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Darolutamide in extended duration shows safety and efficacy for nonmetastatic CRPC


“The ARAMIS Rollover Study extended the duration of darolutamide treatment and demonstrated the long-term safety of darolutamide in patients with [nonmetastatic CRPC],” said Neal D. Shore, MD.

For patients with nonmetastatic castration-resistant prostate cancer (CRPC), darolutamide (Nubeqa) treatment that was given in an extended duration was associated with long-term clinical benefit as well as safety.1

Findings from the ARAMIS Rollover Study (ROS; NCT04464226) were presented during the 2023 American Urological Association Annual Meeting in Chicago, Illinois.

At the data cutoff date of January 31, 2022, 30.1% of patients had received darolutamide for at least 4 years and 24% of patients were still on treatment with the androgen receptor (AR) inhibitor. Additionally, the safety profile with darolutamide was maintained with long-term exposure, with a minimal increase in incidences of exposure-adjusted treatment-emergent adverse effects (TEAEs) that are often linked with AR therapies. No new safety concerns were reported in ARAMIS ROS.

Neal D. Shore, MD

Neal D. Shore, MD

“The ARAMIS Rollover Study extended the duration of darolutamide treatment and demonstrated the long-term safety of darolutamide in patients with [nonmetastatic CRPC],” lead investigator Neal D. Shore, MD, director of Carolina Urologic Research Center, and coinvestigators, wrote in a poster presented during the meeting.

Darolutamide is a next-generation AR inhibitor with low blood–brain barrier penetration and low potential for drug-drug interactions that are clinically relevant. In July 2019, the FDA approved darolutamide for use in this patient population, based on data from the ARAMIS trial (NCT02200614).2

The double-blind, multicenter, international, randomized phase 3 ARAMIS trial, which had an open-label ROS, was unblinded following the primary analysis.3,4 Patients in both treatment arms could have open-label darolutamide. Following completion of the study, patients who had no evidence of metastases and clinical benefit (n = 294) could continue treatment with darolutamide on ARAMIS ROS.

ARAMIS results showed that darolutamide significantly improved metastasis-free survival (MFS) by nearly 2 years vs placebo and was associated with a 31% reduction in the risk of death (HR, 0.69; 95% CI, 0.53-0.88; P = .003). Additionally, the AR inhibitor showed up to a 2% difference compared with placebo in adverse effect (AE) incidence commonly linked with darolutamide. The treatment discontinuation rate due to AEs was 8.9% with darolutamide and 8.7% with placebo.

In the ARAMIS ROS study, investigators sought to report on the duration of treatment and time course profile of AEs linked with AR-directed therapy in those who received long-term darolutamide.1 At the 2023 AUA Annual Meeting, darolutamide duration and long-term safety were described for the 954 patients who received darolutamide from randomization along with follow-up across the ARAMIS double-blind (DB), open-label (OL), and ROS periods.

In the DB treatment period, patients with nonmetastatic CRPC with a PSA doubling time (DT) up to 10 months (n = 1509) were randomly assigned 2:1 to receive darolutamide at 600 mg twice daily plus androgen deprivation therapy (ADT; n = 955) or placebo twice daily plus ADT (n = 554). Following unblinding, and in the OL treatment period, patients on darolutamide continued treatment with the AR inhibitor (n = 591) and those on placebo crossed over to receive darolutamide (n = 170). Subsequently, 294 patients migrated onto the ARAMIS ROS portion of the research.

Stratification factors included PSA doubling time (≥6 months vs >6 months), and whether osteoclast-targeted therapy was received (yes vs no).

Results showed that darolutamide’s clinical benefit and safety profile were maintained for several years in select patients with nonmetastatic CRPC.

In the patients randomized to receive darolutamide, the median treatment duration in the DB period was 1.5 years (range, 0.0-4.0), 2.1 years (range, 0.0-4.9) in the DB plus OL periods, and 2.8 years (range, 0.0-6.8) in the DB plus OL plus ROS periods.

Additional data showed that 37.6% of patients received the AR inhibitor for up to 2 years, 32.3% were on treatment between 2 and 4 years, 17.3% received it for 4 to 5 years, and 12.8% were on darolutamide for at least 5 years.

Regarding safety, the incidence of TEAEs that are often liked with AR inhibitors proved to be low with the prolonged darolutamide treatment, with slight increases observed across the DB plus OL plus ROS periods. Furthermore, most of these effects occurred during the first 2 years of darolutamide treatment.

Any-grade TEAEs were 85.7% in the DB period, 89.8% in the DB plus OL period, and 91.5% in the DL plus OL plus ROS periods. Grade 3/4 TEAEs occurred in 26.3%, 31.8%, and 35.5%, respectively. TEAEs that led to treatment discontinuation occurred in 8.9%, 10.5%, and 12.9% of those in the DB, DB plus OL, and DB plus OL plus ROS periods, respectively.

In the DB period, reported TEAEs often linked with AR inhibitors included fatigue (incidence rate, 13.2%; exposure-adjusted incidence rate [EAIR] per 100 patient-years [PY], 8.3), fracture (5.5% and 3.4), fall (5.2% and 3.3), rash (3.1% and 2.0), mental impairment disorder (2.0% and 1.3), and hypertension (7.8% and 4.9).

In the DB plus OL periods, the incidence rate and EAIR per 100 PY rate were also reported for fatigue (14.3% and 6.8, respectively), fracture (8.3% and 4.0), fall (6.9% and 3.3), rash (3.8% and 1.8), mental impairment disorder (2.3% and 1.1), and hypertension (9.0% and 4.3).

Finally, these rates were reported in the DB plus OL plus ROS periods for fatigue (14.9% and 5.3), fracture (9.3% and 3.3%), fall (8.0% and 2.8), rash (4.1% and 1.4), mental impairment disorder (3.0% and 1.1), and hypertension (10.3% and 3.6).


1. Shore ND, Luz M, Ulys A, et al. Treatment duration and long-term safety and tolerability with darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC): ARAMIS Rollover Study. Presented at: 2023 AUA Annual Meeting; April 28-May 1, 2023; Chicago, IL. Abstract MP11-14.

2. FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. FDA. July 30, 2019. Accessed April 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer

3. Fizazi K, Shore N, Tammela T, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2019; 380(13):1235-1246. doi:10.1056/NEJMoa1815671

4. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342

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