FDA and EMA Approval Sought for Darolutamide Plus Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer

FDA

A supplemental new drug application and a Variation Type II application have been submitted to the FDA and the European Medicines Agency, respectively, seeking the approval of darolutamide (Nubeqa) plus docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC).¹

The applications were supported by findings from the phase 3 ARASENS trial (NCT02799602), which showed that the addition of darolutamide to docetaxel and androgen deprivation therapy (ADT) reduced the risk of death by 32.5% vs docetaxel plus ADT (HR, 0.68; 95% CI, 0.57-0.80; P < .001).² The 4-year overall survival (OS) rates in the investigative and control arms were 62.7% (95% CI, 58.7%-66.7%) and 50.4% (95% CI, 46.3%-54.6%), respectively.

“For men with mHSPC, there remains a high need for new treatment options that can extend OS and delay the progression to CRPC,” Christine Roth, member of the executive committee of the Pharmaceutical Division and head of the Oncology SBU at Bayer, stated in the 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 phase 3 trial enrolled 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.

If patients had regional lymph-node involvement only or if they received ADT more than 12 weeks prior to randomization, they were excluded. Other exclusion criteria included having received androgen-receptor pathway inhibitors, chemotherapy, or immunotherapy for their disease prior to randomization, or having received radiotherapy within 2 weeks before randomization.

All participants were given ADT or underwent orchiectomy within 12 weeks prior to randomization. They also received docetaxel for 6 cycles at a dose of 75 mg/m² on day 1 of every 21-day cycle, as well as prednisone or prednisolone, which was given at the discretion of the study investigator; this was started within 6 weeks before they underwent randomization.

A total of 1306 study participants were randomized 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, and key secondary end points included time to castration-resistant disease, time to pain progression, symptomatic skeletal event-free survival, 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.

A total of 1305 patients were included in the full analysis set; 651 of these patients were on the investigative arm and 654 of these patients were on the control arm. Demographic and baseline characteristics were noted to be well balanced between the 2 treatment arms.

The median age of study participants spanning arms was 67 years. The majority of patients had an ECOG performance status of 0 (71%) and a Gleason score of 8 or higher (78.2%). Moreover, all participants had metastatic disease at baseline, with 79.5% having bone metastases and 17.5% having visceral metastases. Approximately 86% of patients had metastatic disease at the time of their diagnosis.

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

A total of 1302 patients comprised the safety analysis set; 652 patients in this group received darolutamide and 650 received placebo. Any-grade adverse effects (AEs) were experienced by 99.5% of those on the investigative arm and 98.9% of those on the control arm; grade 3 or higher effects were experienced by 70.2% and 67.5% of patients, respectively. Moreover, serious AEs occurred in 44.8% of those who received darolutamide and 42.3% of those given placebo.

In the darolutamide arm, select grade 3 or 4 toxicities of interest 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 led to permanent discontinuation of darolutamide or placebo in 13.5% of those on the investigative arm and 10.6% of those on the placebo arm. Moreover, 8.0% and 10.3% of those on the darolutamide and placebo arms, respectively, permanently discontinued docetaxel due to toxicities.

Additional submissions in mHSPC are being planned on a global scale, according to Bayer.

References

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. https://bit.ly/3CrqSAW
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