Darolutamide Takes Root With New Prostate Cancer Benchmark

Oncology Live®Vol. 20/No. 24
Volume 20
Issue 24

Matthew R. Smith, MD, PhD, discusses key facets of darolutamide (Nubeqa) therapy in the treatment of patients with nonmetastatic prostate cancer.

Matthew R. Smith, MD, PhD, director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center and an associate professor of medicine at Harvard University

Matthew R. Smith, MD, PhD, director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center and an associate professor of medicine at Harvard University

Matthew R. Smith, MD, PhD

Darolutamide (Nubeqa) is the third androgen receptor inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer on the basis of metastasis-free survival (MFS) findings. In 2018, the FDA began issuing approvals supported by MFS data for this patient population with indications for apalutamide (Erleada) and enzalutamide (Xtandi).1,2

In the pivotal ARAMIS trial (NCT02200614), darolutamide prolonged MFS and improved other key clinical outcomes compared with placebo while demonstrating a favorable safety profile, according to Matthew R. Smith, MD, PhD. In an interview with OncLive, Smith, director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center and an associate professor of medicine at Harvard University, both in Boston, discussed key facets of darolutamide therapy in the nonmetastatic setting.

OncLive: Could you please provide an overview of the patient population eligible for this therapy?

Smith: [These were] patients with nonmetastatic castration-resistant prostate cancer, defined as patients with a rising PSA [prostate-specific androgen level] despite ongoing androgen deprivation therapy and no detectable metastases by conventional imaging—bone scan and abdominal pelvic CT scan or MRI. The reason that is important is because one of the considerations that always comes up is when people say, “Why do you call it nonmetastatic?”

The term metastatic was already taken; that is the preferred terminology. The corollary to that is patients who were not included in those trials, meaning patients who do not have detectable metastases. With more sensitive molecular imaging like PSMA [prostate-specific membrane antigen], PET [positron emission tomography], or FDG [fluorodeoxyglucose] PET, we can identify metastatic disease.

When you use PSMA PET in this population, it in fact finds detectable distant disease in the majority of patients. The big picture: None of that is a surprise.

Can you discuss the efficacy data that led to the approval of darolutamide?

Approval of darolutamide was based largely on the demonstrated benefit of metastasis-free survival, which is defined as the time from study entry to the time of detectable metastases by conventional imaging.

ARAMIS was a placebo-controlled trial and, when compared with placebo, darolutamide treatment decreased the risk of metastases or death by 59%, with a hazard ratio of 0.41, and improved metastases-free survival from 18.4 months in the placebo group to 40.4 months in the darolutamide group—almost 2 years. Regulatory approval was based on large treatment effects for the primary outcome and from secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to symptomatic skeletal event.

Now there are 3 drugs approved in this space, and all approvals are based on the primary end point of metastasis-free survival. The results of the SPARTAN trial [NCT01946204] for apalutamide were published first, and some months later in 2018, the results of the PROSPER study [NCT02003924] were published by Hussein et al in the New England Journal of Medicine [NEJM] leading to the label expansion of enzalutamide. In that same issue of NEJM, there was an editorial by the FDA on MFS and also an editorial by me on the history of development of the drugs in the space.1

Can you describe darolutamide’s mechanism of action?

Darolutamide is a structurally unique androgen receptor antagonist that inhibits the androgen receptor, which is a validated target in prostate cancer. In contrast to the other 2 approved antiandrogens in this setting, apalutamide and enzalutamide, darolutamide is structurally distinct, and in nonclinical models, it is shown to not cross the blood-brain barrier. Part of the basis for development was the expectation that that attribute may confer benefit for improved tolerability.

What else do we know about the tolerability of darolutamide?

The nice thing about placebo-controlled trials is that you can really look at attribution when it comes to adverse events. Although there is no head-to-head comparison between darolutamide and the 2 other antiandrogens approved in this setting, we can look between the trials and observe the differences between drug and placebo.

In contrast to those 2 other drugs, darolutamide had rates of treatment discontinuation that were indistinguishable with placebo and had no observed increase risk for falls or fractures. When you compare between trials, those are the distinct things. That differs from the other trials, where there were higher rates of treatment discontinuation due to adverse events, as well as excess falls and fractures. The latter may reflect the nonclinical expectation that darolutamide does not cross the blood-brain barrier, meaning falls and fractures may be an indication of CNS [central nervous system] adverse events.

The other adverse event of interest is fatigue, and darolutamide appeared to be associated with less fatigue than enzalutamide. Rates of fatigue of any grade were 16% in the darolutamide group compared with about 11% in the placebo group, and that is quite different from the enzalutamide study in a similar patient population.

What are the next steps for darolutamide?

Future studies to better characterize the comparative safety and tolerability of darolutamide compared with the other antiandrogens are ongoing. A French head-to-head trial [ODENZA; NCT03314324] with enzalutamide and darolutamide is currently recruiting and will observe which antiandrogen patients prefer and compare safety data.

An ongoing study called ARASENS [NCT02799602], which is fully accrued, is evaluating the role of darolutamide in patients with metastatic hormone-sensitive prostate cancer. Other studies look to better characterize the CNS adverse events of the different antiandrogens and specifically evaluate if darolutamide crosses the blood-brain barrier.


  1. Smith MR. Progress in non-metastatic prostate cancer. N Engl J Med. 2018;378(26):2531-2532. doi: 10.1056/NEJMe1805733.
  2. FDA approves enzalutamide for castration-resistant prostate cancer. FDA website. bit.ly/35CcYKI. Updated July 16, 2018. Accessed November 26, 2019.
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