In this interview, Shore discusses findings of a study of darolutamide (Nubeqa) presented at the 2021 AUA annual meeting and their significance for patients with nonmetastatic castration-resistant prostate cancer.
In a study presented at the 2021 American Urological Association Annual Meeting, Neal D. Shore, MD, FACS, and co-authors examined local symptoms associated such as prostate-specific antigen (PSA) response, urinary and bowl adverse events (AEs), time to deterioration in quality of life, and prostate cancer-related invasive procedures in the phase 3 ARAMIS trial (NCT02200614) of the androgen receptor inhibitor darolutamide (Nubeqa).1 In this interview, Shore discusses these findings and their significance for patients with nonmetastatic castration-resistant prostate cancer. Shore is the director of the Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina.
Could you discuss the background for this study?
The background for the ARAMIS trial was to evaluate rising PSA, PSA doubling times of less than or equal to 10 months, castrate levels of testosterone, and negative findings with conventional imaging, [and] CT scan technetium bone scan in nmCRPC patients. A little over 1500 patients were randomized in the study 2 to 1 to continue to receive ADT plus a placebo or ADT plus darolutamide, 2 pills twice daily. The concept here was to evaluate for metastasis-free survival. That was the primary end point. It's a composite end point of radiographic progression-free survival plus death. At the initial analysis that demonstrated that we met the primary end point, only about 20% of the events were death. So, we achieved the study's primary end point and we presented that in a New England Journal of Medicine paper.2
And then in our secondary end points, the first of the hierarchical end points was overall survival, and we achieved that as well. That also had a separate NEJM publication.3
What we wanted to do, looking at this very large, phase 3, global, double-blind, prospective trial, was to see what the impact or difference in the patients in the darolutamide versus the placebo arm was regarding their urinary symptoms, or even local pelvic symptoms, including bowel symptoms.
We found that, looking at FACT-P subscales as well as the EORTC quality of life scales, there was a statistically significant difference in less voiding symptoms and less invasive procedures, whether it be catheterization, cystoscopies, or a TUR of any type, for the patients who received darolutamide. We also found that patients' overall total bowel symptom scores were improved for those of the patients who received the active therapeutic treatment of darolutamide versus placebo.
This is an important evidence-based finding because 1, we've demonstrated with darolutamide for patients with nmCRPC that we delay metastasis by a median of nearly 2 years. Number 2, that also results in the survival prolongation well in excess of a year. And then thirdly, now we're able to demonstrate that these same men, as opposed to those who got a placebo for nmCRPC, have a decreased likelihood of having urinary or bowel symptoms.
We've realized now that darolutamide is a very active androgen receptor pathway inhibitor. We have other very active androgen receptor pathway inhibitors, but the drugs sometimes can differ in what's been published, in terms of their safety and tolerability and drug-drug interactions. Really, the exciting aspect of the darolutamide trial development is looking at it in terms of its efficacy in mCSPC and mCRPC as well as with other approved advanced prostate cancer combinations.
The take-home message for all practicing urologists should be that if you have an nmCRPC patient, don't wait for them to develop mCRPC based on conventional imaging, or even for that matter, next-generation imaging. We have 3 really efficacious level 1 evidence studies that have demonstrated the value for starting any of these 3 drugs. Our study that I presented at the AUA is focusing on darolutamide in particular. It’s decreasing the likelihood of a urinary or invasive procedure, as well as the stability of bowel symptoms. So, that's a third thing to discuss with patients: not only are we going to prolong your survival and delay the onset of metastases, and then additional anti neoplastic therapies, while maintaining quality of life; we’ve now shown in a subset that urinary symptoms and bowel symptoms are also improved compared to not treating at all.
I would just again re-emphasize the importance of having what we oftentimes describe as the patient-physician shared decision-making discussion, and really have a good comprehensive understanding of the multiple benefits: delaying metastasis, prolonging survival, lessening a risk of worsening urinary and bowel symptoms. Of course, this has to be balanced against a patient's overall performance status and how they would look at any of the safety and tolerability of an androgen receptor pathway inhibitor and drug-drug interactions.
1. Shore S, Stenzl A, Pieczonka C, et al. Impact of darolutamide on local symptoms in patients with nonmetastatic castration-resistant prostate cancer. Paper presented at the 2021 American Urological Association Annual Meeting; September 10-13; virtual. Abstract PD34-10
2. Fizazi K, Shore N, Temmela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235-1246. doi: 10.1056/NEJMoa1815671
3. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383:1040-1049. doi:10.1056/NEJMoa2001342