Pfizer makes haste to go EZ

There isn’t much competition in the field of EZH2 inhibition, but that hasn’t stopped Pfizer from fast-tracking its contender mevrometostat. A clinicaltrials.gov listing reveals that the company has leapt straight from phase 1 into phase 3 in castration-resistant prostate cancer with the start of the pivotal Mevpro-1 study.

The trial is notable for several reasons: first, Pfizer has stuck with EZH2 inhibition, despite efforts by others to develop projects that also hit EZH1. Second, the group is going against the grain by targeting prostate cancer, with most similarly acting assets in lymphoma trials. Third, there might be questions about the control arm being used in Mevpro-1.

Weak control?

The trial will enrol patients previously treated with Johnson & Johnson’s androgen receptor-directed therapy Zytiga, who will be randomised to receive either mevrometostat plus Pfizer’s rival androgen therapy Xtandi, or physician’s choice of either Xtandi or docetaxel.

Doubts have been raised about giving an androgen therapy to someone who has progressed on this type of drug – indeed, this so-called hormone-switch approach was dubbed a “weak control” during last year’s ESMO meeting.

At least Pfizer’s trial gives the option of chemo, and it will be interesting to see if the data, when reported, are broken down by the different control groups. There is no mention of patients being given the second-generation taxane Jevtana while on study.

In February, during its oncology innovation day, Pfizer presented data from a phase 1 trial of mevrometostat plus Xtandi in heavily pre-treated metastatic CRPC patients. Among 12 post-Zytiga patients median radiographic PFS was 17.1 months, while rPFS was 11.7 months among 35 post-Xtandi patients. A 2019 study testing Jevtana against hormone switch found rPFS of around 4 months with the latter.

The big pharma said earlier this year that it was also planning a phase 3 first-line CRPC trial, testing mevrometostat plus Xtandi, versus Xtandi alone – again, slated to start in 2024.

Dual duel

Pfizer hopes that mevrometostat will become the first EZH2 inhibitor approved in prostate cancer, but it won’t be the first to hit the market. That honour goes to Ipsen’s Tazverik, approved for epithelioid sarcoma not eligible for complete resection, and relapsed/refractory follicular lymphoma patients with either EZH2 mutations or no other options.

Tazverik, which Ipsen gained via the $247m purchase of Epizyme, made €23m in the first half of 2024. Early prostate cancer data have been presented, and more are due at ESMO this year. Still, Ipsen’s focus, for now, appears to be the confirmatory Symphony-1 study in follicular lymphoma.

The remainder of the EZH2 inhibitor pipeline is dominated by Chinese companies, an analysis of OncologyPipeline shows.

Other groups are looking at dual EZH1 and 2 inhibition, including Daiichi Sankyo, MorphoSys (now part of Novartis), China’s Haihe Biopharma and South Korea’s Hanmi Pharmaceuticals. Last year’s ASH meeting featured duelling datasets from Daiichi’s valemetostat and Haihe’s HH2853 in peripheral T-cell lymphoma.

With data mostly early, it might be a while until it becomes clear which strategy is better – and whether Pfizer’s decisive move was inspired or premature.

EZH2 inhibitors in clinical development

Notes: *EED/EZH2 inhibitor; DLBCL=diffuse large B-cell lymphoma; FL=follicular lymphoma; PTCL=peripheral T-cell lymphoma. Source: OncologyPipeline.