Asco-GU – Arvinas sees the path to a prostate cancer niche

The company’s androgen receptor degrader might have a pathway to approval, but the potential market looks small.

The good news for Arvinas is that ARV-110, an asset some had virtually written off, might arguably have legs. The bad is that its opportunity will probably be limited to a small, genetically defined population of late-stage prostate cancer patients.

Much still depends on the full data from ARV-110’s phase 1/2 Ardent study, due to be presented at the Asco Genitourinary Cancers Symposium on Thursday evening. But the abstract, which went live last night, shows responses in 12 of 26 AR T878X/H875Y-positive patients, an important update versus Arvinas’s last Ardent disclosure, in December 2020, which comprised just five subjects with this genetic mutation.

It should be stressed that the responses here are in terms of PSA50 rate, meaning reductions in prostate-specific antigen levels of 50% or more. The actual confirmed overall remission rate at the August data cutoff is 29%, but this comes from only seven AR T878X/H875Y-positive castration-resistant prostate cancer patients who were Recist-evaluable, according to the abstract.

Analysts point to Astrazeneca’s Lynparza and Clovis’s Rubraca, which both saw PSA50 responses translate into overall remissions that were good enough to see these two drugs gain accelerated approvals in genetically defined prostate cancer subgroups.

Thus Arvinas investors will hope that once Ardent yields data in around 100 patients with the mutation these results can back an accelerated approval. ARV-110 (bavdegalutamide) is a Protac degrader of the androgen receptor; while it is one of Arvinas’s most advanced pipeline projects the attention has mainly been on ARV-471, a Serd that Arvinas licensed to Pfizer last year for $650m up front plus $350m in equity.

Not enough?

Still, bulls were hoping that ARV-110 would show promise beyond the AR T878X/H875Y population, which analysts reckon is a market worth just $300m at peak.

Another cohort of Ardent looked at patients not defined genetically but who instead had received less pretreatment. Among 19 evaluable subjects here only five achieved PSA50, and the resulting 26% PSA50 rate seems identical to what sequential treatment with an already available androgen receptor inhibitor, like Xtandi, has shown.

Focus on Thursday will fall on the chances of the PSA50 responses seen in the AR T878X/H875Y cohort translating into additional confirmed remissions, and on the duration of these remissions. It is clear that ARV-110 is ineffective in the absence of the AR T878X/H875Y mutation: among 114 such patients in Ardent just 10% achieved PSA50.

Investors will of course want to look deeper into these data; for instance, are there any other mutations that made this population especially intractable? One such is the AR-V7 splice variant, against which ARV-110 has no activity, but against which Arvinas has a separate Protac in preclinical development.

Evaluate Pharma sellside consensus shows ARV-110 selling $296m in 2026, though this will include analyst estimates including some contribution from settings beyond AR T878X/H875Y. This morning Arvinas stock traded down slightly, suggesting that there must have been some hope of a broader efficacy signal.

ARV-110 (bavdegalutamide) activity in metastatic castration-resistant prostate cancer (Ardent)
Cohort Evaluable patients PSA50 rate
1-2 prior novel hormonal agents +/- chemo, AR T878X and/or H875Y mut 26* 46%
1-2 prior novel hormonal agents +/- chemo, AR L702H** or AR-V7** mut 114 10%
1-2 prior novel hormonal agents +/- chemo, wild-type AR or other AR alterations
Less pretreated: 1 prior novel hormonal agent, no prior chemo 19 26%
Total 159 16%
Note: 26 Aug 2021 data cutoff; *2 of 7 evaluable patients had confirmed disease remissions; **variants not degraded by ARV-110 in preclinical studies. Source: Asco-GU.

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