Darolutamide Nears EU Approval for Nonmetastatic CRPC

Scott Z. Fields, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for a Marketing Authorization Application for darolutamide (Nubeqa) for the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC) who are at high risk for developing metastatic disease.^1,2

The CHMP recommendation is based on results from the phase III ARAMIS trial, in which darolutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) compared with placebo plus ADT (HR, 0.41; 95% CI, 0.34-0.50; P <.0001).^3,4 The median MFS was 40.4 months versus 18.4 months for darolutamide/ADT and placebo/ADT, respectively.

The opinion follows a recent announcement regarding results of a preplanned final OS analysis from ARAMIS, which showed that the darolutamide regimen led to a significant improvement in overall survival (OS) compared with placebo and ADT in patients with nonmetastatic CRPC.⁵ Full findings from the analysis will be presented at an upcoming medical meeting.

If approved, darolutamide will be available as a 300-mg film-coated tablet. The European Commission is expected to make a final decision on the application in the coming months. Additional filings in Brazil and Japan are underway, according to a statement by Bayer, which jointly develops darolutamide with Orion Corporation.

"For patients with nonmetastatic CRPC who typically have asymptomatic disease, it is critical that they have treatment options that delay metastases, and that also can limit the burdensome side effects of therapy,” Scott Z. Fields, MD, senior vice president, and head of Oncology Development at Bayer, stated in a press release. "This positive CHMP opinion for darolutamide marks a significant step forward in delivering a potential new therapeutic option that has the potential to both extend MFS in nonmetastatic CRPC and limit the impact of side effects, meeting an unmet medical need."

In the double-blind, placebo-controlled, multicenter, phase III ARAMIS study, investigators evaluated the efficacy and safety of darolutamide in combination with ADT in 1509 patients with nonmetastatic CRPC who were receiving a concomitant gonadotropin-releasing hormone analog or had a bilateral orchiectomy. Patients were randomized 2:1 to receive 600 mg of oral darolutamide twice daily or placebo plus ADT. All patients had an ECOG performance status of 0 to 1. The primary endpoint was MFS, and key secondary endpoints were OS, time to pain progression, time to initiation of first cytotoxic chemotherapy, time to first symptomatic skeletal event, and characterization of the safety and tolerability.

At the time of the final MFS analysis, OS data were immature, but data also showed a trend toward improved survival. The 3-year rates of OS were 83% in the darolutamide arm versus 73% with placebo, translating to a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.50-0.99, P = .0452), according to results of an interim OS analysis.

Additional ARAMIS findings showed that darolutamide also maintained quality of life and led to a 35% reduction in the risk of pain progression versus placebo in this patient population (HR, 0.65; 95% CI, 0.53-0.79; P <.0001).⁶ The AR inhibitor also led to a 57% reduction in the risk of symptomatic skeletal event development compared with placebo (HR, 0.43; 95% CI, 0.22-0.84; P = .011).

Regarding safety, adverse events (AEs) that occurred more frequently with the androgen receptor inhibitor versus placebo were fatigue (16% vs 11%), pain in extremity (6% vs 3%) and rash (3% vs 1%).

Moreover, data presented at the 2019 ESMO Asia Congress from the ARAMIS trial also showed that darolutamide delays disease progression and subsequent treatment for patients with nonmetastatic CRPC compared with placebo, while maintaining quality of life.⁷

The international, double-blind, placebo-controlled, phase III ARASENS study is exploring darolutamide plus ADT in combination with docetaxel in approximately 1300 patients with newly diagnosed, metastatic hormone-sensitive prostate cancer (NCT02799602).

"The positive CHMP opinion takes us one step closer to bringing this new therapeutic option to men with nonmetastatic CRPC in the [European Union] and demonstrates our ongoing commitment to delivering innovative medicines,” Satu Ahomäki, senior vice president of Commercial Operations, Orion Corporation, stated in the press release. “We are looking forward to the co-promotion with Bayer to support patients with prostate cancer and their healthcare professionals.”

References

1. Bayer receives positive CHMP opinion for darolutamide as a new treatment for men with non-metastatic castration-resistant prostate cancer [news release]: Berlin. Bayer. Published January 31, 2020. https://bit.ly/31cdNJ2. Accessed January 31, 2020.
2. Nubeqa [news release]. European Medicines Agency. Published January 30, 2020. https://bit.ly/3b5jTQb. Accessed January 31, 2020.
3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2019;380(13):1235-1246. doi: 10.1056/NEJMoa1815671.
4. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7s; abstr 140). doi: 10.1200/JCO.2019.37.7_suppl.140.
5. Nubeqa (darolutamide) plus androgen deprivation therapy achieved the secondary endpoint of overall survival (OS) in men with non-metastatic castration-resistant prostate cancer [news release]: Whippany, NJ. Bayer. Published January 30, 2020. https://bit.ly/3aTXBAD. Accessed January 30, 2020.
6. Fizazi K, Shore ND Tammela T, et al. Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 15; abstr 5000). doi: 10.1200/JCO.2019.37.15_suppl.5000.
7. Pang J S-T, Shore N, Smith MR, et al. Efficacy and safety of darolutamide in non-metastatic castration-resistant prostate cancer (nmCRPC) in the ARAMIS trial. Ann Oncol. 2019;30(suppl_9):mdz424.001. doi: 10.1093/annonc/mdz424.001.