Darolutamide OS Stands Up to Other Approved Drugs for the nmCRPC

Neal D. Shore, MD

At the American Urological Association (AUA) 2020 Virtual Annual Meeting, experts in the field of prostate cancer have shown research around 3 approved agents for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), which include darolutamide (Nubeqa), enzalutamide (Xtandi), and apalutamide (Erleada). Prior to AUA 2020, new findings were announced for darolutamide and presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

The overall survival (OS) results from the final analysis of the phase 3 ARAMIS study showed 254 deaths total, representing 15.5% of the darolutamide plus androgen deprivation therapy (ADT) population compared with 19.1% of the placebo plus ADT population. Overall, the 31% reduction in the risk of death compared with placebo was statistically significant.

In terms of the secondary end points of the trial, the median time to pain progression was 40.3

months with darolutamide and ADT versus 25.4 months in the control arm (HR, 0.65; 95% CI, 0.53-0.79: P =.001). The time to first cytotoxic chemotherapy was not reached in either arm (HR, 0.58; 95% CI, 0.44-0.76; P =.001). Finally, the time to first symptomatic skeletal event was also not reached in either arm (HR, 0.48; 95% CI, 0.29-0.82; P =.005). Darolutamide also demonstrated similar favorable and tolerable safety to previously published data regarding the drug.

In an interview with Targeted Oncology, Neal Shore, MD, director, Carolina Urologic Research Center, discussed the OS analysis for the phase 3 ARAMIS study and explained a match-adjusted indirect comparison (MAIC). He also discussed how these data connect with presentations around the 3 approved agents for nmCRPC being presented at AUA 2020.

TARGETED ONCOLOGY: Can you describe the mechanism of action for darolutamide?

Shore: We are in a fortunate time right now for patients with nmCRPC. We have 3 FDA approved oral molecules known as androgen receptor signaling inhibitors, and those are enzalutamide, apalutamide, and darolutamide.

Darolutamide does have some distinct differences, and that is its organic molecular structure is different, which 1 could easily see if you look at these molecules side by side. The darolutamide molecules [are] larger, and it's been described as having a marked difference in polarity.

This becomes relevant to its mechanism of action in that preclinical [data] have shown that darolutamide can negligibly penetrate the blood-brain barrier, and because of this, in all of the early phase studies like ARADES, ARAFORES, and also in the phase 3 ARAMIS study, a prior history of seizure was never exclusionary. That is different from the trials involving the other approved molecules in nmCRPC.

The benefit or presumed benefit of darolutamide was that with negligible blood-brain barrier penetration, there appears to be a minimal full effect on patients’ spectrum of symptoms. Even though we do see some differences in fatigue, which is known across the class of androgen receptor (AR) signaling inhibitor drugs, we don't see increases in falls, cognitive impairment, or seizure.

TARGETED ONCOLOGY: What was the rationale for the ARAMIS study?

Shore: Prior to 2018, we didn't have any level 1 evidence that an AR signaling inhibitor could improve metastasis-free survival (MFS) or OS, including androgen biosynthesis inhibitors or such as abiraterone.

The importance of a trial like ARAMIS was to demonstrate that for patients who have a rising PSA, a confirmed castrate level of testosterone suppression, and no positivity on conventional imaging, what could we do for these patients?

TARGETED ONCOLOGY: Can you explain the study design and the key findings from this clinical trial?

Shore: The ARAMIS trial took over 1500 patients globally in a 2 to 1 randomization to darolutamide 600 mg, given 2 pills twice daily versus placebo. Both arms continue to receive ADT.

The trial met the MFS end point in a statistically significant way. The MFS end point is a composited end point of continued radiographic progression.

TARGETED ONCOLOGY: What are the implications of these findings?

Shore: When darolutamide was approved and [data were] published in the New England Journal of Medicine (NEJM), there was really an immature number of deaths that were recorded. At ASCO 2020, the final OS analysis showed a key secondary end point within the ARAMIS trial. It demonstrated a hazard ratio of 0.69, in favor of the darolutamide treatment arm over placebo.

Now, darolutamide has shown that it not only delays the onset for metastasis and

subsequent tumor burden associated with that but also OS. The MFS was nearly a 2-year benefit versus the control placebo, and it also delayed the onset of pain and the requirement for next line anaplastic therapy such as chemotherapy. The drug also showed that same safety profile as was published in NEJM.

TARGETED ONCOLOGY: Can you provide background on the MAIC and explain the goals and data presented?

Shore: The MAIC was intended to look at adverse events recorded in trial where we could try to separate out differences and how the terminology was used in each of the trials and some other methodological differences to assess covariates where there was consistency in the frequency of recording, as well as inclusion and exclusion criteria.

What we found was based upon what's in the published literature, primarily the 3 NEJM articles that led to the approval of all 3 of these drugs, that the safety profile of darolutamide when compared to enzalutamide demonstrated less risk of falls, fractures, hypertension, and cognitive impairment.

This comparison is not a substitute for a direct comparator prospective study, but I think for now, it’s something for different clinicians and for patients to consider.

TARGETED ONCOLOGY: How do these 2 analyses connect what is being presented at AUA?

Shore: At AUA, we will again hear the great news that for patients with nmCRPC, there's an opportunity to offer 3 oral medications that are remarkably effective for the patient population. This is a tremendous breakthrough for optimizing patient care.

There are some inter-trial differences in terms of the inclusion/exclusion criteria. They’re not major, but they are worth understanding. OS differences have been observed now for all 3 of the approved agents, and it is an exciting time for physicians who are dedicated to the advanced prostate cancer disease population.