SAN FRANCISCO — Treatment with darolutamide prolonged metastasis-free survival compared with placebo among men with asymptomatic nonmetastatic castration-resistant prostate cancer, according to results of the double-blind phase 3 ARAMIS trial presented at Genitourinary Cancers Symposium.
Darolutamide (ODM-201; Bayer, Orion Pharma) — an androgen receptor antagonist — also was associated with a low incidence of treatment-related adverse events.
Despite recent treatment advances, there is still significant unmet need for new therapeutic options for men with nonmetastatic castration-resistant prostate cancer, Karim Fizazi, MD, PhD, head of the department of cancer medicine at Institut Gustave Roussy in Villejuif, France, and professor in oncology at University of Paris, told HemOnc Today.
“Nonmetastatic castration-resistant prostate cancer has not spread beyond the prostate region; PSA levels are elevated, despite treatment with hormone therapy, and men with nonmetastatic castration-resistant prostate cancer generally feel well and do not have symptoms,” he said. “The unmet medical need is for treatments that achieve disease control and delay the spread of the cancer without impacting their daily lives or increasing the burden of disease with treatment side effects.
“Although the current treatments in this space are effective in delaying onset of metastases, the side effects can be unpleasant and disruptive to men’s lives; particularly cognitive issues, seizures, impact on balance which may lead to falls and bone fractures, rash and hypertension,” he added. “Further, new treatment options that have limited interactions with medications typically used in this patient population also are important.”
Fizazi and colleagues randomly assigned 1,509 men (median age, 74 years) in a 2:1 ratio to receive 600 mg twice-daily darolutamide (n = 955; median PSA doubling time, 4.4 months) or placebo (n = 554; median PSA doubling time, 4.7 months) while continuing androgen deprivation therapy. All men had baseline PSA of at least 2 ng/mL, an ECOG performance status of 0 to 1, and a PSA doubling time of 10 or fewer months.
Metastasis-free survival served as the study’s primary endpoint. Secondary endpoints included OS, time to pain progression — assessed using the Brief Pain Inventory — time to first cytotoxic chemotherapy, time to first symptomatic skeletal event and safety.
Median duration of treatment was 14.8 months in the darolutamide group and 11 months in the placebo group. Median follow-up was 17.9 months.
Results showed darolutamide conferred a 59% reduction in the risk for metastases or death (median metastasis-free survival, 40.4 months vs. 18.4 months; HR = 0.41; 95% CI, 0.34-0.5).
This benefit occurred across patient subgroups, Fizazi said during his presentation, including those for baseline PSA doubling time, age and ECOG performance status.
“Metastasis-free survival is a meaningful endpoint because one-third of patients with nonmetastatic castration-resistant prostate cancer go on to develop metastases within 2 years,” Fizazi told HemOnc Today. “Metastases are associated with increased mortality and morbidity and reduced quality of life. Prolonging metastasis-free survival in men with prostate cancer is a key therapeutic goal, as it has been associated with increased survival.”
Therapies have been approved in the U.S. and European Union based on metastasis-free survival, which is an endpoint now accepted by health authorities as meaningful in this setting, he added.
Darolutamide also showed a trend toward benefit in terms of OS, although median OS was not yet reached (3-year OS, 83% vs. 73%; HR = 0.71; 95% CI, 0.5-0.99), and time to pain progression (median, 40.3 months vs. 25.4 months; HR = 0.65; 95% CI, 0.53-0.79).
PFS — an exploratory endpoint — also appeared significantly improved in the darolutamide group (median, 36.8 months vs. 14.8 months; HR = 0.38; 95% CI, 0.32-0.45).
Time to cytotoxic chemotherapy (median, not reached vs. 38.2 months; HR = 0.43; 95% CI, 0.31-0.6) and time to first symptomatic skeletal event (median, not reached for both; HR = 0.43; 95% CI, 0.22-0.84) also favored the darolutamide group.
Most adverse events were grade 1 or grade 2. Twenty-five percent of men assigned darolutamide and 20% assigned placebo experienced grade 3 or grade 4 adverse events.
Drug discontinuation due to side effects was “remarkably similar” between the two groups, Fizazi said, at about 9% for each.
All treatment-related adverse events occurred in fewer than 10% of patients, with the exception of fatigue (darolutamide, 12.1%; placebo, 8.7%).
Treatment-related adverse events associated with next-generation androgen receptor inhibitors — including fractures, falls, seizures and weight loss — occurred among a comparable proportion of men in each group.
“A favorable safety profile is critical for these largely asymptomatic men because treatment decisions can impact their overall well-being, prognosis and compliance with the treatment, as well as with other medications that are typical for this patient population,” Fizazi told HemOnc Today.
The Brief Pain Inventory-Short Form for pain interference (P = .0006) and pain severity (P = .0007), as well as the EORTC Quality of Life Questionnaire-Prostate Cancer Module urinary symptoms subscale (P < .0001) showed significantly better outcomes with darolutamide. Men assigned darolutamide also demonstrated a significantly longer time to deterioration of the Functional Assessment of Cancer Therapy-Prostate subscale score (median, 11.1 months vs. 7.9 months; HR = 0.8; 95% CI, 0.7-0.91).
“These data are exciting for the prostate cancer community,” Fizazi told HemOnc Today. “They show that darolutamide has the potential to address an important unmet medical need that remains despite recent advances in nonmetastatic castration-resistant prostate cancer treatment; they not only demonstrate darolutamide’s significant efficacy in preventing the spread of prostate cancer, but also its favorable safety profile that, if approved by regulatory authorities, may allow men with nonmetastatic castration-resistant prostate cancer to continue their day-to-day life without increasing the burden of disease with treatment side effects.” – by Alexandra Todak
Fizazi K, et al. Abstract 140. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.
Disclosures: Fizazi reports honoraria from Astellas Pharma, Janssen, Merck and Sanofi; consultant/advisory roles with Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, CureVac, ESSA, Janssen Oncology, Orion Pharma, Roche/Genentech and Sanofi; and travel expenses from Amgen and Janssen. Please see the abstract for all other authors’ relevant financial disclosures.