Positive Results Correlate With Use of Darolutamide in nmCRPC

ARAMIS (NCT02200614), a phase 3 trial consisting of 1,509 patients, studied the relationship between prostate-specific antigen (PSA) response and urinary and bowel adverse events (AEs), time to deterioration in quality of life (QoL), and prostate cancer (PC)–related invasive procedures.

The study followed a 2:1 randomization, and patients received either darolutamide (Nubeqa) or placebo while continuing androgen deprivation therapy (ADT).

According to Neal Shore, MD, FACS, the US chief medical officer of surgery and oncology at GenesisCare USA, and the director and certified principal investigator at the Carolina Urologic Research Center, the study concluded that treatment with darolutamide correlated with reduction in local urinary and bowel symptoms as well as delayed deterioration in patient QoL. A reduction in locally invasive procedures after darolutamide treatment was also observed.

The FDA recognizes metastasis-free survival (MFS). as a pathway for approvability for drug indications. An almost 2-year delay in MFS was caused by the study agent, with 80% of events being radiographic progression and the secondary end point of overall survival also met.

In an interview with Targeted OncologyTM, Neal Shore discusses the findings of ARAMIS which looked at darolutamide in men with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC), and its primary end point of MFS.

For background, can you talk about the purpose of this analysis of symptoms, and what the key goals were?

Shore: The purpose of this analysis was to further interrogate urinary and bowel symptoms after we had demonstrated in ARAMIS that the primary end point of MFS was met as well as the secondary end point of overall survival and the hierarchical order were also met. What we looked at was the different subscales for the FACT- P PCS as well as validated instruments of the EORTC quality of life questionnaire for both prostate and bowel symptoms. And this had here to for not been evaluated and not presented nor published. And that's why we're really excited to have presented the positive findings here at the American Urological Association.

Targeted Oncology: Can you provide a recap of the metastasis-free survival results from ARAMIS?

ARAMIS was the largest of the very well conducted phase 3 nmCRPC trials. We had 1,509 patients in our study. As with the other 2 and nmCRPC studies, there was a 2:1 randomization for nmCRPC patients by conventional imaging, a 2:1 randomization for patients receiving ADT plus darolutamide, versus ADT and a placebo. Ultimately, what we were able to demonstrate very successfully was that metastasis-free survival was our primary end point, and that was successful. Our subsequent secondary end points, the first in the hierarchical order, was overall survival, and that was also met very successfully.

What that has demonstrated in two separate New England Journal of Medicine publications is that starting patients on darolutamide, a well described androgen receptor pathway inhibitor, which in preclinical models demonstrates a very minimal amount of blood-brain barrier penetration. I say that because I think that's important regarding the neuro oncologic tolerability that we see so well with darolutamide. But then, most importantly, [it] not only delayed radiographic progression, it delayed its requirement for antineoplastic therapies. We saw wonderful PSA responses, PSA 50s [and] PSA 90s, delays in skeletal-related events.

Now in this particular study, what we've demonstrated is the patients who received darolutamide and as opposed to placebo for nmCRPC had marked improvements in their requirement for locally invasive procedures for urinary symptoms, particularly catheterizations, endoscopic resections, urinary retention, even urinary symptoms of burning frequency urgency, and also, we found a decrease in total bowel type symptoms. And these were both evaluated with validated questionnaires.

Can you explain why MFS is now an important end point ? How can community oncologists use this end point to make decisions in their practice?

MFS is a somewhat of a composite end point that has largely been driven by studies to look at both radiographic progression, and that's really where most of the events occur, but then also death or survival. Really wonderful work by Christopher Sweeney, MBBS and others in the ICECaP analysis, demonstrated in a meta-analysis that MFS correlated very well also with overall survival in the castration sensitive population.

I think to the credit of the FDA, they recognize that MFS is now a pathway for approvability for drug indications. And in ARAMIS, we certainly in a very statistically significant way, demonstrated the benefit of MFS for nmCRPC patients. A near 2-year delay improvement in MFS, largely driven by 80% of the events, was radiographic progression. But the subsequent secondary end point of overall survival was also robustly demonstrated. So, I think this is a really great example of strategic trial development, in collaboration with FDA recognizing the importance of approvable pathways beyond just overall survival. And fortunately, overall survival was also subsequently demonstrated.

Do you recommend this strategy to other oncologists? What advice can you provide?

So, I think for my colleagues who are contemplating the decision to start a patient who has an nmCRPC, who's largely asymptomatic, except for the T suppression chronicity, one can comfortably perscribe to their patient, not only a delay in MFS, which was largely driven by radiographic progression, but clearly corroborated with a survival benefit, but now, we're demonstrating improvement in urinary symptoms or avoidance of deterioration of urinary symptoms as well as bowel symptoms.