Darolutamide with ADT cuts radiological progression or death risk by 46% in metastatic hormone-sensitive prostate cancer

ORION CORPORATION PRESS RELEASE 16 SEPTEMBER 2024 at 11.30 EEST

Darolutamide, when combined with androgen deprivation therapy (ADT), significantly reduces the risk of radiological progression or death by 46% compared to a placebo plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to results from the pivotal Phase III ARANOTE trial. The trial's findings demonstrate a substantial increase in radiological progression-free survival (rPFS) for darolutamide plus ADT versus placebo plus ADT in mHSPC patients. These results were shared at the ESMO 2024 Congress and published in The Journal of Clinical Oncology.

The ARANOTE trial reveals that darolutamide combined with ADT offers consistent benefits in rPFS across various prespecified subgroups, including patients with both high- and low-volume mHSPC. The safety profile of darolutamide remains consistent with previous trials (ARAMIS and ARASENS), showing low treatment-emergent adverse events (TEAEs).

ORION's Senior Vice President of Innovative Medicines and Research & Development, Professor Outi Vaarala, expressed enthusiasm about the ongoing clinical benefits delivered by darolutamide for patients with mHSPC. Bayer, a key collaborator with Orion, plans to submit the ARANOTE data to health authorities worldwide to support the broader use of darolutamide in mHSPC patients.

Currently, darolutamide is marketed under the brand name Nubeqa® and is approved in over 80 markets for mHSPC treatment in combination with ADT and docetaxel. It is also approved for treating non-metastatic castration-resistant prostate cancer (nmCRPC) in over 85 countries.

Detailed ARANOTE results indicate that darolutamide plus ADT significantly reduces the risk of radiological progression or death by 46% (HR 0.54; 95% CI 0.41–0.71; P<0.0001) compared to placebo plus ADT. Both high- and low-volume mHSPC subgroups benefited, with risk reductions of 40% and 70%, respectively. Preliminary data on overall survival (OS) suggests potential benefits with darolutamide plus ADT (HR=0.81, 95% CI 0.59-1.12) versus placebo plus ADT.

Additional secondary endpoints showed clinical benefits with darolutamide plus ADT, including delays in time to castration-resistant prostate cancer (CRPC) (HR 0.40; 95% CI, 0.32–0.51), time to PSA progression (HR 0.31; 95% CI 0.23–0.41), time to pain progression (HR 0.72; 95% CI, 0.54–0.96), and time to initiation of subsequent systemic therapy (HR 0.40; 95% CI, 0.29–0.56) compared to placebo plus ADT.

TEAEs incidence was low and similar between treatment arms, with fewer patients discontinuing treatment due to TEAEs in the darolutamide group compared to placebo plus ADT (6.1% vs. 9.0%). Common adverse events (≥10%) for darolutamide plus ADT were anemia, arthralgia, and urinary tract infections, with lower fatigue incidence than the placebo group (5.6% vs. 8.1%).

The ARANOTE trial, a randomized double-blind, placebo-controlled Phase III study, evaluated the efficacy and safety of darolutamide plus ADT in mHSPC patients. The trial involved 669 patients randomized 2:1 to receive either 600mg of darolutamide twice daily or placebo alongside ADT. The primary endpoint was rPFS, and secondary endpoints included overall survival, time to CRPC, subsequent anti-cancer therapy initiation, PSA progression, PSA undetectable rates, pain progression, and safety assessments.

Darolutamide, an oral androgen receptor inhibitor (ARi), binds to the androgen receptor with high affinity, exhibiting antagonistic activity that inhibits receptor function and prostate cancer cell growth. It has a low potential for blood-brain barrier penetration, supported by preclinical and neuroimaging data, and a low incidence of CNS-related adverse events.

The ARANOTE trial is part of a comprehensive clinical program investigating darolutamide across various prostate cancer stages, including the Phase III ARASTEP trial for hormone-sensitive high-risk biochemical recurrence (BCR) prostate cancer and the Phase III DASL-HiCaP trial, evaluating darolutamide as an adjuvant treatment for localized prostate cancer with high recurrence risk.

Prostate cancer, the second most common cancer in men, had an estimated 1.5 million new cases and approximately 397,000 deaths globally in 2022. Prostate cancer diagnoses are expected to rise to 2.9 million annually by 2040. At diagnosis, most men have localized prostate cancer, which can be treated surgically or with radiotherapy. mHSPC, a stage where cancer has spread beyond the prostate, presents in up to 10% of initial diagnoses. ADT, often combined with chemotherapy and/or an ARi, is the primary treatment for mHSPC, although many patients eventually progress to metastatic castration-resistant prostate cancer (mCRPC).