Shore Speaks to Updates Showcasing Benefits, Safety of Darolutamide in Nonmetastatic CRPC

Neal Shore, MD

Darolutamide (Nubeqa) significantly improved overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to Neal Shore, MD, and the agent has also been shown to have more favorable safety outcomes compared with apalutamide (Erleada) and enzalutamide (Xtandi).

Updated results from the pivotal phase 3 ARAMIS trial presented during the 2020 ASCO Virtual Scientific Program showed that treatment with darolutamide in combination with androgen deprivation therapy (ADT) resulted in a statistically significant improvement in OS benefit compared with ADT alone in patients with nonmetastatic CRPC. Specifically, darolutamide led to a 31% reduction in the risk of death compared with placebo in this patient population (HR, 0.69; 95% CI, 0.53-0.88; two-sided P = .003). Furthermore, the 3-year OS rate was 83% in the darolutamide arm and 77% in the placebo arm. Notably, the safety profile of darolutamide was consistent with what had been reported in the primary analysis.

“Prior to 2018, no approved therapies were available [in this space]; now, we have 3 options. Results from ARAMIS demonstrated [that darolutamide significantly prolonged] metastasis-free survival (MFS),” said Shore. “Similar to other therapeutics in its class, it met the primary end point [of the trial], which is a composite end point of radiographic progression, as well as mortality or death.”

Moreover, a second study presented during the meeting assessed the safety outcomes of darolutamide versus apalutamide and enzalutamide. In the analysis, patient-level data for darolutamide were obtained from the ARAMIS trial (n = 1,509), data for apalutamide were extracted from the phase 3 SPARTAN trial (n = 1,207), and data for enzalutamide were pulled from the phase 3 PROSPER trial (n = 1,401).

Results showed that darolutamide had a statistically significant lower risk of adverse effects (AEs) such as falls, fractures, and rashes, compared with apalutamide, and a lower risk of falls, dizziness, mental impairment, and fatigue compared with enzalutamide.

In an interview with OncLive, Shore, the medical director of the Carolina Urologic Research Center, further discussed recent updates with darolutamide in the treatment of patients with nonmetastatic CRPC.

OncLive: Could you speak to the updated data from the ARAMIS trial with darolutamide that had been reported during the 2020 ASCO Virtual Scientific Program?

Data from the ARAMIS trial were previously presented and published in the New England Journal of Medicine, and the patient population was comprised of those with non-metastatic castration-resistant prostate cancer, what was previously described as M0 CRPC or index case 1 in the American Urological Association CRPC guidelines.

At the ASCO meeting, Karim Fizazi, MD, PhD, of Gustave Roussy, presented on behalf of all the co-authors and co-investigators of the trial, that the OS was [significantly improved with darolutamide] in our final analysis for ARAMIS, with a hazard ratio of 0.69. For many of our colleagues, survival is still the primary [challenge] or achievement to attain to feel comfortable with [using] a particular medication.

Patients with nonmetastatic CRPC, in particular, are largely asymptomatic irrelative to their tumor burden. These patients don't have a great deal of tumor burden; it’s often microscopic disease. They may have some AEs [from] chronic ADT use. The main concerns were the rising PSA and suppressed testosterone levels, so we needed evidence to demonstrate benefit [with the agent]. The benefit was met with [regard to] MFS in our earlier publication, and now we see a positive improvement in OS benefit, as well.

Safety outcomes of darolutamide versus apalutamide and enzalutamide in nonmetastatic CRPC were also reported at the meeting. Could you shed light on this analysis?

We have 3 well-performed, global, prospective studies that have led to the approvals of 3 new medications for patients with nonmetastatic CRPC; these agents are apalutamide, enzalutamide, and darolutamide. We did an analysis based upon the published literature from the PROSPER, SPARTAN, and ARAMIS studies, as well as additional data from our own databank.

Using match-adjusted indirect drug comparisons methodology, we were able to examine key terms and data regarding the safety profiles [of the agents]. This is the best we can do, at the current time, until we conduct prospective, directly comparative studies to further evaluate the tolerability and safety [of these agents].

For this analysis, we examined a whole series of AEs that are well known within this class of AR-signaling inhibitor drugs. When looking at that, we saw [enhanced] tolerability and safety benefits with darolutamide [compared with] the other 2 approved agents, [especially with regard to] risks of fracture, falls, cognitive impairment, rash and hypertension.

References

1. Fizazi K, Shore ND, Tammela T, et, al. Overall survival results of phase III ARAMIS study of darolutamide added to androgen deprivation therapy for nonmetastatic castration-resistant prostate cancer. J Clin Oncol. 2020;38(suppl 15):5514. doi:10.1200/JCO.2020.38.15_suppl.5514
2. Jiang S, Terasawa E, Shore ND, et al. Safety outcomes of darolutamide versus apalutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer: Matching-adjusted indirect comparisons. J Clin Oncol. 2020;38(suppl 15):5561. doi:10.1200/JCO.2020.38.15_suppl.5561