Symptom Burden May Be Reduced With Darolutamide Treatment in mCRPC

Investigators set out to determine the relationship between prostate-specific antigen response and urinary and bowel adverse events, QOL deterioration, and prostate cancer-related invasive procedures.

Treatment with the androgen receptor inhibitor, darolutamide (Nubeqa) led to a reduction in local urinary and bowel symptoms as well as a delay in the deterioration in the quality of life (QOL) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated in the phase 3 ARAMIS clinical trial (NCT02200614).

In the primary analysis of ARAMIS, darolutamide demonstrated improvement in both metastasis-free survival (MFS) and overall survival (OS). Investigators then set out to determine the relationship between prostate-specific antigen (PSA) response and urinary and bowel adverse events (AEs), QOL deterioration, and prostate cancer-related invasive procedures.

Patients included in the analysis were randomized 2:1 to receive either darolutamide (n = 955) or placebo (n = 554) both with androgen deprivation therapy (ADT). The impact of PSA response was determined by declines for baseline to week 16. Investigators used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PR25) to measure time to deterioration in QOL and the Functional Assessment of Cancer Therapy–Prostate, Prostate Cancer Subscale (FACT-P PCS) to measure bowel symptoms. Further, the difference in decline from baseline was calculated using Kaplan-Meier estimators and stratified Cox proportional hazard models.

With darolutamide, compared with placebo, the rate of prostatectomy was 25.0% versus 18.5%, respectively, and the rate of radiotherapy was 24.2% versus 16.1%. Fewer urinary AEs were observed with darolutamide at 5.4% compared with 5.8% in the placebo arm. Darolutamide also led to fewer cases of hematuria, urinary retention, and dysuria. In terms of PSA responses and how they impact urinary retention and dysuria, patients did better if their PSA response was either > 90%, between 50% and 90%, and < 50%.

In the darolutamide arm compared with the placebo arm, time to deterioration of QOL was 25.8 months compared with 14.8 months, respectively (HR, 0.64; 95% CI, 0.54-0.76; P < .01). Bowel symptoms occurred in 18.4% of the darolutamide arm versus 11.5% of the placebo arm (HR, 0.78; 95% CI, 0.66-0.92; P < .01). Finally, invasive procedures were needed for only 4.7% of the darolutamide arm versus 9.6% of the placebo arm.

In an interview with Targeted Oncology™, Neal Shore, MD, FACS, US chief medical officer of Surgery and Oncology at GenesisCare USA, and director, CPI, at Carolina Urologic Research Center, discussed the relevance of understanding the symptom burden in the ARAMIS study and importance of investigating MFS in the future.

Targeted Oncology ™: For background, what were the metastasis-free survival results from the ARAMIS trial?

Shore: ARAMIS was a global phase 2 trial and what was particularly compelling about ARAMIS was that this study was the largest of the very well-conducted phase 3 mCRPC trials. We had 1509 patients in our study. As with the other 2 and mCRPC studies where there was a 2 to 1 randomization for patients with mCRPC by conventional imaging, we had a 2:1 randomization for patients with 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.

Then our subsequent secondary end points, the first was overall survival and that was also met very successfully. So really, what that has demonstrated in 2 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, it not only delayed radiographic progression, but delayed the requirement for anti-neoplastic therapies. We saw wonderful PSA responses, delays in skeletal-related events.

It is fairly recent that MFS was deemed a relevant end point in this disease. Can you explain its importance?

Metastasis-free survival is somewhat of a composite end point that has largely been driven in studies to look at the radiographic progression. That's really where most of the events occur, but it’s also used to look at death or survival. A wonderful work by Chris J. Sweeney, MBBS, and others involved 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 provability for drug indications, and in ARAMIS, we certainly in a very statistically significant way demonstrated the benefit of metastasis-free survival for patients with mCRPC. There was a near 2-year improvement in MFS largely driven by the fact that 80% of the events were radiographic progression, but the subsequent secondary end point of overall survival was also robustly demonstrated.

So, I think this is a great example of strategic trial development in collaboration with the FDA, recognizing the importance of approvable pathways beyond just overall survival. And fortunately, overall survival was also subsequently demonstrated.

What is the purpose of analyzing symptoms that are related to patients with mCRPC in the ARAMS study? What were the key goals of the analysis?

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 metastasis-free survival was met as well as the first over secondary end point of overall survival and the hierarchical order was also met. And so, 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. This had here to for not been evaluated and not presented nor published. And that's why we were excited to have presented the positive findings during the AUA annual meeting.

Can you discuss the findings?

Now in a new analysis, what we've demonstrated is the patients who received darolutamide and as opposed to placebo for mCRPC had marked improvements and 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.

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


Shore N, Stenzi A, Pieczonka C, et al. PD34-10 Impact of darolutamide on local symptoms in patients with nonmetastatic castration-resistant prostate cancer. J Urol. 2021;206(3):e586-e587. doi: 10.1097/JU.0000000000002038.10