Dr Smith on the Role of Darolutamide in Metastatic Hormone-Sensitive Prostate Cancer

“If you have your [own] favorite ARPI, you can pick and choose different studies to support your argument. [However], at the end of the day, they’re all similarly effective and, in my opinion, darolutamide is best in class for safety.”

Matthew R. Smith, MD, PhD, the Claire and John Bertucci Endowed Chair in Genitourinary Cancers at Massachusetts General Hospital, as well as a professor of medicine and the director of the Genitourinary Malignancies Program at Harvard Medical School, discussed the current standing of darolutamide (Nubeqa) in the treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC).

In June 2025, the FDA approved darolutamide monotherapy for the treatment of patients with mHSPC. The agent was previously approved for use in this patient population in combination with docetaxel. The regulatory decision was supported by data from the phase 3 ARANOTE trial (NCT04736199), which demonstrated that patients who were treated with darolutamide (n = 446) experienced a significant progression-free survival (PFS) benefit compared with those who received placebo (n = 223; HR, 0.54; 95% CI, 0.41-0.71; P < 0.0001). However, a statistically significant benefit in terms of overall survival (OS) was not observed (HR 0.78; 95% CI: 0.58, 1.05).

Smith began by noting that androgen receptor pathway inhibitors (ARPIs) such as darolutamide generally have similar efficacy across the prostate cancer spectrum. However, these agents have notable tolerability differences, he emphasized. Due to these differences, patient characteristics must be carefully considered when selecting an ARPI, he added.

Darolutamide in combination with androgen deprivation therapy (ADT) is usually Smith’s preferred regimen because it provides similar efficacy with a better safety profile, he explained. Smith added that when considering any clinical trial in isolation, limitations can be identified. For example, ARANOTE does not yet have data OS demonstrating an OS benefit, he said.