FDA Updates Label for Darolutamide in Nonmetastatic CRPC to Include OS Data

January 8, 2021 - The FDA has approved a supplemental new drug application to add overall survival and other secondary end point data from the phase 3 ARAMIS trial to the prescribing information for darolutamide for the treatment of patients with nonmetastatic prostate cancer.

The FDA has approved a supplemental new drug application to add overall survival (OS) and other secondary end point data from the phase 3 ARAMIS trial (NCT02200614) to the prescribing information for darolutamide (Nubeqa) for the treatment of patients with nonmetastatic prostate cancer (nmCRPC).1

Darolutamide led to a 31% reduction in the risk of death, extending survival for patients with nmCRPC (HR, 0.69; 95% CI, 0.53-0.88; P = .003).2 The additional findings comprise time to pain progression (HR, 0.65; 95% CI, 0.53-0.79; P <.0001) and time to the initiation of cytotoxic chemotherapy (HR, 0.58; 95% CI, 0.44-0.76; P <.0001).

Moreover, the prescribing information was also updated to include additional guidance on drug interactions. The final analysis of the trial reinforced the safety profile of darolutamide with an extended follow-up of median 29 months for the overall study population.

"A key goal of cancer treatment is to ensure that patients can live longer while minimizing side effects," said Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division. “[Darolutamide] has a proven efficacy and safety profile in men with nmCRPC and delayed the effects of disease progression in men who are otherwise generally asymptomatic. This update also gives physicians added certainty that [darolutamide] should be prescribed to appropriate patients at nmCRPC diagnosis to help ensure optimal outcomes for these men.”

In July 2019, the FDA approved darolutamide for the treatment of patients with nmCRPC based on data from ARAMIS, which showed that the combination of the androgen receptor inhibitor plus ADT resulted in a 59% reduction in the risk of metastases or death versus placebo/ADT in this population (n = 1509; HR, 0.41; 95% CI, 0.34-0.50; 2-sided P <.0001).3 The median MFS was 40.4 months in those who received darolutamide plus androgen deprivation therapy (ADT; n = 955) versus 18.4 months with placebo/ADT (P <.0001).

In the multicenter, double-blind, placebo-controlled, randomized phase 3 trial, investigators examined the safety and efficacy of darolutamide in patients with nmCRPC who were on standard ADT and at high risk for developing metastatic disease. Participants were randomized 2:1 to receive darolutamide at a twice-daily dose of 600 mg in combination with ADT or placebo/ADT.

All patients had an ECOG performance status of 0-1. The primary end point of ARAMIS was MFS, while secondary end points comprised OS, time to pain progression, time to initiation of first cytotoxic chemotherapy, time to first symptomatic skeletal event, and characterization of safety and tolerability.

Data for OS had been immature at the time of the primary analysis. At a median follow-up of 29.0 months, the OS at 3 years was 83% (95% CI, 80-86) and 77% (95% CI, 72-81) in the investigational and control arms, respectively.

The OS benefit with darolutamide/ADT still proved to be statistically significant despite 31% (n = 170) of patients in the placebo/ADT having crossed over to the investigational arm. Overall, 55% of patients (n = 307) in the control arm ended up crossing over to darolutamide/ADT or went on to receive another life-prolonging treatment prior to the analysis.

Fifty-five percent of patients on the control arm received subsequent treatment with darolutamide or other life-prolonging therapy. Of 384 patients in the placebo group who had discontinued treatment prior to the unblinding of the data, 137 were given a subsequent life-prolonging treatment beyond darolutamide; these included docetaxel, abiraterone acetate (Zytiga), and enzalutamide (Xtandi). In the investigational arm, 15% of 955 patients were given subsequent treatment beyond darolutamide.

Additional results indicated that darolutamide/ADT resulted in a significantly longer time to pain progression compared with placebo/ADT, at 40.3 months versus 25.4 months, respectively. At 3 years, the percentage of participants who had not yet received their first cytotoxic chemotherapy was 83% versus 75% of those in the investigational and control arms, respectively.

Moreover, the percentage of patients who had not experienced a first symptomatic skeletal event was 96% versus 92%, respectively, at 3 years. The time to first symptomatic skeletal event was significantly improved with darolutamide (HR, 0.48; 95% CI, 0.29-0.82; P = .005).

Regarding safety, 85.7% of patients who received darolutamide/ADT experienced toxicities versus 79.2% of those on placebo/ADT in the double-blind treatment period; 70.0% of patient who crossed over during the open-label period also experienced adverse effects (AEs). In the darolutamide/ADT arm, 8.9% of patients discontinued treatment versus 8.7% of patients in the placebo/ADT arm. Incidence of serious AEs and grade 5 toxicities in the investigational and control arms proved to be consistent with what had previously been revealed in the primary analysis.

References

  1. US FDA approves addition of overall survival and other secondary endpoint data to Nubeqa (darolutamide) prescribing information. News release. Bayer. January 8, 2021. Accessed January 8, 2021. http://bwnews.pr/2XAIhDL.
  2. Nubeqa (darolutamide tablets). Prescribing information. Bayer; 2021. Accessed January 8, 2021.
  3. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342.