Darolutamide Submitted for FDA Approval in Nonmetastatic CRPC

Based on findings from the phase III ARAMIS trial, a new drug application for darolutamide has been submitted to the FDA seeking the&nbsp;investigational agent&#39;s approval as a treatment for&nbsp;patients with nonmetastatic castration-resistant prostate cancer, according to&nbsp;the codevelopers of the investigational agent, Bayer and Orion Corporation.<br /> &nbsp;

Based on findings from the phase III ARAMIS trial, a new drug application (NDA) for darolutamide has been submitted to the FDA seeking the investigational agent's approval as a treatment for patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to the codevelopers of the investigational agent, Bayer and Orion Corporation.

In results from the trial, darolutamide added to androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) compared with placebo plus ADT in patients with nonmetastatic CRPC.

At a median follow-up of 17.9 months, median MFS was 40.4 months in the darolutamide arm versus 18.4 months in the placebo arm, corresponding to a 59% reduction in the risk of metastases or death in favor of darolutamide (HR, 0.41; 95% CI, 0.34-0.50;P<.0001).1This benefit to MFS with darolutamide occurred across patient subgroups, including those for baseline PSA doubling time, use of bone-targeting agents, Gleason score, age, and ECOG performance status.

At an interim analysis for overall survival (OS), the 3-year rates of OS were 83% in the darolutamide arm versus 73% in the placebo arm, corresponding to a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.50-0.99,P= .0452). Median OS was not yet reached in either arm.

"We are grateful to the patients, their families and the clinical investigators who have made this important study possible," Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division, said in a press release. "The NDA submission is a key milestone bringing us closer to providing darolutamide as a potential treatment option for men with nonmetastatic CRPC."

When presenting the ARAMIS findings at the 2019 Genitourinary Cancers Symposium, lead study author Karim Fizazi, MD, reported that the median time to pain progression, using the Brief Pain Inventory-Short Form or by opioid use, also favored darolutamide, at a median of 40.3 months, compared with 25.4 months with placebo, consistent with a 35% risk reduction (HR, 0.65; 95% CI, 0.53-0.79;P<.0001).

“Darolutamide also has a very favorable safety profile,” said Fizazi, head, Department of Cancer Medicine, Institut Gustave Roussy in Villejuif, France, and professor of oncology at the University of Paris. “Specifically, we didn’t find any increase in side effects such as falls, fractures, cognitive disorders, seizures, and hypertension compared to placebo.”

Progression-free survival (PFS), which included local relapse, distant metastases, or death, was an exploratory endpoint. Median PFS was 36.8 months in the darolutamide arm versus 14.8 months in the placebo arm, for a 62% risk reduction with darolutamide (HR, 0.38; 95% CI, 0.32-0.45; P <.0001).

Time to cytotoxic chemotherapy (HR, 0.43; 95% CI, 0.31-0.60;P<.0001) and time to first symptomatic skeletal event (HR, 0.43; 95% CI, 0.22-0.84;P= .0113) also favored darolutamide.

Nonmetastatic CRPC is associated with high risk for progression and cancer-specific mortality. In men with high-risk nonmetastatic CRPC, 2 next-generation androgen receptor inhibitors, apalutamide and enzalutamide, have been shown recently to improve MFS,2,3“although they were associated with increased cognitive impairments, falls, and other side effects,” said Fizazi. Both apalutamide and enzalutamide have received approval from the FDA for the treatment of nonmetastatic CRPC.

Darolutamide is structurally distinct from apalutamide and enzalutamide, and is characterized by low blood-brain barrier penetration, “which may result in less central nervous system-related side effects,” he said. Preclinical data show that darolutamide has a high affinity to the androgen receptor and a low potential for drug-drug interactions.

In the early development program, robust anticancer activity was observed in men with CRPC, including patients who previously received a taxane and, to a lesser degree, abiraterone, said Fizazi. No clear drug-related side effects could be detected in these studies.

The multicenter, double-blind phase III ARAMIS trial accrued 1509 patients with nonmetastatic CRPC and a PSA doubling time <10 months who were being treated with ADT and determined to be at-risk for developing metastatic disease. All men had an ECOG performance status of 0 to 1. Patients were randomized in a 2:1 ratio to darolutamide at 600 mg twice daily while maintaining ADT or matching placebo plus ADT.

At baseline, the median PSA doubling time was 4.4 months and 4.7 months in the darolutamide and placebo groups, respectively. Only 3% and 6%, respectively, were taking a bone-sparing agent. The median duration of treatment was 14.8 months for darolutamide and 11.0 months for placebo. At data cutoff of September 3, 2018, 64% of patients on darolutamide and 36% on placebo were still on treatment.

Grade 3 /4 adverse events were rarely observed, “which is an important finding for this population of asymptomatic men,” said Fizazi. “The incidence of drug discontinuation due to side effects was remarkably similar in the darolutamide and the placebo groups, about 9%.”

The only adverse event with an all-grade rate >10% in the darolutamide arm was fatigue (12.1% vs 8.7% in the placebo arm). The difference in the rate of fatigue between groups disappears when adjusting for duration of exposure, said Fizazi. The incidences of falls and fractures were not different between arms (about 4% for each adverse event in both arms), as was the incidence of hypertension (6.6% in darolutamide arm vs 5.2% in the placebo arm).

Pain interference and pain severity scores and urinary symptom scores favored darolutamide.


  1. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC).J Clin Oncol. 37(suppl 7s; abstr 140). meetinglibrary.asco.org/record/170190/abstract.
  2. Small EJ, Saad F, Chowdhury S et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).J Clin Oncol. 2018;36(suppl 6s; abstr 161). doi: 10.1200/JCO.2018.36.6_suppl.161.
  3. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC).J Clin Oncol. 2018;36(suppl 6S; abstr 3). doi: 10.1200/JCO.2018.36.6_suppl.3.