FDA Accepts sNDA for Darolutamide Plus ADT in Metastatic Hormone-Sensitive Prostate Cancer

FDA

The FDA has accepted a supplemental new drug application (sNDA) seeking the approval of darolutamide (Nubeqa) in combination with androgen deprivation therapy (ADT) for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC).¹

The sNDA is supported by data from the phase 3 ARANOTE trial (NCT04736199). Findings presented at the 2024 ESMO Congress demonstrated that patients treated with darolutamide plus ADT (n = 446) achieved a median radiographic progression-free survival (rPFS) that was not reached (NR; 95% CI, NR-NR) compared with 25.0 months (95% CI, 19.0-NR) in those given placebo plus ADT (n = 223; HR, 0.54; 95% CI, 0.41-0.71; P< .0001).² The 24-month rPFS rates were 70.3% and 52.1%, respectively.

“Bayer is dedicated to addressing unmet needs in prostate cancer treatment for various stages of the disease, and today’s acceptance of our sNDA for [darolutamide] plus ADT for the treatment of patients with mHSPC brings us closer to adding an additional treatment option for [darolutamide] to benefit those living with mHSPC,” Christine Roth, executive vice president of Global Product Strategy and Commercialization and member of the Pharmaceuticals Leadership Team at Bayer, stated in a news release.¹ “If approved, this would expand the indication for [darolutamide] in patients with mHSPC to include [darolutamide] both with and without chemotherapy, providing physicians and their patients with an additional [darolutamide] treatment option in this setting. We are working closely with the FDA to bring this additional [darolutamide] treatment option to patients as soon as possible.”

In August 2022, the FDA approved darolutamide in combination with docetaxel for the treatment of patients with mHSPC.³ The agent was initially approved by the regulatory agency in July 2019 for the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC).⁴

ARANOTE was a global, randomized, double-blind, placebo-controlled trial that enrolled patients with mHSPC who had an ECOG performance status of 0 to 2.²

Patients were randomly assigned 2:1 to receive darolutamide at 600 mg twice per day plus ADT or placebo plus ADT. Stratification factors included visceral metastases (yes vs no) and prior local therapy (yes vs no).

The trial’s primary end point was rPFS per central blinded review. Secondary end points included overall survival (OS), time to subsequent anticancer therapy, time to mCRPC, time to prostate-specific antigen (PSA) progression, rates of undetectable PSA, time to pain progression, and safety.

Additional data showed that the rPFS benefit associated with the darolutamide regimen was consistent across all subgroups.

OS data were immature at the June 7, 2024, data cutoff; the median OS was NR in both the darolutamide and placebo arms (HR, 0.81; 95% CI, 0.59-1.12). The median time to mCRPC was NR in the darolutamide arm vs 13.8 months in the placebo arm (HR, 0.40; 95% CI, 0.32-0.51).

The median time to PSA progression was NR in the darolutamide arm vs 16.8 months in the placebo arm (HR, 0.31; 95% CI, 0.23-0.41). The time to subsequent systemic therapy was NR in both groups (HR, 0.40; 95% CI, 0.29-0.56), and the median time to pain progression was NR in the darolutamide group vs 29.9 months in the placebo group (HR, 0.72; 95% CI, 0.54-0.96).

The median treatment duration was 24.2 months for the darolutamide regimen vs 17.3 months for the placebo regimen. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 91.0% of patients in the experimental arm vs 90.0% of patients in the placebo arm. The rates of grade 3 or 4 TEAEs were 30.8% and 30.3%, respectively. Grade 5 TEAEs were reported in 4.7% of patients in the darolutamide arm vs 5.4% of patients in the placebo arm. The rates of serious TEAEs were 23.6% for darolutamide vs 23.5% for placebo, and TEAEs led to treatment discontinuation in 6.1% of patients in the experimental arm vs 9.0% of patients in the control arm.

TEAEs associated with androgen receptor pathway inhibitors included fatigue (darolutamide arm, 5.6%; placebo arm, 8.1%), mental impairment disorder (1.6%; 0.5%), hypertension (9.4%; 9.5%), cardiac arrhythmias (8.8%; 6.8%), coronary artery disorders (3.6%; 1.4%), heart failure (0.9%; 0.9%), falls (1.3%; 0.9%), bone fracture (4.0%; 2.3%), vasodilatation and flushing (9.2%; 7.2%), diabetes mellitus and hyperglycemia (9.0%; 9.5%), and rash (4.3%; 3.6%).

References

1. U.S. FDA accepts supplemental new drug application for Nubeqa (darolutamide) for the treatment of patients with metastatic hormone-sensitive prostate cancer. News release. Bayer. November 21, 2024. Accessed November 21, 2024. https://www.biospace.com/press-releases/u-s-fda-accepts-supplemental-new-drug-application-for-nubeqa-darolutamide-for-the-treatment-of-patients-with-metastatic-hormone-sensitive-prostate-cancer
2. Saad F, Vjaters E, Shore ND, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial. Ann Oncol. 2024;35(suppl 2):S1257-S1258. doi:10.1016/j.annonc.2024.08.2311
3. FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer. FDA. August 5, 2022. Accessed November 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-tablets-metastatic-hormone-sensitive-prostate-cancer
4. FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. FDA. July 30, 2019. Accessed November 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer