SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention.
The first-generation NonSteroidal Anti-Androgen (NSAA) agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is often prescribed along with GnRH (Gonadotropin-Releasing Hormone) agonists for metastatic disease, or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists.
NUBEQA® (Darolutamide) is a potent second-generation Androgen Receptor (AR) inhibitor with a new chemical structure and has a high affinity to the AR. NUBEQA® does not cross the blood-brain barrier and for this reason has a favorable safety and tolerability profile in prespecified adverse events such as seizures, when compared with other second-generation AR inhibitors such as ERLEADA® (Apalutamide) and XTANDI® (Enzalutamide). It has been associated with increased Overall Survival (OS) among patients with non-metastatic Castration-Resistant Prostate Cancer (CRPC) and has been approved by the FDA for this indication. Whether a combination of NUBEQA®, in combination with Androgen Deprivation Therapy (ADT), and Docetaxel would increase survival among patients with metastatic Hormone-Sensitive Prostate Cancer, is unknown.
ARASENS is an international, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated the efficacy and safety of NUBEQA® (Darolutamide) added to Androgen Deprivation Therapy (ADT) and Docetaxel in patients with metastatic Hormone Sensitive Prostate Cancer. In this study, a total of 1306 patients were randomly assigned 1:1 to receive NUBEQA® (N=651) or placebo (N=655), both in combination with ADT and Docetaxel. All the patients received ADT (either a Luteinizing Hormone Releasing Hormone (LHRH} agonist or antagonist) or underwent Orchiectomy within 12 weeks before randomization and received six cycles of Docetaxel 75 mg/m2 IV given on Day 1 every 21 days, with Prednisone or Prednisolone. Patients received LHRH agonists along with a first-generation anti-androgen agent for at least 4 weeks before randomization to help prevent a tumor flare, and the anti-androgen agent was discontinued before randomization. Patients were then randomly assigned to receive either NUBEQA® 600 mg orally twice daily or matched placebo, and treatment was continued until disease progression or unacceptable toxicities.
Eligible patients had biopsy proven prostate cancer with bone metastases and had to be candidates for ADT and Docetaxel. Patients with regional lymph node involvement only (N1, below the aortic bifurcation) or if they had received ADT more than 12 weeks before randomization, second-generation Androgen Receptor pathway inhibitors, chemotherapy, or immunotherapy for prostate cancer before randomization, or radiotherapy within 2 weeks before randomization, were excluded. The median age was 67 years and both treatment groups were well balanced. All patients had metastatic disease at baseline, 78% of the patients had a Gleason score of 8 or greater, about 80% had bone metastases (Stage M1b) and 18% had visceral metastases (Stage M1c). The Primary end point was Overall Survival (OS) and Secondary end points included were time to Castration-Resistant Prostate Cancer, time to pain progression, symptomatic Skeletal Event-Free Survival and time to initiation of subsequent systemic antineoplastic therapy, as well as Safety. The median follow up for Overall Survival was 43 months.
The median Overall Survival was not estimable in the NUBEQA® group versus 48.9 months in the placebo group. The addition of NUBEQA® to the combination with ADT and Docetaxel reduced the risk of death by 32%, compared to the placebo group (HR=0.68; P<0.001). This OS benefit was noted across most subgroups. Further, the significant OS benefit with the addition of NUBEQA® was observed, despite receipt of subsequent life-prolonging systemic therapies such as different Androgen-Receptor pathway inhibitors by 75.6% of patients in the placebo control group. The OS at 4 years was 62.7% in the NUBEQA® group and 50.4% in the placebo group.
With regard to Secondary endpoints, the addition of NUBEQA® to ADT and Docetaxel demonstrated consistent benefits. The time to development of Castration-Resistant Prostate Cancer was significantly longer in the NUBEQA® group (HR=0.36; P<0.001), the time to pain progression was also significantly longer in the NUBEQA® group (HR=0.79; P=0.01), as well as symptomatic Skeletal Event-Free Survival (HR=0.61; P<0.001). Further, the time to the initiation of subsequent systemic antineoplastic therapy was also significantly longer in the NUBEQA® group (HR=0.39; P<0.001). Adverse events were similar in the two groups.
The authors concluded that among patients with metastatic Hormone Sensitive Prostate Cancer, the addition of NUBEQA® to Androgen Deprivation Therapy and Docetaxel resulted in significantly longer Overall Survival, as well as improvement in key Secondary end points, with no increase in adverse events.
Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. Smith MR, Hussain Saad F, et al. for the ARASENS Trial Investigators. NEJM. February 17, 2022. DOI: 10.1056/NEJMoa2119115.
