Dr Tomasz M. Beer reviews the use of darolutamide for nonmetastatic CRPC as seen in the ARAMIS trial and metastatic CRPC as seen in the ODENZA trial.

Tomasz M. Beer, MD, FACP: Darolutamide is a potent androgen receptor inhibitor. It’s the third approved next-generation drug in this space, with enzalutamide and apalutamide preceding it. Darolutamide has a distinct chemical structure, and it’s thought to be less capable of penetrating the blood-brain barrier. As a consequence, it’s thought to have much lower concentrations in the central nervous system than the other 2 drugs. The 3 drugs haven’t been compared head-to-head until the ODENZA study—we’ll talk about that in a minute—but they’ve all been studied in nonmetastatic castration-resistant prostate cancer. That’s a situation where a patient has a rising PSA [prostate-specific antigen] on primary hormonal therapy, leuprolide or equivalent and doesn’t have visible metastases on imaging. In that setting we’ve seen 3 randomized studies conducted, SPARTAN, PROSPER, and ARAMIS, evaluating apalutamide, enzalutamide, and darolutamide, respectively.

It’s certainly not appropriate for us to compare across studies, and it’s challenging to do so because when we look at specific adverse effects, it’s important to recognize that studies are done at different sites, so the way investigators collect adverse-effect data may differ. There are differences across studies that we must be careful about. Having said that, the observations from ARAMIS were quite thought-provoking. What we saw was no increase in falls relative to placebo, no increase in dizziness relative to placebo, no increase in patient-reported mental impairment relative to placebo, and a modest increase in fatigue. But when corrected for duration of exposure of the drug relative to placebo, there was no clear increase in fatigue either. All those findings support the hypothesis that perhaps darolutamide is less capable of entering the central nervous system and less capable of causing the kinds of adverse effects that you’d expect from the central nervous system.

With those thoughts in mind, several studies are underway. One is a study that I’m personally involved with, called DaroAcT, which is carefully looking at both physical and cognitive function and comparing darolutamide and enzalutamide. Another study is ODENZA, which is a randomized crossover study with a planned enrollment of about 250 participants, with the primary end point being patient preference. In the ODENZA study, participants are treated with either enzalutamide or darolutamide for 12 weeks, and then they cross over to the other drug, and they’re queried about which drug they prefer—they’ve experienced both. Some secondary end points focus on cognitive assessment. Preliminary results of those cognitive assessment tests were reported at the recent ESMO [European Society for Medical Oncology Congress], and there are some findings that suggest an advantage for darolutamide. But at this point, it’s quite preliminary. I’ll be looking forward to a peer-reviewed complete publication of those results.

Transcript Edited for Clarity

A 62-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

Jan. 2017

Initial presentation

  • A 62-year-old man is found to have a firm prostate nodule of 1.5 mm on his routine physical exam

Clinical workup

  • PSA 15.5 ng/mL
  • Family history of prostate cancer
  • Hypertension
  • Digital rectal exam and transrectal ultrasound (TRUS) of the prostate confirm advanced adenocarcinoma of the prostate and Gleason score of 7 (3 + 4)
  • MRI shows lack of metastasis and node involvement (cT2bN0M0)
  • His ECOG PS is 1


  • In Feb. 2017, patient was treated with radical prostatectomy (RP) with nerve sparing surgery and there were no complications.
  • PSA levels go down to 0.3 ng/ml post-operatively but rise to 1.5 ng/ml within 3 months.
  • Patient receives local salvage radiation therapy and PSA goes down to 0.1 ng/ml.
  • PSA levels are checked every 3 months.

Nov. 2017

  • PSA doubling time increased between 2 last check-ups and now PSA is 3.5 ng/ml.
  • Patient undergoes CT and bone scans and is found to 1 metastatic bone lesion.
  • Patient is treated with androgen deprivation therapy (ADT), leuprolide, as continuous treatment and PSA levels go down to 0.2 ng/ml.

May 2018

  • PSA levels rise to 5 ng/ml, but patient is asymptomatic and has adequate organ and bone marrow function.
  • Patient meets the inclusion criteria for the ODENZA trial and is enrolled in it.
  • Patient is treated with darolutamide(1200 mg/day) for 12 weeks, followed by enzalutamide (160 mg/day) for 12 weeks, in addition to continuing on ADT
  • Patient is currently in the extension phase of the study and is being treated with darolutamide.
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