The real-world OPTYX study (NCT05467176) has completed enrollment and reported early data regarding the use of the oral androgen deprivation therapy (ADT) relugolix (Orgovyx), which many patients with advanced prostate cancer preferred over injection administration, according to findings presented during the 

Data from OPTYX showed that most patients (52.2%) in the overall population (n = 999) received relugolix in combination with other prostate cancer therapies, including radiation and systemic treatments. Moreover, a notable portion of treatment initiated was due to a preference for oral relugolix over injection by physicians (41.5%) and patients (36.4%). Other key factors for physician and patient initiation of the agent included rapid testosterone suppression (34.6% vs 9.8%, respectively), safety profile (29.0% vs 9.5%), efficacy data (25.5% vs 6.6%), and rapid testosterone recovery (21.0% vs 10.2%).

“The OPTYX study focuses on the clinical characteristics and preferences for initiating relugolix in a cohort of US patients in real-world care settings,” Daniel E. Spratt, MD, chairman and professor in the Department of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University, and member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center in Cleveland, Ohio, said in a presentation of the data. “OPTYX is the first prospective study to collect long-term, real-world data on relugolix for [the treatment of] advanced prostate cancer. This study aims to provide evidence on the safety, effectiveness, treatment patterns, disease course, and patient outcomes with relugolix.”

 for the treatment of adult patients with advanced prostate cancer.

 The approval was supported by findings from the phase 3 HERO (NCT03085095), which demonstrated that patients who received the agent (n = 622) experienced a medical castration rate of 96.7% (95% CI, 94.9%-97.9%) compared with 88.8% (95% CI, 84.6%-91.8%) among patients who received leuprolide acetate(Eligard, n = 308).

OPTYX Study Design and Additional Patient Characteristics

The multicenter, observational OPTYX study included adult patients with advanced prostate cancer in the US who initiated treatment with the agent at the time of enrollment or within 1-month preceding enrollment and who were willing to complete patient assessments. Patients with a history of surgical castration, a medical or psychiatric condition that precludes participation, and/or an original treatment plan that is intended to be less than a total of 4 months of relugolix were excluded from the study.

Over the course of 3 to 5 years, investigators will collect patient data twice annually. Patient-reported outcomes will be assessed via the Functional Assessment of Cancer Therapy–Prostate scale and patient adherence assessments will be via the simplified medication adherence questionnaire. Patient and disease demographics will also be obtained, including key comorbidities, cardiac risk factors, prostate cancer history, disease progression, current prostate treatments, and prostate-specific antigen (PSA) levels. Relugolix efficacy and safety data will also be tracked, including the instances of nonserious and serious adverse effects (AEs) leading to treatment discontinuation.

Patients will be followed for up to 5 years. If a patient discontinues treatment with relugolix, they may be followed for up to 2 years after treatment cessation. Follow-up will also be ended with patient withdrawal, loss to follow-up, death, or end-of-study, whichever occurs first.

The primary objectives of the study are to describe the real-world demographics and clinical characteristics of patients with prostate cancer who are initiating treatment with relugolix, as well as safety, health outcomes, and changes in health-related quality of life among patients who are treated with the agent. Secondary objectives include examining prostate cancer progression during treatment with and following cessation of relugolix therapy and to describe patient adherence and persistence.

Between October 2022 and September 2024, 28.2% of patients included in OPTYX discontinued treatment with relugolix, primarily due to completing the treatment course (15.9%) and AEs (5.0%).

 The median treatment duration was 243.8 days.

Additional preliminary data from OPTYX indicated that evaluable patients who received relugolix monotherapy (n = 477) or relugolix combination therapy (n = 522) at baseline most commonly had local (n = 190 vs n = 231, respectively) or locally advanced (n = 97 vs n = 69) disease. Patients also had prostate cancer with biochemical recurrence (n = 60 vs n = 53), metastatic castration sensitive prostate cancer (n = 80 vs n = 107), nonmetastatic castration resistant prostate cancer (CRPC; n = 7 vs n = 7), and metastatic CRPC (n = 19 vs n = 29), as well as other (n = 16 vs n = 22) and unknown (n = 8 vs n = 4), disease states at baseline.

Patients who received baseline relugolix monotherapy or relugolix in combination with other prostate cancer therapies were a mean age of 71.7 years (SD, 7.98) vs 69.9 years (SD, 8.69), respectively. Most patients in both groups were White (73.8% vs 80.5%) and did not have distant metastasis at enrollment (62.9% vs 64.8%). Gleason score ranges were comprised of 6 or less (7.3% vs 3.8%), 3+4 = 7 (17.4% vs 17.2%), 4+3 = 7 (21.8% vs 27.4%), 8 (19.7% vs 18.2%), and 9 to 10 (21.4% vs 24.7%).

Initial types of treatment in the monotherapy and combination groups consisted of active surveillance/watchful waiting (21.6% vs 18.0%, respectively), prostatectomy (27.0% vs 20.9%), ADT (7.8% vs 8.4%), radiotherapy (7.3% vs 11.5%), and other treatments (36.3% vs 41.2%). Most patients in the monotherapy group (99.2%) did not undergo prostate cancer radiotherapies at enrollment; 60.7% of patients in the combination group received radiotherapies at enrollment, including external beam therapy (50.6%), brachytherapy (1.3%), external beam therapy and brachytherapy (3.4%), and other forms of radiotherapy (5.4%). Most patients in both arms (78.4% vs 62.6%) had a urologist as their health care provider.

In the overall population, the median testosterone concentration at baseline was 271.5 ng/dL (range, 2.0-1250.0); 19.3% of patients had a median testosterone concertation of less than 50 ng/dL and 14.9% of patients had a median concentration of less than 20 ng/dL. The median PSA concentration at baseline was 7.1 ng/mL (range, 0.0-5000.0) and only 1.0% of patients had a median concentration of less than 0.02 ng/mL.

“Baseline testosterone and PSA levels were higher in ADT-naive patients compared with those [who received] prior ADT,” Spratt said. “This highlights the importance of considering patient history when initiating treatment with relugolix.”

Additional reasons for relugolix initiation by physicians and patients included tolerability (11.9% vs 5.5%, respectively), comorbid disease (7.6% vs 1.7%), physician recommendation (6.0% vs 72.3%), and other/unknown (16.0% vs 5.6%).

“As more data [are] collected, the results will help inform clinical decision making for [patients with] prostate cancer,” Spratt concluded.

Disclosures: Dr Spratt reported having consulting or advisory roles with Janssen Oncology, AstraZeneca, Boston Scientific, Bayer, Blue Earth Diagnostics, Pfizer, Astellas Scientific and Medical Affairs Inc, and Novartis. He also reported receiving research funding from Janssen and uncompensated relationships with the NCCN.

Spratt D, McKay R, Ross A, et al. OPTYX study: clinical characteristics and preferences for initiating relugolix in a cohort of US patients in real-world care settings. 

. 2025;43(suppl 5):67. doi:10.1200/JCO.2025.43.5_suppl.67

FDA approves relugolix for advanced prostate cancer. FDA. December 18, 2020. Accessed February 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-relugolix-advanced-prostate-cancer

Orgovyx. Prescribing information. Bushu Pharmaceuticals; 2020. Accessed February 19, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214621s000lbl.pdf

Spratt DE, Dorff T, McKay RR, Lowentritt BH, Fallick M, Gatoulis SC, Flanders SC, Ross AE. Evaluating relugolix for the treatment of prostate cancer in real-world settings of care: the OPTYX study protocol. 

. 2024;20(12):727-738. doi:10.2217/fon-2023-0748

Articles

The OPTYX study has provided early data on the use of oral androgen deprivation therapy (ADT) relugolix for advanced prostate cancer, showing a preference for oral administration over injections. The study, which enrolled 999 patients, revealed that relugolix was often used in combination with other therapies. Key reasons for choosing relugolix included rapid testosterone suppression, safety, and efficacy. The study aims to provide real-world data on relugolix's safety, effectiveness, and patient outcomes. Preliminary findings indicate a significant portion of patients discontinued treatment due to adverse effects or completing the treatment course.

Patients with advanced prostate cancer who initiated treatment with relugolix indicated various treatment preferences and reasons for therapy initiation. 

OPTYX Study Offers Preliminary Glance Into Real-World Use of Relugolix in Advanced Prostate Cancer

More than 90% of patients on Medicare with prostate cancer adhered to relugolix (Orgovyx) through 24 months when receiving therapy regardless of metastatic disease status, supporting the use of the androgen deprivation therapy (ADT) in this patient population, according to findings from a real-world study presented at the 

The retrospective cohort study found that the probability of being adherent as well as persistent to relugolix in the first 3 months was 86% in each group. Respective adherence and persistence rates among those with metastatic (n = 1599) vs nonmetastatic (n = 3512) disease who had at least an 80% proportion of days covered were as follows at 6-months (82% vs 76%), 9-months (71% vs 55%), 12-months (67% vs 49%), 18-months (58% vs 38%), and 24-months (55% vs 28%). Notably, in both groups of patients, rates of adherence improved the longer patients received therapy; the overall rate of adherence was 93% and rates were 90% at month 3 and 98% at month 24.

Additionally, patients with metastatic prostate cancer (n = 1671) remained on relugolix for longer compared with patients who had nonmetastatic disease (n = 3603) as the median duration of relugolix was 9 months (IQR, 5-15) in the metastatic cohort vs 7 months (IQR, 4-12) and in the nonmetastatic group. The median follow-ups were 14 months (IQR, 8-23) and 15 months (IQR, 9-23), respectively.

“[The] mean (standard deviation) time to discontinuation [was] 10.9 (8.1) and 9.2 (6.8) months, respectively (log-rank test, 

 < .0001),” Rana R. McKay, MD, FASCO, medical oncologist, UC San Diego Health, and professor, Department of Medicine and Urology, UC San Diego School of Medicine, and lead study author, wrote in a poster presentation of the data. “These findings, along with the adherence results from the randomized, phase 3 HERO trial [NCT03085095], support the use of relugolix in patients with prostate cancer.”

Background to the Study and Evaluating Persistence/Adherence Outcomes

Relugolix is the only oral once-daily dosed ADT and is a highly, selective gonadotropin-releasing hormone receptor antagonist. Data from HERO showed that the treatment adherence rate was more than 99% with relugolix and 90.2% of the patients completed 48 weeks of treatment compared with 89.0% of those who received leuprolide.

 Although the adherence rate to relugolix was greater than 99% in HERO, investigators of the retrospective study noted that further research was warranted to understand persistence and adherence rates associated with oral ADTs outside of the clinical trial setting.

Patients with metastatic and nonmetastatic prostate cancer were evaluated separately in this analysis during the study period of December 1, 2019, to December 31, 2023, as the treatment protocols for these groups differ; those with recurrent nonmetastatic disease receive intermittent ADT and those with metastatic disease receive continuous ADT as the backbone of their treatment. Those included in the study had initiated relugolix and were in the US Medicare fee-for-service beneficiary population with prostate cancer (n = 5274). The baseline period was 1 year before the index date, defined as the first observed prescription fill of relugolix. Patients must have filled 2 or more pharmacy claims for the ADT to be evaluated in the study.

Additionally, patients in the analysis were adult males with at least 1 diagnosis code for prostate cancer based on International Classification of Diseases, 10th Revision, Clinical Modification, in the baseline period through 90 days after the index date. Exclusion criteria included those who had bilateral orchiectomy, participated in a clinical trial, or had been diagnosed with other cancers aside from nonmelanoma skin cancer during the baseline period.

“Persistence on relugolix was assessed from index date to first discontinuation, defined as the earliest of 1) switch to a different ADT, 2) a gap of [at least] 90 days between prescription end and next relugolix claim, 3) death, or 4) end of the study period,” McKay and coauthors noted.

The study defined adherence using a proportion of days covered calculation of at least 80% which was assessed as the “percentage of nonoverlapping days patients had access to relugolix based on prescriptions filled and days supplied.” Additionally, calculations were adjusted for inpatient and skilled nursing facility stays, and adherence outcomes were assessed via 2 ways. The first way evaluated them at 3-, 6-, 9-, 12-, 18-, and 24-months among those with follow-up where outcomes “provide the probability of being both adherent and persistent on relugolix in each time period, provided that patients did not die during the entirety of the time period.” Second, they were examined every 3 months through month 24 following the index date among patients who persisted on the ADT where “outcomes provide the proportions of patients adherent on relugolix while remaining on therapy.”

Baseline Patient Characteristics and Limitations of the Retrospective Analysis

Of the 5274 patients included in the study, 32% had metastatic disease and 68% had nonmetastatic. Patients had previously received ADT therapy (39% vs 21%), were predominately White (81% vs 79%), were eligible for the Medicare Part D low-income subsidy (11% vs 12%), and had a COVID-19 diagnosis during the baseline period (10% vs 10%), respectively. Additionally, the median age was 75 years in both arms.

Regarding limitations of the study, investigators noted that reasons for discontinuation and confirmed medication ingestion information was unavailable as the results were based on administrative claims data which does not include this information. They also added that “the generalizability of the results may be limited to the US Medicare population captured in the Centers for Medicare and Medicaid Services Medicare 100% research identifiable data source.”

Disclosures: McKay has a consulting or advisory role with Ambrx, Arcus Biosciences, Astellas Medivation, AstraZeneca, AVEO, Bayer, Blue Earth Diagnostics, Bristol-Myers Squibb, Calithera Biosciences, Caris Life Sciences, Dendreon, Esiai, Exelixis, Janssen, Lilly, Merck, Myovant Sciences, NeoMorph, Novartis, Pfizer, Sanofi, Seagen, Sorrento Therapeutics, Sumitomo Pharma Oncology, Telix Pharmaceuticals, Tempus, and Vividion Therapeutics. She has also received institutional research funding from Artera, AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Oncternal Therapeutics, and Tempus.

McKay RR, Hong A, Razo JF, et al. Real-world persistence and adherence to relugolix (REL) in US patients with nonmetastatic (nm) vs metastatic (m) prostate cancer (PC). 

2025;43(suppl 5):88. doi:10.1200/JCO.2025.43.5_suppl.88

Shore ND, Saad F, Cookson MS, et al; HERO Study Investigators. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. 

. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325

A real-world study presented at the 2025 Genitourinary Cancers Symposium demonstrated that over 90% of Medicare patients with prostate cancer adhered to relugolix therapy over 24 months, regardless of metastatic status. The study highlighted higher adherence and persistence rates in metastatic patients compared to nonmetastatic ones. Relugolix, an oral ADT, showed improved adherence over time, with a 98% adherence rate at 24 months. The study's findings support relugolix's use in prostate cancer treatment, although limitations include reliance on administrative claims data and generalizability to the US Medicare population.

Adherence rates improved the longer patients with metastatic and nonmetastatic prostate cancer received relugolix for a high overall adherence rate.

Real-World Relugolix Adherence Rates Are High in Patients on Medicare With Prostate Cancer 

The addition of olaparib (Lynparza) to abiraterone acetate (Zytiga) demonstrated clinical benefit regarding radiographic progression-free survival (rPFS) and overall survival (OS) vs placebo plus abiraterone as first-line therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) and germline or somatic 

 mutations, according to a post hoc analysis from the phase 3 PROpel trial (NCT03732820) presented at the 

Regarding rPFS in patients with a germline 

 mutation (n = 25), events occurred in 33.3% vs 100% of those in the olaparib/abiraterone (n = 15) and placebo/abiraterone (n = 10) arms, respectively.; the median rPFS was not reached (NR) vs 6.9 months (HR, 0.13; 95% CI, 0.04-0.38). In patients with a somatic 

 mutation (n = 52), events occurred in 25.9% vs 68.0% of those in the olaparib/abiraterone (n = 27) and placebo/abiraterone (n = 25) arms, respectively; the median rPFS was NR vs 11.1 months (HR, 0.19; 95% CI, 0.07-0.45).

Additionally, OS events occurred in 33.3% vs 90.0% of patients with germline 

 mutations in the olaparib/abiraterone and placebo/abiraterone arms, respectively; the median OS was NR vs 18.4 months (HR, 0.23; 95% CI, 0.07-0.67). In patients with a somatic 

 mutation, OS events occurred in 22.2% vs 60.0% of those in the olaparib/abiraterone and placebo/abiraterone arms, respectively; the median OS was NR vs 27.5 months (HR, 0.26; 95% CI, 0.09-0.65).

“First-line use of olaparib plus abiraterone resulted in clinical benefit for rPFS and OS in patients with mCRPC and a germline or somatic 

 mutation,” said Fred Saad, CQ, MD, FRCS, FCAHS, in a poster presentation at the meeting. “[Therefore,] our results highlight the importance of comprehensive biomarker testing, including tumor tissue and circulating tumor DNA [ctDNA] testing to inform treatment options, such as intensification of therapy with the combination of olaparib plus abiraterone.”

Saad is a full professor in the Department of Surgery at the Université de Montréal, uro-oncologist and the Raymond Garneau Chair in Prostate Cancer at the University of Montréal Hospital Center (CHUM) Research Center (CRCHUM), head of Urology at CHUM, and director of Prostate Cancer Research at the Montréal Cancer Institute/CRCHUM in Canada. 

 for the treatment of patients with deleterious or suspected deleterious 

-mutated mCRPC, as determined by an FDA-approved companion diagnostic test.

At the primary analysis data cutoff of July 30, 2021, the trial met its primary end point of rPFS, demonstrating significantly prolonged rPFS with olaparib/abiraterone vs placebo/abiraterone HR, 0.66; 95% CI, 0.54-0.81; 

The multicenter, randomized, double-blind, placebo-controlled PROpel study evaluated the efficacy, safety, and tolerability of first-line olaparib/abiraterone compared with placebo/abiraterone in patients with mCRPC who did not previously receive chemotherapy or new hormonal agents (NHAs) for mCRPC.

 Patients were randomly assigned to the olaparib/abiraterone (n = 399) or placebo/abiraterone arms (n = 397).

 Those in the olaparib/abiraterone arm were treated with olaparib at 300 mg twice daily plus abiraterone at 1000 mg once daily in combination with prednisone or prednisolone at 5 mg twice daily; those in the placebo/abiraterone arm received placebo plus abiraterone at 1000 mg once daily with prednisone or prednisolone at 5 mg twice daily.

Eligibility criteria included being 18 years of age or older; having histologically or cytologically confirmed prostate adenocarcinoma; an ECOG performance status of 0 or 1; metastatic status with at least 1 documented metastatic lesion via bone scan or CT/MRI scan; and mCRPC in the first line.

 Additionally, patients needed to be asymptomatic, mildly symptomatic, or symptomatic with no prior exposure to abiraterone. Other NHAs were allowed if they were discontinued at least 12 months before enrollment.

 Stratification factors included site of distant metastases (bone only vs visceral vs other), and receipt of prior taxane therapy for metastatic hormone-sensitive prostate cancer (yes vs no).

In addition to investigator-assessed rPFS and OS, which served as the primary and key secondary end points, respectively, additional planned analyses included time to first subsequent therapy or death; prostate-specific antigen (PSA) progression; time to second progression or death; confirmed decrease in PSA from baseline by 50% or greater; health-related quality of life; objective response rate; homologous recombination repair (HRR) mutation status; and safety and tolerability.

Baseline Characteristics of the Entire Study Population

Patients in the olaparib/abiraterone arm had a median age of 69.0 years (range, 63-74), and the majority were White (71%) and not Hispanic or Latinx (78%).

The majority of patients had a Gleason score of 8 or greater (66%) and an ECOG performance status of 0 (72%). A total of 26% of patients in this arm were symptomatic, and 24% were treated with docetaxel prior to mCRPC. Most patients had their site of disease in the bone (87%), and did not have HRR gene mutations (aggregate, 70%; ctDNA testing, 67%; tumor tissue testing, 52%) or 

In the placebo/abiraterone arm, the median age was 70.0 years (range, 65-76), and the majority were White (69%) and not Hispanic or Latinx (77%). Most patients had a Gleason score of 8 or greater (65%) and an ECOG performance status of 0 (69%). A total of 20% of patients in this arm were symptomatic and 25% were treated with docetaxel prior to mCRPC. Most patients had their site of disease in the bone (85%), and did not have HRR gene mutations (aggregate, 69%; ctDNA testing, 67%; tumor tissue testing, 53%) or 

At the data cutoff of July 30, 2021, in the intent-to-treat (ITT) population the median rPFS per investigator assessment was 24.8 months vs 16.6 months in the olaparib/abiraterone arm vs the placebo/abiraterone arm, with a two-sided boundary for significance of 0.0324 (HR, 0.66; 95% CI, 0.54-0.81; 

 = .0001). Of note, the greatest effect size was demonstrated in the subgroup of patients with 

 mutations, with a median investigator-assessed rPFS that was NR vs 8.4 months in the olaparib/abiraterone (n = 47) vs placebo/abiraterone arms (n = 38; HR, 0.23; 95% CI, 0.12-0.43), according to post hoc analyses published in 

At the data cutoff of October 12, 2022, the median OS among patients from the ITT population was 42.1 months vs 34.7 months in the olaparib/abiraterone and placebo/abiraterone arms, respectively, with a two-sided boundary for significance of 0.0377 (HR, 0.81; 95% CI, 0.67-1.00; 

 mutation subgroup had a median OS that was NR vs 23.0 months in the olaparib/abiraterone vs placebo/abiraterone arms (HR, 0.29; 95% CI, 0.14-0.56).

Saad F, Armstrong A, Oya M, et al. Efficacy of olaparib (ola) plus abiraterone (abi) versus placebo (pbo) plus abi in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with a germline or somatic BRCA mutation in the PROpel trial. 

2025;43(suppl 5):219. doi:10.1200/JCO.2025.43.5_suppl.219

FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 31, 2023. Accessed February 13, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration

Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. 

. 2022;1(9):EVIDoa2200043. doi:10.1056/EVIDoa2200043

Study on olaparib plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated October 8, 2024. Accessed February 13, 2025. https://clinicaltrials.gov/study/NCT03732820

Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. 

. 2023;24(10):1094-1108. doi:10.1016/S1470-2045(23)00382-0

The combination of olaparib and abiraterone significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA mutations, compared to placebo plus abiraterone. The PROpel trial demonstrated that patients with germline or somatic BRCA mutations experienced fewer progression events and longer survival when treated with the combination therapy. These findings underscore the importance of comprehensive biomarker testing to guide treatment decisions. The FDA approved this combination for BRCA-mutated mCRPC in 2023.

First-line therapy with olaparib plus abiraterone demonstrated clinical benefit in rPFS and OS in mCRPC harboring germline and somatic BRCA mutations. 

Olaparib Plus Abiraterone Improves Radiographic PFS and OS in BRCA+ mCRPC

Efficacy outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC) were improved following treatment with darolutamide (Nubeqa) in combination with androgen deprivation therapy (ADT) compared with placebo plus ADT irrespective of disease volume, according to findings from the phase 3 ARANOTE trial (NCT04736199).

Data from a subgroup analysis of ARANOTE presented during the 

 demonstrated that patients with high-volume disease who received darolutamide (n = 315) achieved a median radiological progression-free survival (rPFS) of 30.2 months (95% CI, 28.8-not reached [NR]) compared with 19.2 months (95% CI, 16.1-26.0) among those who received placebo (n = 157; HR, 0.60; 95% CI, 0.44-0.80). Patients with low-volume disease achieved a median rPFS of NR (95% CI, NR-NR) in the investigational arm (n = 131) vs NR (95% CI, 25.0-NR) in the control arm (n = 66; HR, 0.30; 95% CI, 0.15-0.60).

“The phase 3 ARASENS study [NCT02799602] demonstrated a greater than 30% reduction in the risk of death with the combination of darolutamide plus ADT and docetaxel, which has become a standard of care for the treatment of patients with mHSPC,” Fred Saad, MD, FRCS, said during a presentation of the data. “In ARANOTE, darolutamide plus ADT significantly improved rPFS, reducing the risk of radiological progression or death by 46%. Volume of disease is a prognostic factor for patients with mHSPC and here we report a post-hoc analysis of ARANOTE to evaluate the efficacy and safety of darolutamide by disease volume.”

Saad is the director of prostate cancer research at the Montreal Cancer Institute, a uro-oncologist in the Urology Department, and a full professor in the Department of Surgery at the Centre Hospitalier de l'Université de Montréal in Canada.

FDA accepted a supplemental new drug application

 (sNDA) seeking the approval of darolutamide plus ADT for the treatment of patients with mHSPC.

 The sNDA was supported by previous data from ARANOTE. Findings from ARANOTE presented during the 

 showed that regardless of disease volume patients who received darolutamide plus ADT (n = 446) achieved a median rPFS of NR (95% CI, NR-NR) vs 25.0 months (95% CI, 19.0-NR) in the placebo arm (n = 223; HR, 0.54; 95% CI, 0.41-0.71; 

Diving Into the ARANOTE Trial and Baseline Characteristics

ARANOTE was a global, double-blind study that enrolled patients with mHSPC who had an ECOG performance status of 0 to 2. Patients were stratified based on the presence of visceral metastases (yes vs no) and receipt of prior local therapy (yes vs no). Eligible patients were randomly assigned 2:1 to receive darolutamide at a dose of 600 mg twice daily or placebo, both in combination with ADT.

The primary end point was rPFS by central blinded review. Secondary end points included overall survival (OS), time to initiation of subsequent anticancer therapy, time to metastatic castration-resistant prostate cancer (mCRPC), time to prostate-specific antigen (PSA) progression, rates of undetectable PSA (< 0.2 ng/mL), time to pain progression, and safety.

In the post-hoc analysis that Saad presented, patients were evaluated based on disease volume per CHAARTED criteria.

 High-volume disease was defined as the presence of visceral metastases and/or at least 4 bone lesions with at least 1 lesion beyond the vertebral bodies and pelvis. Low-volume disease was defined as not meeting the high-volume criteria.

At baseline, the median age of the overall patient population was 70.0 years (range, 43-93). Most patients had a Gleason score of at least 8 at initial diagnosis (68.3%) and de novo metastasis at initial diagnosis (72.5%). The study also included patients with visceral metastases (12.0%), those who had received prior local therapy (17.9%), and those with an ECOG performance status of 0 (49.8%). The median serum PSA level at baseline was 21.3 ng/mL (range, 0.02-15,915).

Further Efficacy and Safety Data from the Analysis

Additional findings from the post-hoc analysis showed that patients in the high- and low-volume groups experienced a delayed time to mCRPC with darolutamide plus ADT vs placebo plus ADT, which was consistent with the benefit observed in the overall population (HR, 0.40; 95% CI, 0.32-0.51). Patients with high-volume disease in the investigational and control arms achieved a median time to mCRPC of NR (95% CI, 22.2-NR) vs 12.4 months (95% CI, 11.1-13.9), respectively (HR, 0.46; 95% CI, 0.36-0.60). In the low-volume group, the median time to mCRPC was NR (95% CI, NR-NR) vs 19.8 months (95% CI, 13.8-NR), respectively (HR, 0.21; 95% CI, 0.12-0.37).

The addition of darolutamide to ADT also led to a benefit compared with placebo plus ADT across all secondary end points examined. The greatest benefits were reported in time to initiation of subsequent systemic anticancer therapy in patients with low-volume disease (HR, 0.19; 95% CI, 0.08-0.43), time to PSA progression in patients with low-volume disease (HR, 0.19; 95% CI, 0.10-0.37), and time to PSA progression in patients with high-volume disease (HR, 0.34; 95% CI, 0.25-0.46).

“OS results were immature, but suggestive of a benefit with darolutamide vs placebo,” Saad noted.

Evaluable patients with high-volume disease in the darolutamide arm (n = 304) had undetectable PSA levels 24, 36, and 48 weeks after random assignment at rates of 44%, 48%, and 50%, respectively; 55% of these patients achieved undetectable PSA at any time. Comparatively, patients in the placebo arm (n = 148) achieved undetectable PSA at rates of 11%, 13%, 14%, and 16%, at the respective time points.

Patients with low-volume disease who received darolutamide (n = 121) also experienced undetectable PSA levels at higher rates compared with those who received placebo (n = 63) at the 24- (72% vs 17%, respectively), 36- (78% vs 19%), and 48-week (79% vs 19%) time points. Patients experienced undetectable PSA at any time at rates of 83% vs 25%, respectively.

In terms of safety, patients with high-volume disease who received darolutamide (n = 314) or placebo (n = 156) both experienced any-grade treatment-emergent adverse effects (TEAEs; 93.0% vs 91.7%, respectively), grade 3 or 4 TEAEs (31.2% vs 31.2%), serious TEAEs (28.3% vs 25.6%), and TEAEs leading to study drug discontinuation (7.3% vs 8.3%). Patients with low-volume disease in the darolutamide (n = 131) and placebo (n = 65) arms also experienced any-grade TEAEs (86.3% vs 86.2%), grade 3 or 4 TEAEs (29.8% vs 26.2%), serious TEAEs (12.2% vs 18.5%), and TEAEs leading to study drug discontinuation (3.1% vs 10.8%).

“Efficacy outcomes with darolutamide plus ADT were improved vs placebo plus ADT regardless of disease volume,” Saad said in conclusion. “Darolutamide plus ADT was well tolerated in both high-volume and low-volume subgroups with low treatment discontinuation rates consistent with the overall population and reconfirming the established tolerability of darolutamide. Patients with low-volume mHSPC had marked treatment efficacy with minimal treatment burden.”

Disclosures: Dr Saad reports receiving honoraria from Abbvie; Advanced Accelerator Applications; Astellas Pharma; AstraZeneca; Bayer; Bristol Myers Squibb; Janssen Oncology; Knight Therapeutics; Merck; Myovant Sciences; Novartis; Pfizer; Sanofi; and Tolmar. He has consulting or advisory roles with Abbvie; Advanced Accelerator Applications; Astellas Pharma; AstraZeneca/MedImmune; Bayer; Janssen Oncology; Knight Therapeutics; Myovant Sciences; Novartis; Pfizer; Sanofi; and Tolmar. He has received research funding from Advanced Accelerator Applications; Astellas Pharma; AstraZeneca; Bayer; Bristol-Myers Squibb; Janssen Oncology; Merck; Novartis; Pfizer; and Sanofi.

Saad F, Shore N, Vjaters E, et al. Darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) by disease volume: subgroup analysis of the phase 3 ARANOTE trial. 

. 2025;43(suppl 5):151. doi:10.1200/JCO.2025.43.5_suppl.151

U.S. FDA accepts supplemental new drug application for Nubeqa (darolutamide) for the treatment of patients with metastatic hormone-sensitive prostate cancer. News release. Bayer. November 21, 2024. Accessed February 13, 2025. https://www.biospace.com/press-releases/u-s-fda-accepts-supplemental-new-drug-application-for-nubeqa-darolutamide-for-the-treatment-of-patients-with-metastatic-hormone-sensitive-prostate-cancer

Saad F, Vjaters E, Shore ND, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial. 

. 2024;35(suppl 2):S1257-S1258. doi:10.1016/j.annonc.2024.08.2311

Darolutamide combined with androgen deprivation therapy (ADT) significantly improved radiological progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) compared to placebo plus ADT, regardless of disease volume. The ARANOTE trial demonstrated a 46% reduction in the risk of radiological progression or death. High-volume disease patients showed a median rPFS of 30.2 months with darolutamide versus 19.2 months with placebo. The treatment was well-tolerated, with low discontinuation rates, and showed consistent efficacy across secondary endpoints, including time to metastatic castration-resistant prostate cancer (mCRPC).

The addition of darolutamide to ADT improved rPFS and other efficacy end points vs placebo plus ADT in mHSPC.

Darolutamide Plus ADT Is Efficacious in mHSPC Regardless of Disease Volume

A composite gene expression score (CTCm) calculated from pretreatment circulating tumor cells (CTCs) demonstrated a correlation with outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who had been treated with bavdegalutamide (formerly ARV-110) in the phase 1/2 ARDENT trial (NCT03888612), according to findings from a single-center analysis presented at the 

“A pretreatment CTCm score [of less than] 165 was associated with freedom from radiographic progression at 2 months and time on bavdegalutamide [of longer than] 6 months in this small study of [patients with] mCRPC without androgen receptor [AR] T878/H875 mutations,” Keisuke Otani, MD, PhD, a research fellow in radiation oncology at Massachusetts General Hospital in Boston, and coauthors wrote in the poster presented during the meeting.

Bavdegalutamide is a first-in-class oral proteolysis targeting chimera (PROTAC) protein degrader that selectively targets the AR. 

illustrated the activity of bavdegalutamide in patients with mCRPC whose disease had progressed after 1 to 2 AR-directed therapies.

 Patients with AR wild-type disease exhibited clinical benefit, but the most pronounced activity was seen in those with T878X/H875Y mutations in the AR.

To better understand the patient population who derives the most benefit from bavdegalutamide and potentially identify a biomarker of response investigators evaluated the potential of a CTC RNA biomarker that would enrich for response.

The single-center study enrolled patients with progressive mCRPC following more than 1 prior novel hormonal therapy who were enrolled in the ARDENT trial and had consented for prospective collection of pretreatment blood for CTC analysis.

Per the protocol, CTCs were isolated using a negative selection microfluidic CTC enrichment device and evaluated for RNA expression of a panel of prostate cancer genes using a multiplex droplex digital polymerase chain reaction assay. The genes and proteins that were subject to evaluation included 

, and AR-V7. The CTCm was compared with radiographic response at 2 months, prostate-specific antigen (PSA) response, and duration of time on bavdegalutamide. A cutoff value for CTCm was selected by the receiver operating characteristic curve analysis. The relationship between CTCm and clinical outcomes was evaluated by the 2-sided Fisher’s exact test.

The median age of the patient cohort (n = 20) was 73 years (range, 56-84). Patients were White (90%), Hispanic (5%), or Asian (5%), and had an ECOG performance status of 0 (80%) or 1 (20%). The median PSA level at baseline was 123.1 ng/mL (range, 4.97-1186). Bone and visceral metastases were present in 95% and 20% of patients, respectively. The median number of prior lines of systemic therapy was 5 (range, 3-7). Most patients had received prior chemotherapy (80%) vs not (20%), and 30%, 65%, and 5% of patients had previously received 1, 2, or 3 AR pathway inhibitors, respectively.

All 20 patients who had been treated with bavdegalutamide at doses ranging from 280 mg to 700 mg once daily or 140 mg to 420 mg twice daily consented to pretreatment CTC RNA expression analysis. None of these patients harbored T878/H875 mutations in the AR.

Additional results indicated that 6 patients remained on therapy for at least 6 months with clinical benefit whereas 14 patients discontinued treatment within 6 months. At 2 months, 10 patients had stable radiographic responses, and 7 patients had evidence of progressive disease. Three patients were not evaluable for response. Notably, a pretreatment CTCm score below 165 correlated with stable disease at 2 months (

 = .015) and time on therapy for longer than 6 months (

 = .014). However, CTCm was not associated with PSA reductions of at least 50% (PSA50; 

 > .9) or PSA reductions of at least 30% (PSA30; 

Best PSA50 and PSA30 occurred in 3 and 4 patients, respectively. Notably, the presence of AR-V7 was not associated with radiographic response (

 = .60), or time on therapy for more than 6 months (

“Further investigation of the CTCm biomarker is warranted in [patients with] mCRPC treated with bavdegalutamide and potentially other AR PROTACs,” study authors concluded.

Disclosures: Otani had no relationships to disclose.

Otani K, Gao X, Kusaka E, et al. Circulating tumor cell RNA biomarker for bavdegalutamide (ARV-110) in metastatic castration-resistant prostate cancer without AR T878/H875 mutations. 

. 2025;43(suppl 5):235. doi:10.1200/JCO.2025.43.5_suppl.235

Gao X, Burris III HA, Vuky J, et al. Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). 

. 2022;40(suppl 6):017. doi:10.1200/JCO.2022.40.6_suppl.017

A composite gene expression score (CTCm) from pretreatment circulating tumor cells (CTCs) was linked to outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients treated with bavdegalutamide in the ARDENT trial. A CTCm score below 165 correlated with stable disease at 2 months and extended therapy duration. The study involved patients without AR T878/H875 mutations, highlighting the potential of CTCm as a biomarker for response. Further research is needed to validate CTCm's utility in mCRPC treated with bavdegalutamide and other AR PROTACs.

A low composite gene expression score was associated with improved outcomes in patients with mCRPC who received bavdegalutamide. 

2025 Genitourinary Cancers Symposium Priority Report | Supplements and Featured Publications

OPTYX Study Offers Preliminary Glance Into Real-World Use of Relugolix in Advanced Prostate Cancer

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Olaparib Plus Abiraterone Improves Radiographic PFS and OS in BRCA+ mCRPC

Darolutamide Plus ADT Is Efficacious in mHSPC Regardless of Disease Volume

Composite Gene Expression Score Shows Potential to Predict Bavdegalutamide Benefit in mCRPC