Evidence Mounts for Darolutamide Plus ADT in Hormone-Sensitive Prostate Cancer

WASHINGTON — Darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) significantly improved outcomes compared with ADT alone in men with metastatic hormone-sensitive prostate cancer (mHSPC), the phase II ARASEC trial showed.

In the study, which used an external control arm from the historic CHAARTED trial, median progression-free survival (PFS) was not estimable with the combination of darolutamide plus ADT compared with 14.3 months with ADT alone (HR 0.29, 95% CI 0.20-0.40, P<0.001), reported Rana McKay, MD, of the University of California San Diego, at the American Urological Association annual meeting.

Median overall survival (OS) was also significantly improved in the darolutamide group (HR 0.50, 95% CI 0.30-0.82, P=0.003), with 2-year OS rates of 89% and 80% in the darolutamide and ADT-alone arms, respectively. This OS benefit was achieved despite proportionally more patients in the ADT-alone arm receiving subsequent life-prolonging therapies (65% vs 26%).

Additionally, prostate-specific antigen (PSA) response rates were more than doubled in the darolutamide arm compared with the ADT-alone arm at all time points, with 68% versus 33% of patients achieving a PSA of less than 0.2 ng/mL at any time during the study (P<0.001).

Darolutamide plus ADT and docetaxel is one of the standards of care for mHSPC, based on the phase III ARASENS trial. Subsequently, the combination of darolutamide plus ADT without docetaxel was evaluated in the global phase III ARANOTE study, which showed that the combination significantly improved PFS versus ADT plus placebo. As a result, darolutamide plus ADT was approved for mHSPC by the FDA.

However, the possibility of a U.S. study with an ADT control arm “was really not possible in the U.S. because ADT was no longer the standard of care,” McKay explained.

“This is the first study, to our knowledge, in prostate cancer that uses propensity score matching with external phase III trial control arms,” she noted. “This innovative approach really offers a potentially practice-changing paradigm to accelerate enrollment, enhance operational efficiency, and expedite patient access to emerging therapies in a rapidly evolving landscape.”

Rosalia Viterbo, MD, of the Fox Chase Cancer Center in Philadelphia, told MedPage Today that the study “supports the growing movement toward chemotherapy-free treatment intensification.”

“While triplet therapy remains an excellent option for fit patients with high-volume or aggressive disease, many real-world patients are older, frailer, or simply not good candidates for docetaxel,” she said. “ARASEC suggests that darolutamide combined with ADT may offer an effective and more tolerable alternative for these patients.”

“Initially, darolutamide gained attention largely through the ARASENS triplet data, but studies like ARASEC and ARANOTE suggest it is also a strong doublet partner,” she explained. “This may increase physician comfort with using darolutamide in a broader range of patients.”

The ARASEC study included a prospectively enrolled arm of U.S. men with mHSPC with no prior systemic therapy who were treated with darolutamide 600 mg twice daily plus ADT. Median age was 71, 81.9% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, and median PSA was 6.0 ng/mL.

Using propensity score matching based on baseline prognostic characteristics, including age, ECOG performance status, disease extent, prior local therapy, Gleason score, and baseline PSA, McKay and team matched 120 patients in the darolutamide/ADT arm with 120 patients who received ADT monotherapy in the CHAARTED trial. Results from CHAARTED had previously showed that adding docetaxel to ADT significantly improved OS compared with ADT alone in men with mHSPC.

To address limitations in the trial design, the researchers conducted sensitivity analyses to determine how darolutamide plus ADT would perform against a contemporary arm — in this case the ARANOTE ADT arm.

“The sensitivity analysis … strongly supports the ARASEC primary findings, with all confidence intervals across the primary and key secondary endpoints — including overall survival — below 1,” McKay reported.

Safety and tolerability profiles were in line with what is known about darolutamide. Serious treatment-emergent adverse events occurred in 23.3% of patients receiving the drug plus ADT, and 8.1% discontinued the drug, compared with rates of 23.5% and 9%, respectively, in the ARANOTE ADT arm.

Tolerability is a major consideration, Viterbo observed, noting that darolutamide appears to have fewer central nervous system-related side effects and drug interactions compared with some other androgen receptor pathway inhibitors, “which may make it particularly attractive for older patients, patients with multiple medications, or those concerned about fatigue and cognitive effects.”