A subgroup analysis of the pivotal phase 3 ARAMIS trial showed that the efficacy of darolutamide was sustained in patients with a rapid PSA double time.
Darolutamide (Nubeqa) is effective for the treatment of high-risk patients with nonmetastatic castration-resistant prostate cancer (CRPC) who have a PSA doubling time (PSADT) between 6 and 10 months, according to a subgroup analysis of the phase 3 ARAMIS trial presented during the 2020 European Association of Urology Virtual Congress.1
Among patients with a PSADT ≤6 months, darolutamide reduced the risk of metastases or death by 59% versus placebo (HR, 0.41; 95% CI, 0.33-0.52). This benefit with darolutamide was similar to that observed in patients with a PSADT >6 months, in whom there was a 62% reduction in the risk of metastases or death (HR, 0.38; 95% CI, 0.26-0.55). The safety profile for darolutamide was similar between the 2 populations.
“These results indicate that patients with a PSADT between 6 and 10 months can benefit from darolutamide without increased safety risk,” said lead study author Martin Bögemann, MD, Münster University Medical Center, Department of Urology, Münster, Germany.
Patients with nonmetastatic CRPC who have a PSADT ≤6 months are at the highest risk of metastatic progression; however, the risk remains high in patients with a PSADT between 6 and 10 months. Thus, Bögemann et al sought to examine the efficacy of darolutamide in this subset of patient enrolled in the ARAMIS trial.
Overall, the double-blind ARAMIS trial included 1509 patients with nonmetastatic CRPC. Patients were randomized in a 2:1 ratio to receive oral darolutamide at 600 mg twice daily plus androgen deprivation therapy (ADT; n = 955) or placebo plus ADT (n = 554). Patients had an ECOG performance status of 0 to 1.
Among patients with a PSADT ≤6 months, the median metastasis-free survival (MFS) was 34.3 months in the darolutamide arm (n = 668), compared with 17.2 months for the placebo arm (n = 371). In the group of patients with a PSADT >6 months, the median MFS had not yet been reached among patients receiving darolutamide (n = 286), compared with 30.7 months for the placebo arm (n = 183).
The MFS results for these PSADT-defined subgroups was consistent with the primary analysis results. In the overall population, the median MFS was 40.4 months in the darolutamide cohort and 18.4 months in the placebo cohort, translating to a 59% reduction in the risk of metastases or death (HR, 0.41; 95% CI, 0.34-0.50; P <.001).2 These results led to the July 2019 FDA approval of darolutamide for the treatment of patients with nonmetastatic CRPC.
It was subsequently reported that darolutamide had also significantly improved overall survival compared with placebo in the overall ARAMIS trial population.3 Darolutamide led to a 31% reduction in the risk of death compared with placebo (HR, 0.69; 95% CI, 0.53-0.88; P = .003).
Bögemann said that darolutamide also showed a favorable safety profile in the primary analysis, and likely has a low risk of CNS events and drug–drug interactions.
This favorable safety profile held up in the subgroup analysis, according to Bögemann. He said the safety profile for darolutamide was consistent across the PSADT >6 and ≤6 populations, with a low incidence of grade 3/4 adverse events (AEs) across both groups.
The incidence of grade 3/4 AEs with darolutamide was 27.2% in the PSADT ≤6 months group and 18.9% in the PSADT ≥6 months group. Serious AEs occurred in 18.1% versus 24% of the 2 groups, respectively, with no cases of serious grade 3/4 AEs. AE-related discontinuation occurred in 9.1% and 8.4% of the darolutamide-treated groups of the PSADT ≤6 months and >6 months arms, respectively.
1. Bögemann MWH, Shore ND, Tammela TLJ, et al. Efficacy and safety of darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a prostate-specific antigen doubling time (PSADT) >6 months. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract 919.
2. FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. Published July 30, 2019. https://bit.ly/3105EYB. Accessed July 30, 2020.
3. Fizazi, Karim; Shore, Neal; Tammela, Teuvo, et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program; May 2020. Abstract 5514.