Triple Therapy Prolongs Survival in High-Volume and Any-Risk Metastatic Hormone-sensitive Prostate Cancer
Key findings
- This post hoc analysis of the ARASENS trial examined the effect of disease volume and risk on whether patients with metastatic hormone-sensitive prostate cancer benefited from the combination of darolutamide, androgen-deprivation therapy and docetaxel
- Among patients with high-volume or high-risk/low-risk disease, those randomly assigned to darolutamide showed increased overall survival compared with those assigned to placebo (risk reductions of 29%–38%)
- The results in the low-volume subgroup were suggestive of survival benefit (32% risk reduction) but were not statistically significant
- Time to castration-resistant prostate cancer and time to initiation of subsequent systemic antineoplastic therapy were significantly better with darolutamide than placebo across disease volume and risk subgroups
- These findings cannot be extrapolated to other second-generation androgen receptor pathway inhibitors
The combination of an androgen receptor pathway inhibitor, androgen-deprivation therapy (ADT), and docetaxel for metastatic hormone-sensitive prostate cancer has been evaluated in several phase 3 trials, with varying results. Two of the trials, PEACE-1 and ENZAMET, also showed conflicting results in subgroups by disease volume.
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The third trial, ARASENS, involved treatment with either darolutamide or placebo, in combination with ADT and docetaxel. The darolutamide group had a significant 32.5% reduction in the risk of death compared with the placebo group.
Matthew R. Smith, MD, PhD, director of the Genitourinary Malignancies Program at the Mass General Cancer Center, and colleagues conducted post hoc analyses of ARASENS according to disease volume and disease risk. In the New England Journal of Medicine, they say that triple therapy increased overall survival in most subgroups, which is consistent with the results for the entire cohort.
Patient Characteristics
1,305 patients were included in the full analysis of ARASENS, 77% had high-volume disease, 23% had low-volume disease, 70% had high-risk disease, and 30% had low-risk disease.
High disease volume was defined as the presence of visceral metastases or ≥4 bone metastases with ≥1 beyond the vertebral column and pelvis. High risk was defined as two of the following three factors: Gleason score ≥8, presence of ≥3 bone lesions, or presence of measurable visceral metastasis.
Primary Endpoint
Darolutamide significantly increased overall survival versus placebo in three of the four subgroups:
- High-volume: HR, 0.69 (95% CI, 0.57–0.82)
- High-risk: HR, 0.71 (95% CI, 0.58–0.86)
- Low-risk: HR, 0.62 (95% CI, 0.42–0.90)
In the small low-volume subgroup, the HR was 0.68 (95% CI, 0.41–1.13).
Secondary Endpoints
Compared with placebo, darolutamide improved multiple secondary endpoints, including time to castration-resistant prostate cancer and time to subsequent systemic antineoplastic therapy, in all disease volume and risk subgroups.
Safety
The favorable safety profile of darolutamide was confirmed in all subgroups. In addition, in all subgroups patients receiving darolutamide remained on treatment longer than those receiving placebo, indicating good tolerability of the combination.
Caveat
Given the unique structure, benefit–risk profile and limited drug–drug interactions of darolutamide, the results of ARASENS should not be extrapolated to other second-generation androgen receptor pathway inhibitors.
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