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Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) lived significantly longer if they received an androgen signaling inhibitor (ASI) in addition to conventional androgen deprivation therapy (ADT), three large randomized trials of different drugs showed.

The survival hazard decreased by 20%-30% in men who received enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa) in addition to ADT. The addition of darolutamide to ADT led to a 31% reduction in the survival hazard, followed by 27% with enzalutamide, and 22% with apalutamide. In all three studies, the magnitude of benefit was about an extra year of life.

No new safety signals were reported for any of the drugs evaluated, although differing safety profiles might influence choices going forward, according to presentations at the American Society of Clinical Oncology (ASCO) virtual meeting.

"The data presented today from three large randomized studies make it clear that in castration-resistant prostate cancer, early intensification of hormonal therapy results in an overall survival advantage," said ASCO invited discussant Tomasz Beer, MD, of Oregon Health & Science University in Portland. "Meaningful differences in efficacy between these three studies are not apparent. Potential differences in toxicity warrant further evaluation in the context of a direct comparison between these agents."

"These results create opportunity for further advances and raise thought-provoking questions about hormonal therapy in general," he said. "The main survival results do not reveal an obvious winner ... None of the studies are fully mature for overall survival [OS]; none have actually reached median survival."

Beer said the time has come to consider earlier use of newer antiandrogens, while remaining mindful of the patient population and potential treatment-related risks.

"In this setting, we're recommending treatment for patients who are destined to live many years, and they are asymptomatic from their cancer. Attention to toxicity is important in selecting patients," he said.

Referencing a showing that ASIs increase cardiovascular risk, Beer added, "This is just one example, but clearly a reminder that we need to be thoughtful about patient selection, and we need to be aggressive about studying the other adverse effects of this class of agents."

The three ASCO presentations represented updates of trials that met the previously reported primary endpoint of metastasis-free survival (MFS). OS was a secondary endpoint.

ARAMIS Trial

The included 1,509 men with nmCRPC, randomized 2:1 to receive darolutamide or placebo in addition to conventional ADT. Median follow-up for the OS analysis was 29.1 months, Karim Fizazi, MD, of Gustave Roussy Institute in Villejuif, France.

Median treatment duration was 25.8 months in the darolutamide arm versus 11.6 months in the placebo arm. Crossover to darolutamide at progression was allowed, and patients who crossed over (31%) had a median time on darolutamide of 11.0 months. More than half of patients in the placebo arm received additional therapy, as compared with 19% of patients randomized to darolutamide.

In addition to demonstrating a significant difference in MFS, the trial showed that the addition of darolutamide significantly prolonged time to pain progression (40.3 vs 25.4 months, P<0.001), time to first cytotoxic chemotherapy (not reached in either arm, HR 0.58, 95% CI 0.44-0.76), and time to first symptomatic skeletal event (not reached, HR 0.48, 95% CI 0.29-0.82).

Although median OS had yet to be reached in either arm, available data showed the darolutamide group had a 31% lower survival hazard (95% CI 0.53-0.88, P=0.003).

The frequency and severity of adverse events (AEs) did not differ substantively between treatment arms. Fatigue was the most common AE of interest during randomized therapy, occurring in 13.2% of the darolutamide group and 8.3% of the placebo group.

PROSPER Trial

The involved 1,395 men with nmCRPC randomized 2:1 to enzalutamide or placebo in addition to ADT. The trial had a primary endpoint of MFS, and crossover from placebo to enzalutamide at disease progression was allowed, said, of Weill Cornell Medicine in New York City.

The survival analysis was performed after a median follow-up of 48 months and showed a median OS of 67.0 months in the enzalutamide arm (upper limit of 95% CIs not reached) and 56.3 months in the placebo arm. The difference represented a 27% reduction in the survival hazard in favor of enzalutamide (95% CI 0.61-0.89, P=0.001). The benefit was consistent across all prespecified subgroups.

Two-thirds of patients in the placebo group received at least one subsequent therapy after discontinuing randomized treatment, as compared with a third of patients in the enzalutamide arm. The median time to first subsequent antineoplastic therapy was 66.7 months in the enzalutamide arm and 19.1 months in the placebo arm (HR 0.29, P<0.001).

Patients randomized to enzalutamide had a median treatment exposure of 33.9 months as compared with 14.2 months in the placebo group. Nonetheless, AEs (any grade) occurred more often in the placebo arm (60 vs 34/100 patient-years). The frequency of grade ≥3, serious, and fatal AEs was similar in the two groups, and the exposure adjusted rate of discontinuation associated with AEs was 6/100 patient years in each group.

The results were in the New England Journal of Medicine.

SPARTAN Trial

The third study, known as , included 1,207 men with nmCRPC, randomized 2:1 to apalutamide or placebo in addition to ADT. Like the other two trials, SPARTAN had a primary endpoint of MFS. The OS analysis occurred after a median follow-up of 52.0 months, Eric J. Small, MD, of the University of California San Francisco. Median treatment duration was 32.9 months with apalutamide and 11.5 months with placebo (26.1 months for the 19% of patients who crossed over from placebo to apalutamide).

The OS analysis showed a median of 73.9 months for the apalutamide group and 59.9 months for placebo, which translated into a hazard ratio of 0.784 (P=0.0161). Time to initiation of cytotoxic therapy, symptomatic progression, and PSA progression also were prolonged with apalutamide, as was second progression-free survival.

AEs were somewhat more common in the apalutamide arm, including grade ≥3 (55.9% vs 36.4%), serious (36.1% vs 24.9%), and fatal AEs (3.0% vs 0.5%). Twice as many patients in the apalutamide arm discontinued treatment because of AEs (14.9% vs 7.3%).