Adding darolutamide to ADT improves outcomes in nmCRPC
Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) more than halved their risk of dying or developing distant metastasis when treated with darolutamide in addition to androgen deprivation therapy (ADT), according to findings of the phase III ARAMIS* trial.
“[D]arolutamide prolonged metastasis-free survival [MFS] to 40.4 months, 22 months longer than with placebo … and consistent efficacy was observed for metastasis-free, overall, and progression-free survival [PFS],” said the authors, led by Professor Karim Fizazi from the Institut Gustave Roussy, Université Paris-Sud, Villejuif, France, who presented the findings at ASCO GU 2019.
A total of 1,509 men (median age, 74 years) with nmCRPC and prostate-specific antigen (PSA) doubling time of ≤10 months were randomized to receive darolutamide (600 mg [2 x 300 mg tablets twice/day]) + ADT (n=955) or ADT alone (placebo group; n=554). Patients were treated with darolutamide and placebo for a median 14.8 and 11.0 months, respectively.
After a median follow up of 17.9 months, MFS was significantly greater among patients who received darolutamide compared with placebo (median, 40.4 vs 18.4 months, hazard ratio [HR], 0.41, 95 percent confidence interval [CI], 0.34–0.50; p<0.0001). [ASCO GU 2019, abstract 140; N Engl J Med 2019;doi:10.1056/NEJMoa1815671]
“MFS was improved regardless of PSA doubling time, use of bone targeting agents, the Gleason score, or age,” said Fizazi.
Overall survival (OS) results, though immature, also showed improvement among darolutamide compared with placebo recipients (median, not reached in either group [3-year OS, 83 percent vs 73 percent], HR, 0.71, 95 percent CI, 0.50–0.99; p=0.0452), as did the exploratory endpoint of PFS (median, 36.8 vs 14.8 months, HR, 0.38, 95 percent CI, 0.32–0.45; p<0.0001).
Darolutamide recipients experienced longer time to pain progression than placebo recipients (median, 40.3 vs 25.4 months, HR, 0.65, 95 percent CI, 0.53–0.79; p<0.0001), as well as longer time to receipt of cytotoxic chemotherapy (median, not reached vs 38.2 months, HR, 0.43, 95 percent CI, 0.31–0.60; p<0.0001), and time to first symptomatic skeletal event (not reached in either group, HR, 0.43, 95 percent CI, 0.22–0.84; p=0.0113).
Favourable safety profile
Serious treatment-emergent adverse events (TEAEs) of any grade occurred at a similar rate between groups (24.8 percent vs 20 percent), as did discontinuation due to TEAEs (8.9 percent vs 8.7 percent). The most common grade 3–4 TEAEs were hypertension and urinary retention which occurred in 3.1 and 1.6 percent, respectively, in darolutamide recipients and 2.2 and 2.0 percent, respectively, in placebo recipients.
“[G]rade 3–4 AEs were rarely observed in the trial, which is an important finding for a vast population of asymptomatic men,” said Fizazi. “Quality of life was meaningfully preserved with darolutamide compared with placebo [with] patient-reported scores tending to favour darolutamide for pain and urinary symptoms,” he added.
According to Fizazi, apalutamide and enzalutamide, which have shown encouraging results in improving MFS in nmCRPC, are associated with AEs such as fatigue, falls, and fractures compared with placebo.
In ARAMIS, the incidence of AEs of interest such as fractures and falls occurred at a similar rate between darolutamide and placebo recipients (4.2 percent vs 3.6 percent [fractures] and 4.2 percent vs 4.7 percent [falls]), he said.
“[Furthermore], darolutamide does not cross the blood-brain barrier, which may result in less central nervous system-related side effects,” Fizazi said, highlighting the comparable incidences of fatigue (15.8 percent vs 11.4 percent), dizziness (4.5 percent vs 4.0 percent), cognitive disorder (0.4 percent vs 0.2 percent), memory impairment (0.5 percent vs 1.3 percent), and seizure (0.2 percent in each group) between darolutamide and placebo recipients. Despite patients with a history of seizure being included, none of them experienced a seizure during the trial.
“Darolutamide seems to be very non-toxic as far as we can tell [and] should become a new standard of care for men with high-risk [nonmetastatic] CRPC,” concluded Fizazi.