Darolutamide Demonstrates Improved OS Over Placebo in Phase 3 ARAMIS Trial for Nonmetastatic CRPC

Karim Fizazi, MD, PhD

Patients with nonmetastatic castration-resistant prostate cancer (CRPC) receiving darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) had a 31% reduction for the risk of death compared with placebo and ADT, according to the results of the phase 3 ARAMIS trial’s preplanned final overall survival (OS) analysis presented during the 2020 ASCO Virtual Scientific Program.¹

At a median follow-up of approximately 29 months, the 3-year OS rates were 83% and 77% on the darolutamide and placebo arms, respectively (HR, 0.69; 95% CI, 0.53-0.88; P = .003). Moreover, darolutamide was also found to significantly delay time to pain progression, time to first cytotoxic chemotherapy, and time to first symptomatic skeletal event (SSE) versus placebo.

“These results provide compelling evidence for early darolutamide treatment in men with nonmetastatic CRPC,” lead study author Karim Fizazi, MD, PhD, professor of Medicine at the Institut Gustave Roussy, Villejuif, France, said in a virtual presentation during the meeting. “Darolutamide provides clinical benefits, in addition to prolonging survival for men with M0 CRPC, for whom the development of metastases can cause cancer-related symptoms that affect their daily lives or impose a burden of additional treatments.”

Darolutamide is a structurally distinct androgen receptor (AR) inhibitor with low blood–brain barrier penetration and low potential for drug–drug infection. In July 2019, the FDA approved darolutamide for the treatment of patients with nonmetastatic CRPC, based on earlier results of the ARAMIS trial.

At the primary analysis, the median metastasis-free survival (MFS) was 40.4 months with darolutamide versus 18.4 months with placebo, leading to a 59% reduction in the risk of metastasis or death (HR, 0.41; 95% CI, 0.34-0.50; P <.0001).^2,3 Darolutamide had also demonstrated a favorable safety profile, with no increased incidence of most adverse events (AEs) that are associated with the agent, at this time point.

In the double-blind, placebo-controlled, multicenter, phase 3 ARAMIS study, investigators evaluated the efficacy and safety of darolutamide in combination with ADT in 1509 patients with nonmetastatic CRPC who were receiving a concomitant gonadotropin-releasing hormone analog or had a bilateral orchiectomy. Patients were randomized 2:1 to receive 600 mg of oral darolutamide twice daily plus ADT (n = 955) or placebo plus ADT (n = 554).

All patients had an ECOG performance status of 0 to 1, along with a prostate-specific antigen (PSA) doubling time (PSADT) of 10 months or less. Patients were stratified by PSADT (6 months or less or greater than 6 months) and osteoclast-targeted therapy (yes or no).

The primary end point of the trial was MFS, and key secondary end points included OS, time to pain progression, time to initiation of first cytotoxic chemotherapy, time to first symptomatic skeletal event, and characterization of the safety and tolerability of the AR inhibitor.

The study was unblinded prior to the final analysis, which assessed OS, time to pain progression, time to first cytotoxic chemotherapy, and time to first SSE. Following the unblinding, 170 patients who were randomized to receive placebo crossed over to the darolutamide arm.

Additional findings showed that the OS benefit was observed despite 56% of patients on placebo receiving subsequent darolutamide or another subsequent life-prolonging therapy; 15% of patients on the darolutamide arm received subsequent life-prolonging therapy.

Results also showed that darolutamide significantly delayed time to pain progression, with a median 40.3 months versus 25.4 months with placebo (HR, 0.65; 95% CI, 0.53-0.79; P <.001). The AR inhibitor also delayed the time to first cytotoxic chemotherapy (HR, 0.58; 95% CI, 0.44-0.76; P <.001) and time to first SSE (HR, 0.48; 95% CI, 0.29-0.82; P = .005).

The safety profile of darolutamide was found to be consistent with prior analyses of the AR inhibitor. Moreover, the incidence of treatment–associated AEs, including fatigue, bone fracture, decreased weight, rash, hypertension, and hot flush, were not found to be statistically different between the arms, Fizazi said.

However, he did note that cardiac arrhythmias, including those of grade 3/4 in severity, were higher with darolutamide (7.3% and 1.8%, respectively) than with placebo (4.3% and 0.7%).

Fizazi added that although patients with active or a history of epilepsy were permitted to enter the trial, the rate of seizures were similar in both arms at 0.2%.

Interim findings of the ARAMIS trial also previously showed intriguing quality-of-life (QOL) data with darolutamide in this patient population. Additional ARAMIS findings showed that darolutamide also maintained QOL and led to a 35% reduction in the risk of pain progression versus placebo in this patient population (HR, 0.65; 95% CI, 0.53-0.79; P <.001).⁴ The AR inhibitor also led to a 57% reduction in the risk of SSE development compared with placebo (HR, 0.43; 95% CI, 0.22-0.84; P =.01).

Moreover, data presented at the 2019 ESMO Asia Congress from the ARAMIS trial also showed that darolutamide delays disease progression and subsequent treatment for patients with nonmetastatic CRPC compared with placebo, while maintaining quality of life.⁵

Darolutamide continues to be evaluated in the international, double-blind, placebo-controlled, phase 3 ARASENS study, which is exploring darolutamide plus ADT in combination with docetaxel in approximately 1300 patients with newly diagnosed, metastatic hormone-sensitive prostate cancer (NCT02799602).

_References

_{1. Fizazi K, Shore ND, Tammela T, et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl; abstr 5514). doi:10.1200/JCO.2020.38.15_suppl.5514}

_{2. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7s; abstr 140). doi:10.1200/JCO.2019.37.7_suppl.140}

_{3. Fizazi K, Shore N, Tammela T, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671}

_{4. Fizazi K, Shore ND Tammela T, et al. Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 15; abstr 5000). doi:10.1200/JCO.2019.37.15_suppl.5000}

_{5. Pang J S-T, Shore N, Smith MR, et al. Efficacy and safety of darolutamide in non-metastatic castration-resistant prostate cancer (nmCRPC) in the ARAMIS trial. Ann Oncol. 2019;30(suppl_9):mdz424.001. doi:10.1093/annonc/mdz424.001}