Oric gets a reality check

Oric has settled on a rinzimetostat dose to take forward into a phase 3 prostate cancer trial due to start by the mid-year, but that’s pretty much where the good news ends for this project. An update after market on Tuesday revealed waning efficacy, putting rinzimetostat only just in line with Pfizer’s rival mevrometostat – and that project’s own phase 3 trial reads out soon.

Though Oric’s update showed rinzimetostat to have a promising safety profile, toxicity looms large over this class of molecules, and clearly lies behind Oric’s choice of phase 3 dose. This is to be 400mg daily – the lowest of four doses tested in phase 1 cohorts; Oric shares dropped 29% on Wednesday, perhaps on fears that efficacy would wane even further in phase 3.

The setting in question is metastatic castration-resistant prostate cancer patients progressed on Zytiga, where rinzimetostat is being tested in combination with Bayer’s Nubeqa. The update concerned 15 phase 1 patients dosed at 400mg, which yielded a PSA50 response rate of 33%, and preliminary landmark five-month PFS rate of 84%.

That’s only just about in line with Pfizer’s mevrometostat, whose last phase 1 update last year in a similar setting showed a 34% PSA50 rate and median PFS of 14.3 months. Mevrometostat started its phase 3 Mevpro-1 study in 2024, and this is due to read out around the middle of this year.

Differences and similarities

True, there are a few differences to be aware of here. Firstly, rinzimetostat is a PRC2 inhibitor, while mevrometostat targets EZH2. But EZH2 is one of the subunits of the PRC2 complex, so they effectively have very similar mechanisms.

Secondly, Oric’s focus on post-Zytiga patients and a Nubeqa combo is a narrowing of earlier work on patients relapsed on any AR pathway inhibitor, and given rinzimetostat plus Erleada or Nubeqa. That mirrored Pfizer’s phase 1 strategy, while Mevpro-1 specifically enrols post-Zytiga patients, and combines mevrometostat with Xtandi.

For its part, Oric’s soon-to-be initiated phase 3 trial, Himalayas-1, will test post-Zytiga patients, and combine rinzimetostat with Nubeqa. The design differences aside, the settings are broadly comparable, given that they concern prostate cancer patients who fail on one AR inhibitor, and are then given a combo containing another AR inhibitor.

Waning data

This isn’t the first time rinzimetostat data have waned. Last November Oric was reporting a 40% PSA50 response rate, a decline from the 47% it had cited earlier that year. At the time Oric said rinzimetostat’s PSA90 rate, which some see as a more accurate indicator of activity than PSA50, stood at 20%; on Tuesday the number came in at just 7% for the 400mg dose.

Meanwhile, toxicity hangs over the entire class, a fear triggered by the recent withdrawal form the market of Ipsen/Hutchmed’s Tazverik because of the emergence of secondary haematologic malignancies in a phase 3 study. There’s been no similar signal in trials of mevrometostat or rinzimetostat, but Tazverik is an EZH2 inhibitor, so it shares clear structural similarity with the other two.

Oric had initially tested 400mg to 1.2g rinzimetostat doses, before taking 400mg and 600mg into dose optimisation. The ultimate choice of 400mg for phase 3 was driven by exposure-response analyses that identified “statistically significant relationships between higher drug exposure and toxicities”, at the same time as showing comparable efficacy for the two doses.

Oric gained rights to rinzimetostat from Mirati for just $20m in equity. It might have wanted to dose significantly higher to have a crack at upping response rates, but it seems that this would have been a gamble too far.

Cross-trial comparison in post-ARPI metastatic castration-resistant prostate cancer

Note: ARPI=androgen receptor pathway inhibitor. Source: OncologyPipeline.