FDA approval sought for darolutamide in mHSPC

An FDA supplemental new drug application (sNDA) has been filed for darolutamide (Nubeqa) for use in combination with docetaxel for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to Bayer, the developer of the oral androgen receptor (AR) inhibitor.1

The sNDA is based on findings from the placebo-controlled phase 3 ARASENS trial, which showed that adding darolutamide to standard androgen deprivation therapy (ADT) and docetaxel boosted overall survival (OS) versus ADT/docetaxel alone in patients with mHSPC.

Results reported at the 2022 Genitourinary Cancers Symposium2 and simultaneously published in the New England Journal of Medicine3 showed that at a median follow-up of 43.7 months for darolutamide plus ADT/docetaxel and 42.4 months with placebo plus ADT/docetaxel, the active therapy resulted in a 32.5% reduction in the risk of death (HR 0.68; 95% CI 0.57-0.80; P <.001).

Bayer also submitted a Variation Type II application to the European Medicines Agency for approval in the European Union for this indication.

“For men with mHSPC, there remains a high need for new treatment options that can extend overall survival and delay the progression to castration-resistant prostate cancer (CRPC),” Christine Roth, member of the Executive Committee of Bayer’s Pharmaceutical Division and head of the Oncology SBU at Bayer, stated in a press release. “Prostate cancer is a key area of focus at Bayer and the US and EU submissions for Nubeqa 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.”

Darolutamide is a structurally distinct and highly potent AR inhibitor that was previously approved to treat patients with CRPC in the nonmetastatic setting based on results of the phase 3 ARAMIS trial (NCT02200614).4 Data from the study showed a statistically significant improvement in metastasis-free survival with the agent against matched placebo.

In ARASENS (NCT02799602), patients with cytologically confirmed metastatic adenocarcinoma of the prostate were eligible for the trial. All participants needed to be candidates for ADT and docetaxel, have an ECOG performance status of 0 or 1, and have adequate organ function.

Patients were randomized 1:1 to either 600 mg of daily darolutamide (n = 651) or matched placebo (n = 655) plus ADT/docetaxel. Factors for stratification included extent of disease (M1b/b/c) and alkaline phosphatase (ALP) levels. The primary end point was OS with secondary outcome measures of time to CRPC, time to pain progression, time for first symptomatic skeletal event (SSE), time to initiation of subsequent systemic antineoplastic therapy, and safety.

Patient characteristics were well balanced between the 2 groups. The median age was 67 years for both the darolutamide and placebo groups and most patients had a Gleason score of 8 or greater (77.6% vs 78.9%, respectively) and M1 stage (85.7% vs 86.5%) at initial diagnosis. At initial screening, patients in both groups were most likely to have M1b stage disease (79.4% vs 79.5%) and ALP levels equal to or above the upper limit of normal (55.5% each).

Median OS in the darolutamide arm was not estimable (NE; 95% CI, NE-NE) vs 48.9 months (95% CI, 44.4-NE) with placebo. Rates of OS at 48 months were 62.7% and 50.4%, respectively. The effect of active therapy was consistent across patient subgroups, including by ALP level below (HR, 0.64; 95% CI, 0.46-0.88) or above the upper limit of normal (HR, 0.69; 95% CI, 0.56-0.85), and by either de novo (HR, 0.71; 95% CI, 0.59-0.85) or recurrent (HR, 0.61; 95% CI, 0.35-1.05) metastatic disease status.

Moreover, darolutamide was associated with superior secondary outcomes despite patients in this arm receiving fewer subsequent life-prolonging systemic antineoplastic therapies (56.8%) vs the placebo arm (75.6%). Common subsequent therapies included abiraterone acetate (35.6% vs 46.9%), enzalutamide (Xtandi; 15.2% vs 27.5%), cabazitaxel (Jevtana; 18.1% vs 18.0%), and docetaxel (14.6% vs 18.0%). Notably, 66% of patients in the placebo arm went on to receive life-prolonging therapy with an AR pathway inhibitor. Time to first subsequent antineoplastic therapy was NE (95% CI, NE-NE) in the active therapy arm vs 25.3 months (95% CI, 23.1-28.8) in the placebo group (HR, 0.39; 95% CI, 0.33-0.46; P <.001).

A significant delay in time to castration-resistant disease was noted in the darolutamide vs placebo groups, at NE (95% CI, NE-NE) vs 19.1 months (95% CI, 16.5-21.8), respectively (HR, 0.36; 95% CI, 0.30-0.42; P <.001). Darolutamide was also associated with increased time to pain progression at NE (95% CI, 30.5-NE) vs 27.5 months (95% CI, 22.0-36.1) with placebo (HR, 0.79; 95% CI, 0.66-0.95; P = .01). Time to first SSE was NE in both arms, but statistically significant benefit with the darolutamide combination was noted (HR, 0.71; 95% CI, 0.54-0.94; P = .02).

Rates of treatment-emergent adverse events (AEs) were similar between arms, at 99.5% with the darolutamide regimen and 98.9% with placebo. Consistent with prior clinical experience in other settings, darolutamide had a favorable safety profile. The rates of any treatment-emergent adverse event, serious adverse event, and adverse events leading to permanent discontinuation of study treatment were similar between the darolutamide and the placebo groups.

Grade 3/4 AEs occurring with darolutamide and placebo included neutropenia (33.7% vs 34.2%, respectively), febrile neutropenia (7.8% vs 7.4%), hypertension (6.4% vs 3.2%), and anemia (4.8% vs 5.1%). After adjusting for differences in drug exposure, the was no difference in the occurrence of AEs of special interest for AR pathway inhibitors between groups, including events such as fatigue, bone fractures, rash, falls, hypertension, and cardiac disorders.

Watch these videos for additional expert insight on the phase 3 ARASENS trial supporting this sNDA for darolutamide:

Dr. Neal Shore on phase 3 ARASENS trial: “This is undoubtedly game-changing”

Dr. Benjamin Lowentritt discusses findings from phase 3 ARASENS trial in mHSPC

References

1. Bayer Submits Applications in the U.S. and EU for Additional Indication of NUBEQA® (darolutamide). Published online March 9, 2022. Accessed March 9, 2022. https://bwnews.pr/3Kzhq1f.

2. Smith MR, Hussain MHA, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. J Clin Oncol. 2022;40(suppl 6):abstr 13. doi: 10.1200/JCO.2022.40.6_suppl.013

3. Smith MR, Hussain MHA, 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

4. FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. FDA. July 30, 2019. Accessed February 17, 2022. https://bit.ly/3JDxm26