ≥2 ng/mL, PSA doubling time of ≤20 months, serum testosterone &gt;150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During the lead-in phase, 25 pts will receive DARO 600 mg twice daily for 52 weeks. If serum testosterone criteria are met at 12 weeks, the study will proceed to the randomized phase where approximately 40 pts will be randomized 1:1 to DARO (600 mg twice daily) or ENZA (160 mg once daily) for 52 weeks. The primary endpoint is the change in serum testosterone level from baseline to Week 12. Secondary endpoints include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of endocrine, glycemic, and lipid metabolism markers; incidence of AEs; and quality of life. As of September 2023, 23 of 25 planned pts in the lead-in phase have been enrolled. Clinical trial information: NCT05526248 .

255O Darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) in Chinese patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in the phase III ARASENS study

255O Darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) in Chinese patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in the phase III ARASENS study

1784P Prostate-specific antigen (PSA) outcomes with darolutamide (DARO): Androgen-deprivation therapy (ADT) and docetaxel (DOC) in patients (pts) with high- and low-volume metastatic hormone-sensitive prostate cancer (mHSPC) in ARASENS

1784P Prostate-specific antigen (PSA) outcomes with darolutamide (DARO): Androgen-deprivation therapy (ADT) and docetaxel (DOC) in patients (pts) with high- and low-volume metastatic hormone-sensitive prostate cancer (mHSPC) in ARASENS

1781P Health-related quality of life (HRQoL) deterioration-free survival (DetFS) by prostate-specific antigen (PSA) decline in darolutamide (DARO)-treated patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) from ARAMIS

1781P Health-related quality of life (HRQoL) deterioration-free survival (DetFS) by prostate-specific antigen (PSA) decline in darolutamide (DARO)-treated patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) from ARAMIS

Efficacy and safety of darolutamide in Chinese patients with metastatic hormone-sensitive prostate cancer (mHSPC): A subpopulation analysis of the phase 3 ARASENS study.

e17076 Background: Darolutamide (DARO) is an androgen receptor inhibitor approved in China for the treatment of nonmetastatic castration-resistant prostate cancer (CRPC). In the global ARASENS trial, DARO significantly increased overall survival (OS) vs placebo (PBO) in patients (pts) with mHSPC. The efficacy and safety of DARO in the Chinese subpopulation of ARASENS are reported here. Methods: In this randomized, double-blind phase 3 trial, 1305 pts with mHSPC were randomized 1:1 to receive DARO 600 mg orally twice daily or PBO, in combination with androgen-deprivation therapy (ADT) and docetaxel. The primary endpoint was OS. Results: In mainland China, 202 pts were randomized to the DARO group (n = 104) or the PBO group (n = 98). Demographics and baseline characteristics were well balanced between treatment groups and comparable to the overall ARASENS population, except for a slightly higher proportion of pts with Gleason score ≥8, higher proportion with metastatic disease at diagnosis, and higher median baseline prostate-specific antigen (PSA) in Chinese pts vs the overall population. The risk of death was reduced by 36% (HR 0.64, 95% CI 0.41–0.99) with DARO vs PBO in Chinese pts (Table). The key secondary endpoint time to CRPC (HR 0.32, 95% CI 0.20–0.50) and the exploratory endpoint time to PSA progression (HR 0.22, 95% CI 0.13–0.37) also favored DARO. In the DARO group, 81% of pts had a maximum PSA decline of ≥90% from baseline (PSA90) at week 12, while 88% had PSA90 and 71% reached PSA &lt; 0.2 ng/mL at any time. Incidences of treatment-emergent adverse events (TEAEs) in Chinese pts were similar between treatment groups and comparable to the overall population. The most common grade 3/4 TEAE in Chinese pts was neutropenia (DARO 64%, PBO 62%), a known toxicity of docetaxel; grade 3/4 febrile neutropenia occurred in 4.0% of Chinese pts compared with 7.6% in the overall population. Conclusions: In the ARASENS subpopulation of Chinese pts with mHSPC, DARO + ADT + docetaxel showed favorable efficacy and safety vs PBO + ADT + docetaxel: OS and clinically relevant secondary endpoints favored DARO vs PBO, and the incidences of TEAEs were similar in the two treatment groups. These results are consistent with the findings reported for the overall population in ARASENS. Clinical trial information: NCT02799602 . [Table: see text]

Darolutamide and time to pain progression by disease volume in ARASENS.

e17075 Background: In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced risk of death by 32.5% (hazard ratio [HR] 0.68, 95% confidence interval [CI[ 0.57–0.80; P&lt; 0.0001) and significantly delayed time to pain progression (HR 0.79, 95% CI 0.66–0.95; P= 0.006) vs placebo (PBO) + ADT + docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We report time to pain progression in patients (pts) with high/low disease volume (HV/LV). Methods: Pts with mHSPC were randomized to oral DARO 600 mg twice daily or PBO, both + ADT + docetaxel. Pain was assessed by the Brief Pain Inventory short form “pain at its worst” score (WPS). Pain progression was defined as WPS increase ≥2 points from nadir (and absolute WPS ≥4 if &gt; 0 at baseline) or initiation of opioid therapy for ≥7 consecutive days. A sensitivity analysis assessed pain progression after completion of docetaxel. HV/LV subgroups were defined per CHAARTED. Results: 1305 pts (DARO 651, PBO 654) were analyzed. At baseline, the mean WPS was 1.5 (standard deviation 1.9) vs 1.4 (1.8) in the DARO vs PBO groups; 258 (40%) vs 274 (42%) pts had no pain (WPS 0). DARO + ADT + docetaxel had a robust impact on delaying time to pain progression vs PBO + ADT + docetaxel in the post-docetaxel sensitivity analysis (stratified HR 0.75, 95% CI 0.62–0.90) and in the HV subgroup (unstratified HR 0.75, 95% CI 0.61–0.93) (Table). Overall, median time to pain progression was longer in the LV vs HV subgroup. WPS change from nadir was the main driver of pain progression events. Conclusions: In pts with mHSPC, the addition of DARO to ADT and docetaxel provided clinically meaningful benefit through delayed time to pain progression, notably in pts with HV disease. Increased overall survival, a delay in time to pain progression, and a favorable safety profile set DARO + ADT + docetaxel as a new standard of care for pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]

Open-label study of darolutamide plus androgen-deprivation therapy (ADT) vs ADT in metastatic hormone-sensitive prostate cancer using an external control arm (ARASEC).

TPS5112 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor. In the phase 3 ARASENS study (NCT02799602) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC), DARO + ADT + docetaxel significantly reduced the risk of death by 32.5% vs ADT + docetaxel (hazard ratio 0.68; 95% confidence interval 0.57–0.80), with a favorable tolerability and safety profile. In the global (excluding US), phase 3 ARANOTE study (NCT04736199), DARO + ADT vs ADT alone is being evaluated in pts with mHSPC. ARASEC (NCT05059236) will complement ARANOTE by assessing DARO + ADT in US pts. As ADT alone is no longer an acceptable comparator in the US, the external control arm will be derived from the historical US CHAARTED study (NCT00309985). A real-world analysis of electronic health record data from pts with mHSPC (TIMES) indicated that there was minimal risk of historical time bias associated with the use of the external ADT alone arm from CHAARTED as a comparator for ARASEC (Shore N, et al . J Clin Oncol 2022;40(28 Suppl):Abstract 403). Methods: ARASEC is a phase 2, open-label, single-arm study enrolling pts with confirmed mHSPC and no prior systemic therapy. Pts will receive DARO 600 mg orally twice daily + ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). The external control arm will be derived from 394 pts with mHSPC treated with ADT alone in CHAARTED. To remove biases in evaluating outcomes that could arise due to differences in baseline profiles between arms, pts will be matched 1:1 using a propensity score (PS) summarizing baseline characteristics relevant to disease outcomes. Baseline variables will include age ( &lt; 70 vs ≥70 years), Eastern Cooperative Oncology Group performance status (0–1 vs 2), CHAARTED-defined extent of disease (low vs high volume + bone metastases only vs high volume + visceral metastases ± bone metastases), and prior therapy (yes vs no; as a proxy for recurrent vs de novo disease). Matching patients with scores within a narrow window across the cohorts will ensure that pts in CHAARTED are representative of pts in the DARO + ADT arm. The primary endpoint is progression-free survival (PFS), as defined in CHAARTED. Secondary endpoints include overall survival, radiographic PFS, time to CRPC, undetectable prostate-specific antigen response rate ( &lt; 0.2 ng/mL) at 6 months, and safety. Target enrollment for the DARO + ADT arm is 200 pts at 30 sites. The study will continue until either the event count threshold triggering the primary endpoint analysis has been met (161 PFS events) or all pts have been followed for ≥2 years, whichever occurs later. As of January 2023, 121 pts have been enrolled. A per-protocol, predefined matching exercise on the first 100 pts enrolled will be conducted to ensure that the planned sample size is adequate. Clinical trial information: NCT05059236 .

Darolutamide observational (DAROL) study in patients with nonmetastatic castration-resistant prostate cancer: Second interim analysis.

e17095 Background: In ARAMIS (NCT02200614), darolutamide (DARO) significantly improved metastasis-free survival (MFS) by ~2 years (HR 0.41, 95% CI 0.34–0.50) and reduced the risk of death by 31% (HR 0.69, 95% CI 0.53–0.88) compared with placebo in men with nonmetastatic castration-resistant prostate cancer (nmCRPC), with a favorable tolerability profile. The ongoing DAROL study (NCT04122976) aims to understand the real-world safety and effectiveness of DARO in patients (pts) with nmCRPC. We report results from the pre-planned second interim analysis (IA). Methods: DAROL is a global, open-label, single-arm, non-interventional study in pts aged ≥18 years with confirmed nmCRPC for whom the decision to be treated with DARO is decided pre-enrollment. The primary endpoint is safety, including incidence, severity, and frequency of treatment-emergent adverse events (TEAEs). Secondary endpoints are patient demographics and disease characteristics, treatment duration, MFS, overall survival (OS), time to prostate-specific antigen (PSA) progression, and PSA response. Primary and secondary endpoints are reported after 300 pts completed ≥6 mo of treatment. All treated pts were assessed for safety while efficacy was evaluated in pts who did not violate any eligibility criteria and had ≥1 post-baseline assessment (cut-off October 11, 2022). Results: Of the 300 treated pts, the percentage enrolled in North America/Europe/Asia Pacific/Latin America was 45%/30%/25%/ &lt; 1%, respectively. Median age was 80 years; 51% had a reported Gleason score &gt; 7; 92% had a reported ECOG performance status of 0/1. Median baseline (BL) PSA was 3.9 ng/mL (range 0–248.0), with 21% of pts reporting PSA &lt; 2 ng/mL. Median BL PSA doubling time (PSADT) was 5.3 mo (range 0–36.2), with 42% of pts reporting PSADT &gt; 6 mo. At the data cut-off, median follow-up time was 14.8 mo (interquartile range [IQR] 10.9–19.3) and median treatment duration was 13.4 mo (IQR 9.3–17.8). The incidences of TEAEs and DARO-related TEAEs were generally low (Table), consistent with the safety profile of DARO reported in ARAMIS. Fatigue occurred in ≥5% of pts. For the 263 pts eligible for efficacy analysis, median time to PSA progression was 17.6 mo (95% CI 13.2–19.0); MFS/OS data remain immature. PSA declines from baseline of ≥30%, ≥50%, and ≥90% at any time were observed in 80%, 76%, and 54% of pts, respectively. Conclusions: In the DAROL second IA, under real-world conditions, DARO continued to show a favorable safety profile, consistent with the clinical profile of ARAMIS, with no new safety signals. Clinical trial information: NCT04122976 . [Table: see text]

MP11-14 TREATMENT DURATION AND LONG-TERM SAFETY AND TOLERABILITY WITH DAROLUTAMIDE IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (nmCRPC): ARAMIS ROLLOVER STUDY

You have accessJournal of UrologyCME1 Apr 2023MP11-14 TREATMENT DURATION AND LONG-TERM SAFETY AND TOLERABILITY WITH DAROLUTAMIDE IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (nmCRPC): ARAMIS ROLLOVER STUDY Neal D. Shore, Murilo Luz, Albertas Ulys, Jorge Ortiz, Shankar Srinivasan, Etah Kurland, and Karim Fizazi Neal D. ShoreNeal D. Shore More articles by this author , Murilo LuzMurilo Luz More articles by this author , Albertas UlysAlbertas Ulys More articles by this author , Jorge OrtizJorge Ortiz More articles by this author , Shankar SrinivasanShankar Srinivasan More articles by this author , Etah KurlandEtah Kurland More articles by this author , and Karim FizaziKarim Fizazi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In patients (pts) with nmCRPC, darolutamide (DARO) significantly improved metastasis-free survival by ∼2 years and reduced the risk of death by 31% vs placebo, with a favorable safety profile (ARAMIS study; NCT02200614). We report the long-term safety and tolerability of DARO in the ARAMIS Rollover Study (ROS; NCT04464226). METHODS: In ARAMIS, 954 pts received double-blind (DB) DARO 600 mg orally twice daily, of whom 591 pts continued on open-label (OL) DARO following the primary analysis. On completion of ARAMIS, 294 pts with no evidence of metastases and benefitting clinically from DARO entered the ROS. DARO treatment duration and safety are described for the 954 pts over the DB, DB+OL, and DB+OL+ROS periods. RESULTS: At data cut-off of Jan 31, 2022, the median (range) duration of DARO treatment was DB 1.5 years (0.0–4.0), DB+OL 2.1 years (0.0–4.9), and DB+OL+ROS 2.8 years (0.0–6.8). Of the 954 randomized pts, 32.3% received DARO treatment for ≥2–<4 years, 17.3% for ≥4–<5 years, and 12.8% for ≥5 years. As expected, cumulative incidences of treatment-emergent adverse events (TEAEs) increased slightly with longer observation time. For the DB, DB+OL, and DB+OL+ROS periods, respectively, TEAE incidences were: any grade 85.7%, 89.8%, 91.5%; grade 3/4 26.3%, 31.8%, 35.5%; serious 26.1%, 32.1%, 38.5%; and leading to treatment discontinuation 8.9%, 10.5%, 12.9%. Increases in incidences of TEAEs commonly associated with androgen receptor inhibition across the DB, DB+OL, and DB+OL+ROS periods were mostly minimal (Figure 1). During the first 24 months of DARO treatment, incidences of most of these TEAEs were low and ≤2% different vs placebo, except for fatigue. Onset of these TEAEs by time intervals across all study phases (DB, DB+OL, DB+OL+ROS) will be presented. CONCLUSIONS: Approximately 30% of pts with nmCRPC remained on DARO for ≥4 years, suggesting long-term clinical benefit. Most adverse events (AEs) occurred in the first 2 years of treatment, with small increments over time. The favorable safety profile of DARO was maintained with long-term exposure. No new safety concerns were observed in the ROS. Source of Funding: Bayer AG and Orion Pharma © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e129 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal D. Shore More articles by this author Murilo Luz More articles by this author Albertas Ulys More articles by this author Jorge Ortiz More articles by this author Shankar Srinivasan More articles by this author Etah Kurland More articles by this author Karim Fizazi More articles by this author Expand All Advertisement PDF downloadLoading ...

MP29-02 EFFICACY AND SAFETY OF DAROLUTAMIDE IN COMBINATION WITH ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN THE NORTH AMERICAN POPULATION FROM ARASENS

You have accessJournal of UrologyCME1 Apr 2023MP29-02 EFFICACY AND SAFETY OF DAROLUTAMIDE IN COMBINATION WITH ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN THE NORTH AMERICAN POPULATION FROM ARASENS Neal D. Shore, Bertrand Tombal, Maha Hussain, Fred Saad, Karim Fizazi, Cora N. Sternberg, E. David Crawford, Luke Nordquist, Ronald Tutrone, Laurence Belkoff, Shivani Kapur, Jay Jhaveri, Shankar Srinivasan, Heikki Joensuu, and Matthew R. Smith Neal D. ShoreNeal D. Shore More articles by this author , Bertrand TombalBertrand Tombal More articles by this author , Maha HussainMaha Hussain More articles by this author , Fred SaadFred Saad More articles by this author , Karim FizaziKarim Fizazi More articles by this author , Cora N. SternbergCora N. Sternberg More articles by this author , E. David CrawfordE. David Crawford More articles by this author , Luke NordquistLuke Nordquist More articles by this author , Ronald TutroneRonald Tutrone More articles by this author , Laurence BelkoffLaurence Belkoff More articles by this author , Shivani KapurShivani Kapur More articles by this author , Jay JhaveriJay Jhaveri More articles by this author , Shankar SrinivasanShankar Srinivasan More articles by this author , Heikki JoensuuHeikki Joensuu More articles by this author , and Matthew R. SmithMatthew R. Smith More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced the risk of death by 32.5% (HR 0.68, 95% CI 0.57–0.80; P<0.0001) vs placebo (PBO) + ADT + docetaxel in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC). DARO maintained quality of life, with similar control of disease-related physical symptoms and pain vs placebo, and had a favorable safety profile. We report clinical outcomes in North American (NA) pts in ARASENS. METHODS: This international, double-blind, phase 3 trial randomized pts 1:1 to DARO 600 mg twice daily or PBO in addition to ADT + docetaxel. The primary endpoint was overall survival (OS). Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. RESULTS: Of 1305 pts analyzed, 244 (18.7%) were enrolled in North America (US/Canada 218/26; DARO/PBO 125/119) and of these, 36 (14.8%) were Black/African American (AA) pts. Baseline characteristics of the NA population were generally similar to those of the overall population, except for the proportion of pts with de novo metastatic disease (75.8% NA vs 86.1% overall). In NA pts, DARO + ADT + docetaxel was associated with OS benefit vs PBO + ADT + docetaxel (HR 0.59, 95% CI 0.39–0.89), with 4-year survival rates of 66% vs 50%, respectively. The DARO vs PBO group had longer time to CRPC (HR 0.32, 95% CI 0.21–0.48). The safety profile of DARO in NA pts was consistent with that of the overall population (grade 3/4 treatment-emergent adverse events [TEAEs] 61% NA vs 66% overall; serious TEAEs 44% NA vs 45% overall). The incidences of TEAEs associated with androgen receptor pathway inhibition for DARO vs PBO were generally consistent, particularly when adjusted for treatment exposure. The OS benefit and safety profile of DARO vs PBO was also seen in Black/AA pts, consistent with the overall population. CONCLUSIONS: In NA pts with mHSPC, addition of DARO to ADT + docetaxel led to a clinically meaningful reduction in risk of death by 41% and improved the key patient-relevant secondary endpoint of time to CRPC. Incidences of TEAEs were generally similar between treatment groups in NA pts and consistent with the overall population. Source of Funding: Bayer AG and Orion Pharma. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e380 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal D. Shore More articles by this author Bertrand Tombal More articles by this author Maha Hussain More articles by this author Fred Saad More articles by this author Karim Fizazi More articles by this author Cora N. Sternberg More articles by this author E. David Crawford More articles by this author Luke Nordquist More articles by this author Ronald Tutrone More articles by this author Laurence Belkoff More articles by this author Shivani Kapur More articles by this author Jay Jhaveri More articles by this author Shankar Srinivasan More articles by this author Heikki Joensuu More articles by this author Matthew R. Smith More articles by this author Expand All Advertisement PDF downloadLoading ...

MP29-01 RAPID, DURABLE, AND DEEP PROSTATE-SPECIFIC ANTIGEN RESPONSE FOLLOWING ADDITION OF DAROLUTAMIDE TO ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN ARASENS

You have accessJournal of UrologyCME1 Apr 2023MP29-01 RAPID, DURABLE, AND DEEP PROSTATE-SPECIFIC ANTIGEN RESPONSE FOLLOWING ADDITION OF DAROLUTAMIDE TO ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN ARASENS Fred Saad, Bertrand Tombal, Maha Hussain, Karim Fizazi, Cora N. Sternberg, E. David Crawford, Luke T. Nordquist, Ronald Tutrone, Neal D. Shore, Laurence Belkoff, Shivani Kapur, Jay Jhaveri, Jorge Ortiz, Shankar Srinivasan, Frank Verholen, and Matthew R. Smith Fred SaadFred Saad More articles by this author , Bertrand TombalBertrand Tombal More articles by this author , Maha HussainMaha Hussain More articles by this author , Karim FizaziKarim Fizazi More articles by this author , Cora N. SternbergCora N. Sternberg More articles by this author , E. David CrawfordE. David Crawford More articles by this author , Luke T. NordquistLuke T. Nordquist More articles by this author , Ronald TutroneRonald Tutrone More articles by this author , Neal D. ShoreNeal D. Shore More articles by this author , Laurence BelkoffLaurence Belkoff More articles by this author , Shivani KapurShivani Kapur More articles by this author , Jay JhaveriJay Jhaveri More articles by this author , Jorge OrtizJorge Ortiz More articles by this author , Shankar SrinivasanShankar Srinivasan More articles by this author , Frank VerholenFrank Verholen More articles by this author , and Matthew R. SmithMatthew R. Smith More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In ARASENS (NCT02799602), darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P<0.0001) vs ADT + docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We report on prostate-specific antigen (PSA) responses and kinetics data from ARASENS. METHODS: Patients with mHSPC were randomized 1:1 to DARO 600 mg twice daily or placebo (PBO), both with ADT + docetaxel. Serum PSA was measured at screening and every 12 weeks. Analyses included undetectable PSA (<0.2 ng/mL), ≥50% and ≥90% reductions in PSA from baseline (PSA50, PSA90), and times to PSA progression and PSA50/PSA90. Post hoc landmark analyses evaluated the association between undetectable PSA at weeks 24 and 36 with overall survival (OS) and time to PSA progression. RESULTS: For 1305 patients in the full analysis set (DARO, 651; PBO, 654), 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. Patients in the DARO group demonstrated rapid PSA90 response, with 67.6% achieving PSA90 within 12 weeks, 82.0% within 24 weeks, and 84.9% at any time compared with 42.8%, 54.4%, and 59.0% in the PBO group, respectively (Figure). DARO was associated with deep PSA response, with median PSA at nadir of 0.020 ng/mL vs 0.495 ng/mL for PBO. Undetectable PSA was achieved in more than twice the number of patients receiving DARO vs PBO at 24 weeks (48.7% vs 23.9%), continuing to increase at 36 and 52 weeks with DARO (57.1% and 60.2%). Compared with patients who did not achieve undetectable PSA, patients receiving DARO who achieved undetectable PSA at 24 and 36 weeks had improved OS (HR [95% CI] 0.47 [0.35–0.63] and 0.37 [0.28–0.49]) and prolonged time to PSA progression (HR [95% CI] 0.28 [0.18–0.42] and 0.23 [0.15–0.34]), showing durable PSA response that was maintained over time. CONCLUSIONS: Patients with mHSPC receiving DARO + ADT + docetaxel achieved rapid, durable, and deep PSA responses, correlating with improved OS and prolonged time to PSA progression vs PBO + ADT + docetaxel. Source of Funding: This trial was funded by Bayer AG and Orion Corporation. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e380 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fred Saad More articles by this author Bertrand Tombal More articles by this author Maha Hussain More articles by this author Karim Fizazi More articles by this author Cora N. Sternberg More articles by this author E. David Crawford More articles by this author Luke T. Nordquist More articles by this author Ronald Tutrone More articles by this author Neal D. Shore More articles by this author Laurence Belkoff More articles by this author Shivani Kapur More articles by this author Jay Jhaveri More articles by this author Jorge Ortiz More articles by this author Shankar Srinivasan More articles by this author Frank Verholen More articles by this author Matthew R. Smith More articles by this author Expand All Advertisement PDF downloadLoading ...

First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer

The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown. To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups. For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available. Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC. Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022. Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT. The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Long-term safety and tolerability of darolutamide and duration of treatment in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the ARAMIS Rollover Study.

147 Background: Darolutamide (DARO) significantly improved metastasis-free survival by ~2 y and reduced the risk of death by 31% vs placebo, with a favorable safety profile in patients (pts) with nmCRPC (ARAMIS study; NCT02200614). We report long-term safety and tolerability with continued DARO treatment in the ARAMIS Rollover Study (ROS; NCT04464226). Methods: Following the primary analysis of double-blind (DB) treatment, the ARAMIS study was unblinded, and all pts were permitted to continue on open-label (OL) DARO. After study completion, pts could continue DARO in the ROS if they had no evidence of metastases and were benefitting clinically. Of 955 pts initially randomized to DARO, 954 pts started DB DARO, 466 continued to OL DARO, and 294 entered the ROS. Pts received DARO 600 mg orally twice daily. DARO safety and treatment duration are described for the 954 pts over the DB, DB+OL, and DB+OL+ROS periods, with a data cutoff of Jan 31, 2022. Results: The median (range) treatment duration was 1.5 y (0.0–4.0) for DB DARO, 2.1 y (0.0–4.9) for DB+OL DARO, and 2.8 y (0.0–6.8) for DB+OL+ROS DARO. By the data cutoff date, 62.4% of the 954 pts had received DARO for ≥2 years, 30.1% for ≥4 years, and 12.8% for ≥5 yrs; 24.0% were still receiving DARO at data cutoff. Incidences of treatment-emergent adverse events (TEAEs) increased slightly as expected with longer observation time: any grade (DB 85.7%; DB+OL 89.8%; DB+OL+ROS 91.5%), grade 3/4 (26.3%; 31.8%; 35.5%), serious (26.1%; 32.1%; 38.5%), and leading to treatment discontinuation (8.9%; 10.5%; 12.9%). Increases in incidences of TEAEs of special interest across the DB, DB+OL, and DB+OL+ROS periods were mostly minimal. Conclusions: Approximately 30% of pts with nmCRPC remained on DARO for ≥4 y, suggesting long-term clinical benefit. The favorable safety profile of DARO was maintained with long-term exposure. No new safety concerns were observed with longer DARO treatment in the ROS. Clinical trial information: NCT04464226 . [Table: see text]

Dosing, safety, and pharmacokinetics (PK) of combination therapy with darolutamide (DARO), androgen-deprivation therapy (ADT), and docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study.

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; P&lt;0.001) vs placebo (PBO) + ADT + DOC in patients with mHSPC. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment groups. We report dosing, safety, and PK of coadministration of DARO and DOC with ADT. Methods: Patients with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, plus ADT and DOC (75 mg/m2 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 .

Darolutamide plus androgen-deprivation therapy (ADT) versus ADT in metastatic hormone-sensitive prostate cancer: Open-label single-arm study with an external control arm (ARASEC).

TPS297 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor. In the phase 3 ARAMIS study (NCT02200614) in nonmetastatic castration-resistant prostate cancer (CRPC), DARO + ADT significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT, with a favorable tolerability and safety profile. In the phase 3 ARASENS study (NCT02799602) in metastatic hormone-sensitive prostate cancer (mHSPC), DARO + ADT + docetaxel significantly reduced the risk of death by 32.5% vs ADT + docetaxel (hazard ratio 0.68; 95% confidence interval 0.57–0.80; P&lt;0.0001), with no additional adverse events. DARO + ADT vs ADT alone in patients (pts) with mHSPC is being evaluated in the ongoing, global (ex-US), phase 3 ARANOTE study (NCT04736199). The phase 2 ARASEC study (NCT05059236) will complement ARANOTE by evaluating DARO + ADT in US pts with mHSPC. Given that ADT alone is no longer an acceptable comparator in the US, an external control arm will be derived from a historical study. Methods: To participate in ARASEC, pts must have confirmed adenocarcinoma of the prostate, metastatic disease on conventional imaging for which they have not received prior systemic therapy, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Pts will receive DARO 600 mg twice daily + ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). ADT can be started ≤4 months before DARO, and there must be no evidence of progression on ADT before DARO initiation. The external control arm will be derived from 394 pts with mHSPC treated with ADT alone in CHAARTED (NCT00309985). Pts in the active and control arms will be matched 1:1 on baseline characteristics such as age, ECOG PS, CHAARTED-defined extent of disease, prior therapy, and Gleason score. The propensity score (ie, the assessed probability that a pt is allocated to the DARO + ADT arm based on baseline profile) will be used to address bias in estimating differential effects, by matching pts with scores within a narrow window across the cohorts. The primary endpoint is progression-free survival (PFS), defined as the time from enrollment to prostate-specific antigen (PSA) progression, radiologic or symptomatic progression, clinical deterioration, or death, whichever occurs first, as defined in CHAARTED. Secondary endpoints are OS, radiographic PFS, time to CRPC, 6-month PSA response (&lt;0.2 ng/mL), and safety. The study will continue until either the event count threshold triggering the primary endpoint analysis (161 PFS events) has been met or all pts have been followed for ≥2 years after enrollment, whichever occurs later. ARASEC is enrolling, with the first pt enrolled in November 2021. As of September 10, 2022, 59 pts have been enrolled. The target total enrollment is 200 pts at 30 sites. Clinical trial information: NCT05059236 .