U.S. FDA approves additional indication of darolutamide in combination with docetaxel for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC)

• Darolutamide now has indications in both non-metastatic castration-resistant prostate cancer (nmCRPC) for men at high risk of developing metastatic disease and metastatic hormone-sensitive prostate cancer (mHSPC).
• Approval under the FDA’s Real-Time Oncology Review (RTOR) pilot program was based on the pivotal Phase III ARASENS trial, which showed a significant overall survival (OS) benefit with darolutamide plus androgen deprivation therapy (ADT) and docetaxel compared to ADT plus docetaxel.
• Darolutamide in combination with docetaxel and ADT demonstrated a 32.5% reduction in the risk of death compared to docetaxel plus ADT. Overall incidence of treatment-emergent adverse events (TEAEs) was similar between treatment arms.

Orion’s collaboration partner Bayer today announced the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for the oral androgen receptor inhibitor (ARi) darolutamide in combination with docetaxel for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The approval is based on positive results of the Phase III ARASENS trial that demonstrated darolutamide plus androgen deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% in patients with metastatic hormone-sensitive prostate cancer (mHSPC) compared to ADT plus docetaxel. These results were recently published in The New England Journal of Medicine.¹ Darolutamide is approved in more than 70 markets around the world, including the U.S., the European Union (EU), Japan and China, under the brand name Nubeqa®, for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease. The compound is also being investigated in further studies across various stages of prostate cancer.

Prostate cancer remains the second leading cancer-related cause of death among men in the U.S., with up to one-third of patients developing metastatic disease.^{2, 3} The incidence of mHSPC has increased by 72% in the U.S. over the past 10 years.⁴ Approximately one in three patients who are diagnosed with mHSPC survive the disease five years or longer, with most eventually experiencing progression to castration-resistant prostate cancer (CRPC).^3,4

The application received Priority Review designation granted by the FDA and was submitted under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to provide a more efficient review process of applications to ensure that safe and effective cancer treatments are available to patients as early as possible. Ongoing reviews are also being conducted under the FDA Oncology Center of Excellence’s (OCE) Project Orbis initiative, which provides a framework for concurrent submission and review of cancer treatments among participating international health authorities.

Darolutamide is developed jointly by Orion and Bayer.

About the ARASENS Trial

The ARASENS trial is a randomized, Phase III, multi-center, double-blind, placebo-controlled trial which was prospectively designed to investigate the efficacy and safety of oral darolutamide, an androgen receptor inhibitor (ARi), plus androgen deprivation therapy (ADT) and the chemotherapy docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). A total of 1,306 newly diagnosed patients were randomized in a 1:1 ratio to receive 600 mg of darolutamide twice a day or matching placebo, plus ADT and docetaxel.

The primary endpoint of this trial was overall survival (OS). Secondary endpoints included time to castration-resistant prostate cancer (CRPC), time to pain progression, time to first symptomatic skeletal event (SSE), time to initiation of subsequent anticancer therapy, all measured at 12‐week intervals, as well as adverse events (AEs) as a measure of safety and tolerability. Results from this trial were published in the New England Journal of Medicine¹. The ARASENS trial demonstrated that darolutamide plus androgen deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% compared to ADT plus docetaxel¹. Improvements in the secondary endpoints supported the benefit observed in the primary endpoint, overall survival¹.

About Metastatic Hormone-Sensitive Prostate Cancer

Prostate cancer is the second most commonly diagnosed malignancy in men worldwide. In 2020, an estimated 1.4 million men were diagnosed with prostate cancer, and about 375,000 died from the disease worldwide.⁵

At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. Upon relapse, when the disease will metastasize or spread, androgen deprivation therapy (ADT) is the cornerstone of treatment for this hormone-sensitive disease. Current treatment options for men with metastatic hormone-sensitive prostate cancer (mHSPC) include hormone therapy, such as ADT, androgen receptor pathway inhibitors plus ADT or a combination of docetaxel chemotherapy and ADT. Despite these treatments, a large proportion of men with mHSPC will eventually experience progression to metastatic castration-resistant prostate cancer (mCRPC), a condition with limited survival.

About darolutamide

Darolutamide is an oral androgen receptor inhibitor (ARi) with a distinct chemical structure that binds to the receptor with high affinity and exhibits strong antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells. The low potential for blood-brain barrier penetration for darolutamide is supported by preclinical models and neuroimaging data in healthy humans.^{6, 7} This is supported by the overall low incidence of central nervous system (CNS)-related adverse events (AEs) compared to placebo as seen in the ARAMIS Phase III trial and the maintained verbal learning and memory observed in the darolutamide arm of the Phase II ODENZA trial.⁸

The product is approved under the brand name Nubeqa® in more than 70 markets around the world, including the U.S., EU, Japan, China, for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease. The compound is also being investigated in further studies across various stages of prostate cancer, including in the ARANOTE Phase III trial evaluating darolutamide plus androgen deprivation therapy (ADT) versus ADT alone for metastatic hormone-sensitive prostate cancer as well as the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international co-operative group Phase III trial, evaluating darolutamide as an adjuvant treatment for localized prostate cancer with very high risk of recurrence (DASL-HiCaP, ANZUP1801). Information about these trials can be found at www.clinicaltrials.gov.

Reference

1. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 386:1132-1142 (2022).
2. Siegel DA, O’Neil ME, Richards TB, Dowling NF, Weir HK. Prostate Cancer Incidence and Survival, by Stage and Race/Ethnicity — United States, 2001–2017. MMWR Morb Mortal Wkly Rep 2020;69:1473–1480. http://dx.doi.org/10.15585/mmwr.mm6941a1.
3. Ng, K., Smith, S., Shamash, J. Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Advances and Treatment Strategies in the First-Line Setting. Oncol Ther 8, 209–230 (2020). https://doi.org/10.1007/s40487-020-00119-z.
4. Hahn AW, Higano CS, Taplin ME, Ryan CJ, Agarwal N. Metastatic Castration-Sensitive Prostate Cancer: Optimizing Patient Selection and Treatment. Am Soc Clin Oncol Educ Book. 2018 May 23;38:363-371. https://doi.org/10.1200/edbk_200967
5. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.3322/caac.21660. Accessed May 2022.
6. Zurth C, Sandmann S, Trummel D, et al. Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]Darolutamide in rats using whole-body autoradiography. ASCO GU. Abstract 156.
7. Williams S. Mazibuko N, O’Daly O. Analysis of cerebral blood flow (CBF) in regions relevant to cognitive function with enzalutamide ENZA) compared to darolutamide (DARO) and placebo (PBO) in healthy volunteers American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium; February 13, 2020; San Francisco, CA; Abstract: 326
8. Colomba E, Jonas S. F., Eymard J.C., et al. Objective computerized cognitive assessment in men with metastatic castrateresistant prostate cancer (mCRPC) randomly receiving darolutamide or enzalutamide in the ODENZA trial, ESMO Virtual Congress; September 16 2021; E-Poster: 603P.