Results from an international, randomised, double-blind, placebo-controlled, phase 3 clinical trial provide hope for men suffering from usually fatal metastatic hormone-sensitive prostate cancer. The trial has indicated that adding the androgen-receptor inhibitor darolutamide to androgen-deprivation therapy and chemotherapy can prolong the survival rate of these patients.
The study was conducted by a team led by investigators from Massachusetts General Hospital.
Standard treatment for patients with metastatic, hormone-sensitive prostate cancer includes the addition of either the chemotherapy drug docetaxel or an androgen-receptor pathway inhibitor to androgen-deprivation therapy, with the latter two treatments acting to lower the effects of androgen hormones, such as testosterone.
Clinical trials that have combined all three treatments have generated conflicting results. To provide clarity, investigators designed the large, international ARASENS Trial and randomly assigned 1,306 patients with metastatic, hormone-sensitive prostate cancer in a 1L1 ratio to receive the oral androgen- receptor inhibitor darolutamide or placebo, both in combination with androgen-deprivation therapy and docetaxel.
Survival rates in the two groups were compared after 533 patients had died. Patients were followed for a median of approximately 3,5 years, and those who received darolutamide had a 32,5% lower risk of dying during that time than patients not taking darolutamide. Patients taking darolutamide also experienced greater delays in developing castration-resistant prostate cancer (which no longer responds to treatments that lower testosterone), pain, and the need for other anti-cancer therapies.
The combination of three medications did not result in more toxic effects compared with the combination of androgen-deprivation therapy and docetaxel alone, reports the study, published in the New England Journal of Medicine.
“Despite progress in recent years, survival is short for patients with metastatic prostate cancer. Results from ARASENS are an important step forward, and triplet therapy with darolutamide should become a new standard of care for the treatment of patients with metastatic hormone-sensitive prostate cancer,” said lead author Dr Matthew Smith, PhD, director of the Genitourinary Oncology Program at the Mass General Cancer Center and an associate professor of medicine at Harvard Medical School.
Study details
Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer
Matthew Smith, Maha Hussain, Fred Saad, Karim Fizazi, Cora Sternberg, E. David Crawford, Evgeny Kopyltsov, Chandler Park, Boris Alekseev, Álvaro Montesa-Pino, Dingwei Ye, Francis Parnis, Felipe Cruz, Teuvo L.J. Tammela, Hiroyoshi Suzuki, Tapio Utriainen, Cheng Fu, Motohide Uemura, María Méndez-Vidal, Benjamin Maughan, Heikki Joensuu, Silke Thiele, Rui Li, Iris Kuss, Bertrand Tombal.
Published in the New England Journal of Medicine on 17 February 2022.
Abstract
Background
Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown.
Methods
In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival.
Results
The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively).
Conclusions
In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups.
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