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The phase III ARANOTE trial showed that darolutamide and androgen-deprivation therapy (ADT) without chemotherapy could be an effective option for some patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The combination improved radiological progression-free survival by 46% compared with placebo plus ADT (HR 0.54, 95% CI 0.41-0.71, P<0.0001), with consistent benefits across subgroups, including high- and low-volume disease, reported Fred Saad, MD, of the University of Montreal in Quebec, and colleagues.

"The results of this second pivotal trial of darolutamide in patients with mHSPC add to the body of evidence from ARASENS, providing the option to select treatment in mHSPC with and without docetaxel to meet patients' individual needs and preferences," the team wrote in the .

None of the researchers responded to requests for interview, and the answers in this Q&A are taken from the text of the paper.

Why did you examine the efficacy of darolutamide and ADT alone when previous studies have demonstrated the benefit of triplet combinations, including darolutamide and ADT with docetaxel?

Several phase III trials have demonstrated improved overall survival and delayed progression to mCRPC when ADT is combined with an androgen receptor pathway inhibitor (abiraterone acetate, enzalutamide, or apalutamide), and the ARASENS and PEACE-1 trials found survival benefits with the triplet combination of darolutamide or abiraterone, respectively, plus ADT and docetaxel.

However, these doublet and triplet regimens are underutilized, and many patients with mHSPC continue to receive treatment with ADT alone, due to concerns about drug accessibility, tolerability, safety, drug-drug interactions, and healthcare provider education. Recent studies in the U.S. and Germany have shown that around 30% of patients with mHSPC still receive ADT alone.

Thus, an unmet need remains for treatments that delay progression to mCRPC with recognized tolerability.

Why did you choose ADT monotherapy as the comparator?

Use of placebo plus ADT as the comparator may be considered a limitation of the ARANOTE trial, as ADT monotherapy is no longer considered a standard of care for patients with mHSPC. However, the evidence of continued use of ADT monotherapy indicates that the findings are relevant to physicians making treatment decisions for patients with mHSPC.

ARANOTE included a diverse population. What were the demographics of study participants?

The strengths of the trial include the highly diversified population, broadly representing patients with prostate cancer, including elderly patients (median age of patients was 70, with the eldest age 93), Asian (31%) and Black (10%) populations, and patients treated in a range of healthcare settings (Asia 30%, Latin America 29%, Europe and the rest of the world 41%).

Furthermore, subgroup analyses of radiological progression-free survival showed a significant benefit in patients with low-volume mHSPC, demonstrating the importance of an effective combination therapy with a favorable safety profile for this often undertreated population.

What did you find in terms of overall survival (OS) and other secondary endpoints?

The OS rates at 24 months were 79.8% in the darolutamide group and 75.5% in the placebo group. The benefit was observed despite a greater proportion of patients in the placebo group (42.5%) than in the darolutamide group (32.5%) receiving subsequent life-prolonging anticancer therapy, primarily docetaxel.

Clear benefits were seen across all other secondary endpoints. The time to CRPC (HR 0.40, 95% CI 0.32-0.51) and time to PSA [prostate-specific antigen] progression were longer with darolutamide versus placebo (HR 0.31, 95% CI 0.23-0.41), and a higher proportion of patients receiving darolutamide achieved PSA<0.2 ng/mL at any time during the treatment period (62.6%) versus those receiving placebo (18.5%).

The time to initiation of subsequent systemic anticancer therapy (HR 0.40, 95% CI 0.29-0.56) and time to pain progression, a key patient-relevant endpoint, were also delayed in the darolutamide group compared with the placebo group (HR 0.72, 95% CI 0.54-0.96).

Were there any notable safety/tolerability findings?

ARANOTE is the first study of an androgen receptor pathway inhibitor showing a lower rate of fatigue in the treatment group (5.6%) compared with the placebo group (8.1%), representing a 30% lower incidence of fatigue with darolutamide versus placebo. Enzalutamide and apalutamide are associated with higher rates of fatigue (24.1% and 19.7% in the ARCHES and TITAN trials, respectively).

Moreover, discontinuation rates due to adverse events were lower in the darolutamide group (6.1%) than in the placebo group (9.0%), supporting a favorable tolerability across this widely diverse patient population.

Read the study here.