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SAN FRANCISCO -- Men with nonmetastatic (M0) castration-resistant prostate cancer (nCRPC) remained free of metastasis more than twice as long with the androgen-receptor inhibitor , a placebo-controlled trial showed.

Treatment with darolutamide led to median metastasis-free survival (MFS) of 40.4 months versus 18.4 months. An interim analysis of overall survival at 36 months showed a 10% absolute difference in favor of darolutamide, but did not achieve the necessary level of statistical significance to be definitive.

All secondary endpoints favored the androgen-directed therapy, which had a favorable safety profile associated with a discontinuation rate almost identical to that of the placebo group, as reported here at the . The results were published simultaneously in the .

"We believe that darolutamide should become a new standard of care for newly diagnosed M0 CRPC," said Karim Fizazi, MD, PhD, of Gustave Roussy Institute in Villejuif, France.

With results of the phase III ARAMIS trial, darolutamide became the third new-generation androgen receptor inhibitor to demonstrate significant benefits for men with nCRPC. Previous trials showed at least a doubling of MFS with apalutamide (Erleada) and enzalutamide (Xtandi), and enzalutamide significantly improved overall survival in a trial for men with M1 CRPC. Additionally, abiraterone (Zytiga) plus prednisone improved overall survival and progression-free survival in men with M1 disease.

Invited discussant Ian Davis, MD, of Monash University in Melbourne, Australia, said data regarding darolutamide's safety have been encouraging and that the endpoint of MFS is clinically valuable. However, he suggested that unanswered questions continued to revolve around nCRPC, even though the FDA conditionally accepted MFS as an endpoint.

"Is M0 CRPC an important condition? Some people question whether it even exists," said Davis. "If it is important, which patients need treatment?"

He argued that M0 disease should be considered part of the metastatic (M1) spectrum, as M0 status is defined by conventional imaging criteria, such as CT and bone scans. However, newer imaging techniques have much greater sensitivity for showing disease not detected with conventional imaging. Additionally, Davis said, biological behavior can vary greatly, from "very indolent" to "highly aggressive" on the basis of PSA doubling time.

With regard to whether the trial results should change clinical practice, Davis said nCRPC is a condition that requires treatment, noting that 69% of patients in the study had a short PSA doubling time associated with aggressive behavior. Whether MFS is truly a meaningful endpoint and a surrogate for overall survival remains unclear.

No data have emerged regarding the impact of darolutamide on use and effectiveness of subsequent therapies, Cost-effectiveness cannot be determined at this point because an overall survival benefit has not been demonstrated and the drug's price has not been announced.

"At the moment I think it's unclear whether these results should change practice, but I would be happy to change my conclusion in the future," said Davis.

Although enzalutamide and apalutamide have proven effectiveness, men with adverse effects of androgen deprivation therapy for nCRPC might have additional adverse events and toxicity with both of the new antiandrogens, Fizazi noted. Darolutamide has a unique biological structure compared with enzalutamide and apalutamide, and phase I/II trials produced no clear evidence of drug-related side effects with darolutamide.

Study details

The included 1,509 men with nCRPC associated with a PSA doubling time ≤10 months. They were randomized 2:1 to darolutamide or placebo and followed for the primary endpoint of MFS, defined as development of distant metastases or death from any cause. Radiologic assessments were performed every 16 weeks.

Secondary endpoints included overall survival, time to pain progression, time to first cytotoxic chemotherapy, time to first symptomatic skeletal event, and safety.

Data collection for the primary endpoint analysis occurred after a median follow-up of 17.9 months. The darolutamide group had a median treatment duration of 14.8 months versus 11.0 months for the placebo group. About two thirds of the darolutamide group remained on treatment compared with about a third of the placebo-treated patients.

The 22-month difference in MFS translated into a 59% reduction in the hazard for metastasis or death in favor of darolutamide (P<0.0001). The benefit was consistent across all subgroup analyses.

The interim analysis of survival showed a 36-month overall survival of 83% in the darolutamide group and 73% in the placebo group, representing a 29% reduction in the hazard ratio (95% CI 0.50-0.99, P=0.0452). The median overall survival had yet to be reached in either group.

Analysis of other secondary endpoints showed a significant advantage for darolutamide in the median time to:

• Pain progression: 40.3 vs 25.4 months, P<0.0001
• Cytotoxic chemotherapy: Not reached (NR) vs 38.2 months, P<0.0001
• First symptomatic skeletal event: NR vs NR, HR 0.43, P=0.0113

Rates of adverse events (83.2% vs 76.9%), grade 3/4 events (24.7% vs 19.5%), serious events (24.8% vs 20%), and discontinuation (8.9% vs 8.7%) did not differ significantly between treatment groups, nor did incidence of treatment-emergent adverse events of particular interest.

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