In a post hoc analysis of data from the fourth interim analysis of the DAROL trial, the androgen receptor darolutamide was well tolerated, with no cumulative toxic effects or new safety signals among patients with nonmetastatic castration-resistant prostate cancer receiving concomitant lipid-modifying agents. The results were published by Luz et al in a research letter in JAMA Network Open.
According to the investigators, the findings “support the low risk of clinically relevant drug-drug interactions previously reported.”
Study Rationale and Details
Darolutamide plus androgen-deprivation therapy is approved for the treatment of nonmetastatic castration-resistant prostate cancer, supported by findings from the phase III ARAMIS trial. The ongoing international, prospective DAROL trial is a single-group, open-label, noninterventional, nonrandomized study designed to evaluate clinical practice outcomes with the combination.
Given the frequent concomitant use of lipid-modifying agents in this population, the investigators conducted the present analysis to assess their potential impact on the safety and efficacy of darolutamide. They additionally analyzed rosuvastatin use, as darolutamide has been reported to potentially increase exposure to rosuvastatin.
A total of 799 patients who had received at least 12 months of darolutamide treatment in accordance with local practice were included. At baseline, 258 (32.3%) were receiving at least one lipid-modifying agent, with atorvastatin (n = 110), simvastatin (n = 57), and rosuvastatin (n = 56) being the most frequently used. Patients who started lipid-modifying agents before darolutamide and continued treatment during darolutamide therapy comprised the any–lipid-modifying agent subgroup, whereas those who were not receiving lipid-modifying agents at the start of darolutamide treatment comprised the no–lipid-modifying agent subgroup. Patients with cardiac disease who were not receiving lipid-modifying agents were also evaluated as a comparator subgroup.
The investigators identified safety as the primary endpoint. Metastasis-free survival, time to prostate-specific antigen (PSA) progression, and overall survival were evaluated as secondary endpoints. At the fourth interim analysis, the median duration of follow-up was 23 months.
Safety Outcomes
Treatment-emergent adverse events were more common in the any–lipid-modifying agent vs no–lipid-modifying agent subgroup and in the rosuvastatin vs no-rosuvastatin subgroup. In contrast, incidence appeared similar between the any–lipid-modifying agent subgroup and the subgroup of patients with cardiac disease who were not receiving lipid-modifying agents, as well as between the rosuvastatin subgroup and the subgroup of patients with cardiac disease who were not receiving rosuvastatin. No treatment-related events of grade 5 were reported.
Darolutamide was discontinued because of treatment-emergent adverse events by 18 (7.0%) patients in the any–lipid-modifying agent subgroup and 2 (3.6%) in the rosuvastatin subgroup.
Rates of the most frequently reported treatment-emergent adverse events were similar between the lipid-modifying agent subgroups, according to the investigators, with the exception of fatigue. The frequencies of events commonly associated with lipid-modifying agents, including liver function abnormalities, also appeared similar.
Efficacy Outcomes
The effectiveness of darolutamide appeared to be maintained with concomitant lipid-modifying agent use, the investigators wrote. No differences in overall survival were observed for the any–lipid-modifying agent subgroup vs the no–lipid-modifying agent subgroup (adjusted hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.68–1.70) or vs patients with cardiac disease who were not receiving lipid-modifying agents (HR = 0.79, 95% CI = 0.44–1.42).
Similar time to PSA progression was observed between the lipid-modifying agent subgroups, whereas metastasis-free survival favored the no–lipid-modifying agent subgroup.
Despite limitations inherent to noninterventional, clinical practice studies, the investigators noted that “the study helps physicians to understand the safety and effectiveness of darolutamide in patients observed in clinical practice.”
They concluded, “Consistent with ARAMIS, [this analysis] supports darolutamide as a standard-of-care treatment option for patients with [nonmetastatic castration-resistant prostate cancer], including those receiving concomitant [lipid-modifying agents].”
Murilo A. Luz, MD, of the Icahn School of Medicine at Mount Sinai, New York, is the corresponding author of the article in JAMA Network Open.
Disclosure: The study was supported by Bayer AG. For full disclosures of the study authors, visit jamanetwork.com.
