Asco-GU 2019 – Bayer and Orion have their work cut out with darolutamide

Results of the prostate cancer project’s pivotal Aramis trial, already known to be positive, are presented for the first time.

When entering a prostate cancer market about to see the genericisation of Zytiga, Johnson & Johnson carved out a novel use – non-metastatic disease – for its follow-on drug Erleada. This strategy was copied by Pfizer/Astellas’s Xtandi, and it could soon result in a third entry, darolutamide from Bayer and Orion.

However, results from darolutamide’s pivotal Aramis study, presented today at the Asco-Genitourinary Cancers symposium, show how hard it will be for the newcomers to compete. The efficacy data are virtually identical to those reported in Erleada and Xtandi’s respective Spartan and Prosper studies, meaning that the drugs’ safety profiles will be more important in determining their use.

Writing in today’s New England Journal of Medicine, where the Aramis data were simultaneously published, the trial’s investigators made much of darolutamide’s potential for lower toxicity. This, they argue, was due to the molecule’s distinct structure, which results in low blood/brain barrier penetration and low binding affinity for GABAA receptors.

On the question of efficacy, however, they accepted that: “The metastasis-free survival with darolutamide is similar to that in ... Prosper and Spartan.”

Cross-trial efficacy comparisons in non-metastatic, castration-resistant prostate cancer
Treatment Study mMFS Time to PSA progression mOS
Erleada Spartan 40.5mth vs 16.2mth (HR=0.28) NR vs 3.7mth (HR=0.06) NR vs 39.0mth (HR=0.70)
Xtandi Prosper 36.6mth vs 14.7mth (HR=0.29) 37.2mth vs 3.9mth (HR=0.07) NR vs NR (HR=0.80)
Darolutamide Aramis 40.4mth vs 18.4mth (HR=0.41) 33.2mth vs 7.3mth (HR=0.13) NR vs NR (HR=0.71)
All versus control. mMFS=median metastasis-free survival; NR=not reached; HR=hazard ratio. Source: NEJM.

Among adverse events of note, the authors highlighted fatigue, asthenia (abnormal physical weakness), falls and fractures as less common in Aramis than in rival studies. Cross-trial comparisons are by definition unsound, but in the absence of head-to-head data they are all that prescribers will have to go on.

Also importantly, patients with a history of seizure were not allowed to enter the Spartan and Prosper studies – something that did not apply to Aramis, thanks to darolutamide’s lack of proconvulsive potential in animal trials. In Aramis there were just two seizures on darolutamide and one in the control group.

Cross-trial comparison of selected adverse events reported
  Erleada (Spartan) Xtandi (Prosper) Darolutamide (Aramis)
Any adverse event 775 (97%) 808 (87%) 794 (83%)
Serious adverse event 199 (25%) 226 (24%) 237 (25%)
Fatigue 244 (30%) 303 (33%) 115 (12%)
Hypertension 199 (25%) 111 (12%) 63 (7%)
Dizziness 75 (9%) 91 (10%) 43 (5%)
Cognitive/mental impairment 41 (5%) 48 (5%) 9 (1%)
Source: NEJM.

A separate consideration, of course, is whether non-metastatic prostate cancer is a genuine setting for these types of drugs, or whether it is one that has been invented to get around the loss of patent protection for Zytiga, which is approved only in metastatic and hormone-sensitive settings.

Some might ask, for instance, whether patients can accurately be classified as non-metastatic or whether this is just a shortcoming of conventional imaging techniques, meaning that they might actually be metastatic and could be prescribed Zytiga according to this drug’s label.

The question is whether there is a window between patients becoming castration-resistant and developing metastases and, if so, how big this window might be. The Aramis authors argue that “delaying the development of metastases ... is a key therapeutic goal”.

It is also unclear how big a market this might amount to. Erleada was approved a year ago, but J&J has not disclosed its sales and only says it is "pleased" with the drug’s launch progress. Pfizer does not split out Xtandi sales by metastatic and non-metastatic disease, but on its fourth-quarter analyst call boasted: “In just six months our market share is quadruple that of Erleada.”

Darolutamide is expected to sell $819m in 2024, according to EvaluatePharma’s sellside consensus. Now that the Loxo-derived Vitrakvi has been launched darolutamide is Bayer’s biggest pipeline hope.

Even if Zytiga and its generic alternatives do not enter into the equation, Bayer and Orion will still have a hard task competing against the more established prostate cancer players, J&J and Pfizer/Astellas. Whether darolutamide can achieve forecast sales numbers will therefore depend on pricing and marketing muscle at least as much as on its safety profile.

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