Triplet therapy with the oral androgen receptor inhibitor darolutamide plus docetaxel plus androgen-deprivation therapy significantly improved overall survival in patients with metastatic hormone-sensitive prostate cancer vs docetaxel plus androgen-deprivation therapy, according to results of the phase III ARASENS trial.¹ These results were presented at the 2022 ASCO Genitourinary Cancers Symposium by Matthew R. Smith, MD, PhD, Director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, and Professor of Medicine, Harvard Medical School, and published online in The New England Journal of Medicine to coincide with the oral presentation.^1,2

Matthew R. Smith, MD, PhD

The triplet of darolutamide plus docetaxel plus androgen-deprivation therapy reduced the risk of death by 32.5% compared with docetaxel plus androgen-deprivation therapy (P < .001). Median overall survival was not reached in the experimental arm and was 48.9 months for docetaxel plus androgen-deprivation therapy. At data cutoff for the primary analysis, the median treatment duration was 41.0 months for the triplet vs 16.7 months for docetaxel plus androgen-deprivation therapy.

The survival benefit for the triplet combination was especially striking, given that more than 75.6% of patients in the control arm had received one or more subsequent life-prolonging systemic anticancer therapies and 66% received subsequent life-prolonging therapy with an androgen receptor pathway inhibitor.

“Metastatic prostate cancer is a uniformly fatal disease and despite progress in recent years, only 30% of these men will survive beyond 5 years. ARASENS demonstrated that the addition of darolutamide to docetaxel plus androgen-deprivation therapy significantly increased overall survival compared with standard androgen-deprivation therapy and docetaxel as initial treatment for metastatic hormone-sensitive prostate cancer. The addition of darolutamide also improved the time to castration-resistant prostate cancer and other key secondary endpoints,” said Dr. Smith.

“These results are an important step forward for the treatment of patients with metastatic hormone-sensitive prostate cancer. Darolutamide plus docetaxel plus androgen-deprivation therapy should be the new standard of care for patients with metastatic hormone-sensitive prostate cancer,” Dr. Smith added.

ARASENS is unique in that it is the only randomized, double-blind pivotal study prospectively designed to compare the use of a second-generation androgen receptor inhibitor plus androgen-deprivation therapy and docetaxel to androgen-deprivation therapy plus docetaxel (a guideline-recommended standard of care) in metastatic hormone-sensitive prostate cancer.

Darolutamide is a structurally distinct androgen receptor inhibitor with limited potential for drug-drug interactions and an improved safety profile compared with first-generation androgen receptor inhibitors. Darolutamide is currently approved by the U.S. Food and Drug Administration for the treatment of patients with nonmetastatic castration-resistant prostate cancer.

Study Details

ARASENS is a randomized, phase III, multicenter, double-blind, placebo-controlled trial that was prospectively designed to investigate the efficacy and safety of oral darolutamide plus androgen-deprivation therapy plus docetaxel in patients with metastatic hormone-sensitive prostate cancer. The study was conducted at 286 centers in 26 countries. A total of 1,306 newly diagnosed patients were randomly assigned in a 1:1 ratio to receive darolutamide at 600 mg twice a day or matching placebo; both arms included docetaxel plus androgen-deprivation therapy.

Treatment arms were well balanced. The median age was 67 years, about 77% of patients in both arms had Gleason scores of 8 or higher at diagnosis, about 78% had visceral metastasis, and 86% had de novo metastatic hormone-sensitive prostate cancer.

The primary endpoint of this trial was overall survival. Secondary endpoints included the time to castration-resistant prostate cancer, time to pain progression, time to first symptomatic skeletal event, time to initiation of subsequent anticancer therapy, all measured at 12-week intervals, as well as adverse events.

The significant improvement in overall survival in the triplet combination arm was observed despite the high rate (75.6%) of subsequent life-prolonging therapies (such as abiraterone acetate, enzalutamide, cabazitaxel, docetaxel, radium-223 dichloride, sipuleucel-T, lutetium-177–PSMA-617, or apalutamide) among patients in the placebo group who entered follow-up. A consistent improvement in overall survival was observed across subgroups and by metastatic stage at diagnosis.

Significant improvement for the triplet combination vs the control arm was observed across multiple secondary endpoints. The time to castration-resistant prostate cancer was delayed by 34% (P < .001); the time to pain progression, by 21% (P = .01); the time to first symptomatic skeletal event, by 29% (P = .02); and the time to initiation of subsequent systemic antineoplastic therapy, by 61% (P < .001).

Adverse Events

“The combination had favorable safety,” Dr. Smith noted. “Certain adverse events associated with androgen receptor inhibitors vary within the class. There was no difference between treatment arms for fatigue, falls, rash, hypertension, and central nervous system effects,” Dr. Smith told the audience.

The frequency and types of treatment-emergent adverse events were similar between treatment arms. The most common treatment-emergent adverse events (≥ 10%) were highest during the overlapping docetaxel treatment period for both arms and decreased progressively thereafter. The most frequently reported adverse events were alopecia (40.5% for the triplet and 40.6% for the control arm, respectively), neutropenia (39.3% and 38.8%), fatigue (33.1% and 32.9%), and anemia (27.8% and 25.1%). Grade 3 or 4 adverse events reported in 66.1% vs 63.5% of patients respectively, were mainly due to neutropenia (33.7% vs 34.2%, respectively). Serious adverse events occurred in 44.8% vs 42.3% of patients, and treatment-emergent adverse events that led to treatment discontinuation occurred in 13.5% vs 10.6% of patients, respectively.

Adverse events of special interest in patients treated with androgen receptor pathway inhibitors for prostate cancer such as fatigue, falls, fractures, mental impairment, and cardiovascular events were similar between study arms. 

DISCLOSURE: Dr. Smith has served as a consultant or advisor for Amgen, Astellas Pharma, Bayer, Janssen Oncology, Lilly, Novartis, and Pfizer; has received institutional research funding from Bayer, ESSA, Janssen Oncology, Lilly, and ORJC Pharmaceuticals; and has received reimbursement for travel, accommodations, and expenses from Amgen, Bayer, Janssen, and Lilly.

REFERENCES

1. Smith M, Hussain MHA, Saad F, et al: Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. 2022 ASCO Genitourinary Cancers Symposium. Abstract 13. Presented February 18, 2022.

2. Smith MR, Hussain M, Saad F, et al: Daralutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. February 17, 2022 (early release online).