Approval Sought for Darolutamide With Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer


Supplemental new drug application submitted to the FDA for the approval of darolutamide (Nubeqa) plus docetaxel in patients with metastatic hormone-sensitive prostate cancer.

Bayer has filed a supplemental new drug application (sNDA) to the FDA for the approval of darolutamide (Nubeqa) plus docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC).1

The sNDA was based on the results of the phase 3 ARASENS trial, which found that adding darolutamide to docetaxel and androgen deprivation therapy (ADT) lowered the risk of death by 32.5% compared with docetaxel plus ADT (HR, 0.68; 95% CI, 0.57-0.80; < .001).2 The 4-year overall survival (OS) rates in the investigative cohort was 62.7% (95% CI, 58.7%-66.7%) compared with 50.4% (95% CI, 46.3%-54.6%) in the control group.

“For men with mHSPC, there remains a high need for new treatment options that can extend OS and delay the progression to CRPC,” said Christine Roth, member of the executive committee of the Pharmaceutical Division and head of the Oncology SBU at Bayer, in a press release. “Prostate cancer is a key area of focus at Bayer and the US and European submissions for [darolutamide] in mHSPC represent a significant milestone in our commitment to developing treatments that support men with prostate cancer throughout the different stages of the disease.”

The international, double-blind, placebo-controlled ARASENS trial included patients with histologically or cytologically confirmed prostate cancer who were 18 years of age or older, had an ECOG performance status of 0 or 1, and were eligible for ADT and docetaxel per investigator judgment.

The trial excluded patients with regional lymph-node involvement only or if they received ADT more than 12 weeks prior to randomization. Other exclusions were for patients who received androgen-receptor pathway inhibitors, chemotherapy, or immunotherapy for their disease prior to randomization, or those who received radiotherapy within 2 weeks before randomization.

All participants were administered ADT or underwent orchiectomy within 12 weeks prior to randomization. Patients received docetaxel for 6 cycles at a dose of 75 mg/m2 on day 1 of each 21-day cycle and, at the discretion of the study investigator, were administered prednisone or prednisolone initiated within 6 weeks before they underwent randomization.

Investigators randomized 1306 study participants 1:1 to receive darolutamide at a twice-daily dose of 600 mg (n = 651) or matched placebo (n = 655). Treatment was continued until disease progression, a change in antineoplastic therapy, intolerable toxicity, patient or physician decision, death, or nonadherence.

Stratification factors included stage of metastasis (nonregional lymph-node metastases only vs bone metastases with or without lymph-node metastases vs visceral metastases with or without lymph-node or bone metastases) and alkaline phosphatase level (below the upper limit of normal (ULN) vs above the ULN).

The primary end point of the trial was OS, with key secondary end points including time to castration-resistant disease, time to pain progression, symptomatic skeletal event-free survival (EFS), time to a first symptomatic skeletal event, time to initiation of subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, time to initiation of opioid treatment for 7 or more consecutive days, and safety.

Among 1305 patients in the full analysis set, 651 were placed in the investigative cohort and 654 were in the control cohort, with demographic and baseline characteristics balanced between both groups.

The median age of study participants across both groups was 67 years of age. Most patients had an ECOG performance status of 0 (71%) and a Gleason score of 8 or higher (78.2%). Further, 79.5% of patients had bone metastases and 17.5% had visceral metastases. Approximately 86% of patients had metastatic disease at the time of their diagnosis.

Additional data from the trial published in the New England Journal of Medicine showed that darolutamide improved the time to development of castration-resistant disease compared with placebo (HR, 0.36; 95% CI, 0.30-0.42; < .001), the time to pain progression (HR, 0.79; 95% CI, 0.66-0.95; = .01), symptomatic skeletal EFS (HR, 0.61; 95% CI, 0.52-0.72; < .001), time to a first symptomatic skeletal event (HR, 0.71; 95% CI, 0.54-0.94; = .02), and time to the initiation of subsequent systemic antineoplastic therapy (HR, 0.39; 95% CI, 0.33-0.46; < .001).

Any-grade adverse effects (AEs) were reported by 99.5% of patients in the investigative cohort compared with 98.9% in the control group. Grade 3 or higher AEs were reported by 70.2% and 67.5% of patients, respectively. Further, serious AEs were reported in 44.8% of patients administered darolutamide and 42.3% of patients in the placebo group.

Select grade 3 or 4 toxicities of interest in the darolutamide cohort included neutropenia (33.7%), febrile neutropenia (7.8%), hypertension (6.4%), anemia (4.8%), pneumonia (3.2%), hyperglycemia (2.8%), increased alanine aminotransferase level (2.8%), increased aspartate aminotransferase level (2.6%), and increased weight (2.1%).

Toxicities leading to permanent discontinuation of darolutamide or placebo were reported in 13.5% of patients on the investigative group compared with 10.6% of patients in the placebo group. Further, 8.0% of patients in the darolutamide group and 10.3% of patients in the placebo cohort permanently discontinued docetaxel because of toxicities.


  1. Bayer submits applications in the US and EU for additional indication of NUBEQA (darolutamide). News release. Bayer; March 9, 2022. Accessed March 9, 2022.
  2. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. Published online February 17, 2022. doi:10.1056/NEJMoa2119115
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