Update Shows Depth of Darolutamide Benefit in Nonmetastatic CRPC

Karim Fizazi, MD, PhD

In addition to improving metastasis-free survival (MFS), the combination of darolutamide and androgen deprivation therapy (ADT) maintains quality of life (QoL) and delays pain progression¹ in patients with nonmetastatic castration-resistant prostate cancer (CRPC) compared with ADT alone, said Karim Fizazi, MD, PhD.

MFS served as the primary endpoint of the phase III ARAMIS trial,² in which the androgen receptor (AR) antagonist was explored in combination with ADT (n = 955) versus ADT/placebo (n = 554) in patients with nonmetastatic CRPC. Data from the trial were first reported at the 2019 Genitourinary Cancers Symposium and showed that the addition of darolutamide to standard ADT resulted in a median MFS of 40.4 months versus 18.4 months with ADT alone, as well as a trend toward improved overall survival ([OS]; HR, 0.41; 95% CI, 0.34-0.50; 2-sided, P <.0001).

Time to pain progression and QoL served as secondary endpoints of the trial and were assessed by the Brief Pain Inventory Short Form and the EORTC-QLQ-PR25, the latter of which was employed at baseline and every 16 weeks until the end of treatment.

With this, investigators showed that the addition of darolutamide delayed pain progression by 14.9 months versus placebo (HR, 0.65; 95% CI, 0.53-0.79; P <.0001). Furthermore, the time to deterioration of urinary symptoms was reflective of a statistically and clinically significant delay with darolutamide versus placebo, at 25.8 months and 14.8 months, respectively (HR, 0.64; 95% CI, 0.54-0.76; P <.01). Although the time to deterioration of hormonal treatment—related symptoms were similar between arms, the overall incidences of fatigue, hypertension, hot flush, fracture, falls, cognitive disorder, and seizure were fewer with darolutamide.

Given the agent’s limited quantity of adverse events (AEs) relative to the already FDA-approved AR antagonists enzalutamide (Xtandi) and apalutamide (Erleada), it may become an attractive option for patients, as the FDA granted a priority review designation to the agent in April 2019.³

“Assuming darolutamide is approved in this indication, I expect it will be used because it's very active and well tolerated,” said Fizazi, head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France.

In an interview with OncLive, Fizazi, lead author of the ARAMIS trial, discussed the impact of darolutamide on pain progression and QoL in patients with M0CRPC.

OncLive: Could you discuss the data surrounding darolutamide in nonmetastatic CRPC?

Fizazi: We know that darolutamide is an AR antagonist that has a very nice safety profile. The agent was shown to be very active in phase I/II development. At the 2019 Genitourinary Cancers Symposium, we reported the first set of data from the phase III ARAMIS trial. This is a trial comparing ADT with darolutamide versus placebo in men who have nonmetastatic CRPC as detected by conventional imaging, or in other words, a bone scan and a CT scan.

At the meeting, we were able to show that there was a 59% reduction in the risk of metastasis or death with darolutamide, representing a significant and clinically meaningful improvement in MFS, the primary endpoint of the trial. This came on top of secondary endpoints that showed a very good safety profile with almost no AEs as compared with placebo.

At the 2019 ASCO Annual Meeting, we showed more data regarding patient-reported outcomes. We showed that prostate-specific antigen (PSA) progression is significantly postponed. This means a lot for patients, even though this is a biological parameter. Having a PSA that is under control [has a positive impact on their anxiety level]. We also presented on pain progression [in these patients], which is approximately 30% lower with darolutamide than with placebo.

QoL was assessed by various means, including the FACT-P scale and the EORTC questionnaire. Basically, we found the same thing. Whichever way we looked at it, QoL was maintained with darolutamide. We also showed that we’re doing some good in terms of preventing the onset of local symptoms, urinary symptoms, and bowel-related symptoms; these symptoms were prevented in the darolutamide arm. Altogether, we have a very active and safe drug. The trial is continuing, so we will have even more data soon.

What are some of the other endpoints that are anticipated with longer follow-up?

We're still waiting for mature OS data. Still, there seems to be a trend [toward improved survival with the agent]. The 3-year OS rate is 73% in the control arm versus 83% in the darolutamide arm, which is amazing. The final analysis is planned in the coming months. Hopefully, we will be able to report some data on that next year. This drug has the potential to postpone death on top of metastases and symptoms.

What sets darolutamide apart from some of the other agents in this setting?

A year ago, we heard about the SPARTAN and the PROSPER trials with enzalutamide and apalutamide [in this setting]; MFS was significantly improved [with those agents]. What makes a difference to me is the safety profile. Both enzalutamide and apalutamide cross the blood-brain barrier; darolutamide doesn't. This may explain why we don't see any difference or very mild differences with darolutamide as compared with placebo, whereas we do see fall fractures, cognitive impairment, hypertension, etc. with enzalutamide and apalutamide. That can really make a difference in [treatment] decisions.

How would an FDA approval impact the paradigm?

We'll see whether OS is improved [with darolutamide]. It is also being tested in other settings, but we don't have those data yet. The ARAMIS trial was really the first pivotal phase III trial. We know that the phase III ARASENS trial completed its planned accrual in metastatic castration-sensitive disease last year. Hopefully, in the coming years, we will know [what those results are]. That's a very interesting trial as well because darolutamide is being tested on top of standard of care, which is ADT and docetaxel; again, this has the potential to change how we treat patients.

References

1. Fizazi K, Shore ND Tammela T, et al. Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 15; abstr 5000). doi: 10.1200/JCO.2019.37.15_suppl.5000.
2. U.S. FDA Accepts New Drug Application and Grants Priority Review for Darolutamide [news release]. Bayer. Published April 29, 2019. https://bit.ly/2IMTZFJ. Accessed June 26, 2019.
3. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7; abstr 140). doi: 10.1200/JCO.2019.37.7_suppl.140.