Addition of darolutamide to ADT, docetaxel prolongs OS in metastatic prostate cancer
SAN FRANCISCO — The addition of darolutamide to androgen deprivation therapy and docetaxel prolonged OS among men with metastatic hormone-sensitive prostate cancer, according to study results presented at ASCO Genitourinary Cancers Symposium.
The regimen reduced risk for death by 32.5%.
Results of the randomized phase 3 ARASENS trial — published simultaneously in The New England Journal of Medicine — showed similar incidence of adverse events between the two treatment groups.
“Darolutamide in combination with ADT and docetaxel should become a new standard of care for treatment of [this patient population],” Matthew R. Smith, MD, PhD, Claire and John Bertucci endowed chair in genitourinary cancers at Massachusetts General Hospital Cancer Center and professor of medicine at Harvard Medical School, said during a presentation.
Darolutamide (Nubeqa, Bayer), an oral androgen receptor inhibitor, features a distinct chemical structure that competitively inhibits androgen binding, androgen receptor nuclear translocation and androgen receptor-mediated transcription.
The agent received FDA approval in July 2019 for treatment of men with nonmetastatic castration-resistant prostate cancer.
Whether the addition of darolutamide to ADT and docetaxel would extend survival among men with metastatic hormone-sensitive prostate cancer had not been established.
The ARASENS trial included 1,306 men with metastatic hormone-sensitive prostate cancer treated at 286 centers in 23 countries between November 2016 and June 2018.
Researchers randomly assigned men 1:1 to ADT and docetaxel plus either 600 mg darolutamide twice daily (n = 651) or placebo (n = 655).
OS served as the primary endpoint. Secondary endpoints included time to development of castration-resistant disease, time to pain progression, time to first symptomatic skeletal event, time to initiation of subsequent systematic antineoplastic therapy, time to worsening of disease-related physical symptoms and time to initiation of opioid use for 7 or more consecutive days. Researchers also evaluated safety.
The full analysis set included 1,305 men (darolutamide, n = 651; placebo, n = 654) and the safety analysis included 1,302 men (darolutamide, n = 652; placebo, n = 650).
The darolutamide and placebo groups appeared balanced with regard to median age (67 years in both), ECOG performance status (0, 71.6% vs. 70.6%), race (white, 53% vs. 50.9%; Asian, 35.3% vs. 37.5%; Black, 4% vs. 4.3%) and percentage of men with Gleason score of 8 or higher (77.6% vs. 78.9%).
Most study participants (86.1%) had metastatic disease at the time of initial diagnosis and all men had metastatic disease at baseline.
At data cutoff, the darolutamide group had a median treatment duration of 41 months compared with16.7 months in the placebo group, and a higher percentage of men assigned darolutamide remained on initial treatment (45.9% vs. 19.1%).
Researchers performed the OS analysis after median follow-up of 43.7 months in the darolutamide group and 42.4 months in the placebo group.
Results showed a significant reduction in risk for death in the darolutamide group (HR = 0.68; 95% CI, 0.57-0.8). Investigators observed this improvement even though 75.6% of men who entered follow-up in the placebo group received subsequent life-prolonging systemic therapies, primarily other androgen receptor pathway inhibitors.
Smith and colleagues calculated 4-year OS rates of 62.7% (95% CI, 58.7-66.7) in the darolutamide group and 50.4% (95% CI, 46.3-54.6) in the placebo group.
Darolutamide also appeared associated with consistent benefits in secondary efficacy outcomes, including time to development of castration-resistant disease (HR = 0.36; 95% CI, 0.3-0.42), time to pain progression (HR = 0.79; 95% CI, 0.66-0.95), time to symptomatic skeletal EFS (HR = 0.61; 95% CI, 0.52-0.72), time to first symptomatic skeletal event (HR = 0.71; 95% CI, 0.54-0.94) and time to initiation of subsequent systemic antineoplastic therapy (HR = 0.39; 95% CI, 0.33-0.46).
Researchers observed benefit with the experimental regimen across prespecified subgroups.
The most common adverse events included alopecia (40.5% with darolutamide vs. 40.6% for placebo), neutropenia (39.3% vs. 38.8), fatigue (33.1% vs. 32.9%) and anemia (27.8% vs. 25.1%).
Incidence of the most common adverse events appeared highest during the overlapping docetaxel treatment period in both groups, according to investigators.
A comparable percentage of patients in the darolutamide and placebo groups experienced serious adverse events (44.8% vs. 42.3%) and grade 3/grade 4 adverse events (66.1% vs. 63.5%). The most common grade 3/grade 4 events included neutropenia (33.7% with darolutamide vs. 34.2% with placebo), febrile neutropenia (7.8% vs. 7.4%) and hypertension (6.4% vs. 3.2%).
Grade 5 adverse events occurred among 27 men (4.1%) assigned darolutamide and 26 (4%) assigned placebo.
Adverse events that led to permanent discontinuation occurred among 21.5% of men in the experimental group (13.5% darolutamide, 8% docetaxel) and 20.9% of those assigned the control regimen (10.6% placebo, 10.3% docetaxel).
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The ARASENS trial represents another important data point for men with metastatic hormone-sensitive prostate cancer (mHSPC) in determining the optimal systemic therapy to maximize outcomes. Along with the PEACE-1 trial — which demonstrated the benefit of adding abiraterone and prednisone to ADT and docetaxel (vs. ADT and docetaxel alone) in a similar patient population — we now have multiple trials demonstrating a survival benefit for triple therapy in mHSPC.
The question is: Is this for everyone? I would say no.
The ARASENS and PEACE-1 trial designs were based on the available clinical data at the time they were conceived. Based on CHAARTED and STAMPEDE, the standard of care for mHSPC was docetaxel added to ADT; thus, using this paradigm as the control arm for these trials made sense. However, since then, we have learned the benefit of chemotherapy is primarily for CHAARTED-defined high-volume patients, and multiple trials have demonstrated that similar outcomes can be achieved in high- or low-volume patients with the addition of an androgen receptor axis-targeted therapy (ARAT). As a result, the standard of care has shifted, and the relevance of ARASENS and PEACE-1 no longer are applicable across all patients.
Would the outcomes of these trials differed if the design had been ADT and abiraterone/darolutamide with or without docetaxel? For comparison, an updated post-hoc analysis of the phase 3 ARCHES trial was presented as a poster at this year’s ASCO Genitourinary Cancers Symposium. In ARCHES, researchers randomly assigned men with mHSPC to ADT with or without enzalutamide (Xtandi; Astellas, Pfizer). In the updated OS analysis, 64.2% of patients with low-volume mHSPC on the control arm remained alive at 4 years. In ARASENS, 62.7% of all patients remained alive at 4 years. We don’t yet know the breakdown by volume of disease for the patients in ARASENS, but the point is that we may get similar outcomes with ADT plus ARAT alone for many patients.
So, who should be offered triple therapy? Because the majority of men across both PEACE-1 and ARASENS had de novo metastatic disease, I would primarily consider those patients. Additionally, at this time we do not have evidence that low-volume patients benefit from docetaxel, so I would restrict to high-volume patients. Patients who present with symptomatic disease may get quicker relief of their symptom burden with early addition of docetaxel. Finally, patients must be fit enough to receive chemotherapy. Outside of these scenarios, it would be reasonable to continue to offer men ADT plus an ARAT and reserve docetaxel for later lines of therapy.
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Smith MR, et al. Abstract 13. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.