Adding darolutamide to docetaxel and androgen deprivation therapy significantly prolongs the survival of patients with metastatic hormone sensitive prostate cancer

Results of the phase III ARASENS trial demonstrate that adding darolutamide to docetaxel and androgen deprivation therapy (ADT) significantly prolongs the survival of patients with metastatic hormone sensitive prostate cancer (mHSPC). In addition, also other efficacy endpoint related to pain progression, symptomatic skeletal events, symptom worsening, and next antineoplastic therapy were significantly improved in patients treated with the darolutamide combination. Importantly, this clinical benefit did not come at the cost of a higher incidence of adverse events.

Over the last decade, the treatment landscape for mHSPC patients underwent a dramatic transformation. For many years, ADT alone was the standard of care in this setting, but this only yielded limited 5-year survival rates. More recently, new treatment approaches in which this upfront systemic therapy is intensified with the addition of docetaxel chemotherapy or an androgen receptor pathway inhibitor significantly improved survival rates compared to ADT alone. Building further on these results, studies are now looking into the effect of a further treatment intensification in which ADT is combined with both chemotherapy and an androgen receptor inhibitor. During ASCO GU 2022, results were presented of the phase III ARASENS trial evaluating the addition of the androgen receptor inhibitor darolutamide to ADT and docetaxel in patients with mHSPC.

Study design

The phase III ARASENS trial enrolled a total of 1,305 patients with mHSPC and an ECOG performance status of 0-1. Patients in the study were treated with 6 cycles of docetaxel together with ADT and were randomized (1:1) to receive either darolutamide (600mg twice daily), or placebo. The primary endpoint of the study was overall survival (OS). Secondary study objectives consisted of time to castration-resistant prostate cancer (CRPC), time to pain progression, symptomatic skeletal event (SSE)–free survival, time to a first SSE, time to initiation of subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, time to initiation of opioid treatment for 7 or more consecutive days, and safety.

Results

The median age of the patients enrolled in ARASENS was 67 years and about 70% had an ECOG performance status of 0. Overall, 85% of patients in the study had M1 disease and approximately 78% had a Gleason score of 8 or more at initial diagnosis. Adding darolutamide to docetaxel and ADT significantly improved the OS of patients with a hazard ratio (HR) of 0.68 (95%%CI: 0.57-0.80). The median OS was not yet reached in the darolutamide arm and reached 48.9 months in the control arm. At the 48-month landmark, this translated into an OS rate of 62.7% for patients treated with darolutamide as compared to 50.4% in the control arm. The treatment effect of darolutamide with respect to OS was favorable across most subgroups, irrespective of age, Gleason score (<8 or ≥8), metastatic stage at diagnosis (M1 or M0), PSA level at baseline, ALP level and disease extent (lymph node, bone, or visceral involvement).

Also with respect to secondary endpoints, darolutamide added significant clinical benefit to the ADT + docetaxel combination. In fact, the time to development of castration-resistant disease was significantly longer in the darolutamide group (HR[95%C]: 0.36[0.30-0.42], p< 0.001) as was the time to pain progression (HR[95%CI]: 0.79[0.66-0.95], p= 0.01), the SSE–free survival (HR[95%CI]: 0.61[0.52-0.72], p< 0.001) and the time to a first SSE (HR[95%CI]: 0.71[0.54-0.94]; p= 0.02). Finally, also the time to the initiation of subsequent systemic antineoplastic therapy was significantly longer in the darolutamide group (HR[95%CI]:  0.39[0.33-0.46]; p< 0.001).

Importantly, the clinical benefit obtained by adding darolutamide did not come at the cost of a higher rate of grade 3 (38.0% vs. 35.7%), grade 4 (28.1% vs. 27.8%), grade 5 (4.1% vs. 4.0%) or serious (44.8% vs. 42.3%) adverse events. Also the rate of treatment discontinuation due to adverse events was similar in both arms. The most common grade ≥3 adverse event in ARASENS was neutropenia (33.7% with darolutamide vs. 64.5% with placebo). Febrile neutropenia of grade ≥3 was reported by 7.8% of patients in the darolutamide + ADT + docetaxel arm as compared to 7.4% with the docetaxel + ADT combination

Conclusions

The results of the ARASENS trial support the use of darolutamide in combination with ADT and docetaxel in patients with mHSPC. In fact, the addition of darolutamide to ADT and docetaxel prolongs the OS and induces significant improvements in all secondary efficacy endpoints, without an increase in adverse events.

Reference

Smith M, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. Presented at ASCO 2022; Abstract 13.