Antiandrogen therapy boosts nonmetastatic CRPC survival
medwireNews: Adding an androgen receptor inhibitor to androgen deprivation therapy (ADT) significantly improves the overall survival (OS) of men with nonmetastatic castration-resistant prostate cancer (CRPC), according to results from three trials.
The phase 3 ARAMIS, PROSPER, and SPARTAN studies of the antiandrogens darolutamide, enzalutamide, and apalutamide, respectively, have previously shown a significant boost in their primary endpoint of metastasis-free survival with the active agent versus placebo.
The current reports include data on OS and other secondary endpoints presented at a poster discussion session of the virtual 2020 ASCO Annual Meeting, with the PROSPER results also simultaneously published in The New England Journal of Medicine.
Discussant Tomasz Beer (OHSU Knight Cancer Institute, Portland, Oregon, USA) commented that these findings “make it clear that in castration-resistant prostate cancer, early intensification of hormonal therapy results in an overall survival advantage.”
Tomasz Beer highlights the key messages and caveats of the overall survival data from the PROSPER, SPARTAN, and ARAMIS trials
He added that “meaningful differences in efficacy between these three studies are not apparent,” and although the median OS estimates and hazard ratios look “a bit better” in the trials with longer follow-up, “none of these studies are fully mature for overall survival,” and the estimates “are likely to change with additional follow-up.”
In the ARAMIS trial, the 955 men who were randomly assigned to receive darolutamide 600 mg twice daily plus ADT had a significant 31% reduction in the risk for death relative to their 554 counterparts who instead received placebo alongside ADT over a median follow-up of 29.1 months.
The 3-year OS rates were 83% and 77% for the darolutamide and placebo groups, respectively, reported Karim Fizazi (Institut Gustave Roussy and University of Paris Sud, Villejuif, France) on behalf of his co-authors.
Darolutamide was also associated with significant delays in the time to pain progression, first cytotoxic chemotherapy, and first symptomatic skeletal event.
Cora Sternberg (Weill Cornell Medicine, New York, USA), who presented an OS update from the PROSPER trial at a median follow-up of approximately 48 months, highlighted that the addition of enzalutamide 160 mg/day instead of placebo to ADT was associated with a significant 27% decrease in the risk for death.
The median OS duration was 67.0 months among the 933 patients who received enzalutamide and 56.3 months among the 468 patients given placebo.
And enzalutamide-treated participants had a significantly longer time to first use of subsequent antineoplastic therapy than their placebo-treated counterparts, at a median of 66.7 versus 19.1 months.
Finally, the SPARTAN investigators reported that after a median follow-up of 52 months, the risk for death was a significant 22% lower for the 806 men treated with apalutamide 240 mg/day plus ADT than for the 401 who received placebo plus ADT, with respective median OS times of 73.9 and 59.9 months.
Other endpoints, such as time to initiation of cytotoxic chemotherapy and symptomatic progression, were also significantly improved with the addition of apalutamide versus placebo, said presenting author Eric Small, from the University of California San Francisco in the USA.
All three presenters highlighted that the OS benefit afforded by the androgen receptor inhibitor was observed despite high proportions of placebo-treated patients in the three trials receiving subsequent life-prolonging therapies, including the antiandrogen being evaluated in the study.
The safety results of the three agents were comparable with those from prior analyses and other trials, with the incidence of adverse events generally similar between the active and placebo arms after adjustment for treatment duration.
There were some exceptions, however, with falls and fractures occurring at a higher rate among enzalutamide- than placebo-treated men even after adjustment in PROSPER, and a higher rate of discontinuation due to adverse events with apalutamide than placebo in SPARTAN.
Commenting on the safety data, Beer said that “potential differences in toxicity merit further evaluation in the context of a direct comparison between these agents,” and stressed that attention to toxicity could be key in selecting the appropriate agent for patients.
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