Darolutamide (ODM-201) in the treatment of nmCRPC

Also on Thursday in San Francisco, Dr. Karim Fizazi presented the initial results from the ARAMIS trial of darolutamide (formerly known as ODM-201) in the treatment of men with non-metastatic, castration-resistant prostate cancer (nmCRPC). A media release issued by Bayer is also available on line, and the full results of the trial have been published simultaneously in the New England Journal of Medicine.

We have recently seen the approval of two other drugs — apalutamide (Erleada) and enzalutamide (Xtandi) — in the treatment of men with nmCRPC, i.e. men who have no clear evidence of metastasis on a standard bone scan but who have already stopped responding to standard androgen deprivation therapy (ADT).

Darolutamide will therefore be the third androgen receptor antagonist that is likely to gain an approval for the treatment of men who fall into this set of with advanced forms of prostate cancer. More options is always good, but which of these drugs is actually going to be “the best” of these agents to use in men with this type of prostate cancer will be difficult to determine.

The ARAMIS trial was a multinational, randomized, double-blind, placebo-controlled Phase III trial that enrolled > 1,500 patients with nmCRPC. The patients were randomized to treatment with either

  • Darolutamide (two 300-mg tablets twice daily) + standard ADT or
  • A placebo + standard ADT

The patients were stratified into two groups:

  • Those with a PSA doubling time of ≤ 6 months
  • Those with a PSA doubling time of > 6 months

For the detailed study protocol, please click here.

The primary study endpoint was metastasis-free survival (MFS), with an independent central review of radiographic imaging every 16 weeks. Secondary endpoints included: overall survival (OS), time to pain progression, time to first cytotoxic chemotherapy, and time to a first symptomatic skeletal event.

Here is a summary of the basic results reported by Fizazi et al.:

  • The trial enrolled a total of 1,509 patients
    • 955 patients  were treated with darolutanide + standard ADT
    • 554 patients were treated with a placebo + standard ADT
  • Average (median) MFS was
    • 40.4 months for patients treated with darolutanide + standard ADT
    • 18.4 months for patients treated with a placebo + standard ADT
  • This difference in MFS was highly statistically signifciant (hazard ratio [HR] = 0.41; two-sided p < 0.0001).
  • The overall survival (OS) data showed a trend in favor of darolutamide (HR = 0.71; two-sided p = 0.045).
  • Other secondary and exploratory efficacy endpoints also favored darolutamide.
  • Incidences of treatment-emergent adverse events (AEs) with ≥ 5 percent frequency or of grade 3 to 5 were comparable between darolutamide and placebo arms.
    • Only fatigue occurred in >10 percent of patients.
    • Discontinuation rates due to AEs were 8.9 percent with darolutamide and 8.7% percent with placebo.

Fizazi et al. concluded that

Among men with nmCRPC, MFS was significantly longer with darolutamide than with placebo with a low incidence of treatment-related AEs in this asymptomatic patient population.

The question of when darolutamide bight be approved by regulatory authorities is not yet answered, and nor is the question of whether it will be able to find a significant niche in the marketplace given the prior approval of the two other prodcuts,


6 Responses

  1. On progression the placebo group was treated with Xtandi, Zytiga, Chemo or any combination or sequence according to the medical advice for each patient. I determine that from the NEJM report. So the placebo men went through a conventional sequence of new(ish) drugs on progression. This makes Daro look quite good, I would say.

  2. Darolutamide’s best hope in finding a “significant niche in the marketplace” will depend upon its purported inability to cross the blood-brain barrier, which may result in less cognitive “fog” compared to enzalutamide and apalutamide.

  3. Cost may be the ultimate factor in its use compared to cost of enzalutamide and apalutamide. Interesting this recent competition among manufacturers as to whom is going to make the ultimate $$bucks$$!

  4. Dear John:

    Darolutamide appears to have a similar level of effectiveness to enzalutamide and apalutamide in this cohort of patients. Unless someone was to decide to do a head to head study, we are never going to know exactly which of the three might have the greatest level of efficacy or the most beneficial safety. Abiraterone acetate has never been tested in this cohort of non-metastatic CRPC patients.

  5. It appears that all advanced hormonal agents slow progression in the relatively small group of men who are not yet detectably metastatic yet are castration-resistant. The FDA has approved apalutamide and enzalutamide for this indication without evidence that they increase survival. I expect they will also approve darolutamide and abiraterone. I suspect the patient group would be considerably smaller if they allowed the use of advanced PET scans to determine radiographic progression.

    “Abiraterone acetate has never been tested in this cohort of non-metastatic CRPC patients.” Yes, it was: see here.

  6. Allen:

    I should have been more specific and stated that, “Abiraterone acetate has never been tested in a large, randomized, Phase III pivotal trial suitable for regulatory approval in this cohort of non-metastatic CRPC patients.”

    The IMAAGEN trial was not large enough for the FDA or the EMA to approve abiraterone acetate (Zytiga) in this indication. The developers never intended to seek such an approval because they very specifically developed apalutamide (Erleada) to initially address that market opportunity, and because abiraterone acetate had very limited patent life.

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