Olema takes its antagonist/degrader concept into phase 3

The race to develop oral SERDs for HER2-negative breast cancer has had its share of ups and downs. Yesterday Olema posted on clinicaltrials.gov the first phase 3 study of its contender, palazestrant, only months after Arvinas’s Pfizer-partnered project vepdegestrant entered pivotal development.

The development of both assets will be closely watched. Vepdegestrant disappointed at last year’s San Antonio Breast Cancer Symposium, and one hope is that it might be rescued by efficacy in a biomarker-defined population. Palazestrant, too, remains an asset with much to prove, despite Olema’s insistence that it is differentiated by not being a pure SERD.

The SERD, or selective oestrogen receptor degrader, concept was validated by AstraZeneca’s now off-patent Faslodex. Though this was efficacious and did become a blockbuster, it had poor bioavailability and had to be delivered intramuscularly, characteristics that spurred the industry’s quest for an oral alternative for patients with ER-positive HER2-negative breast cancer.

Not enough

However, Olema insists that palazestrant, earlier coded OP-1250, is not purely a SERD. Though it “degrades quite well”, significant amounts of the oestrogen receptor remain in the cell, the group’s chief executive, Sean Bohen, told last year’s Jefferies London conference. Accordingly, antagonism at the receptor is also required, and palazestrant claims both to antagonise and degrade.

How well it does so will be put to the test when the phase 3 Opera-01 study gets under way in October. The trial is notable for mandating prior CDK4/6 inhibitor use – a relatively new standard of care – and will measure PFS versus endocrine therapy as primary endpoint.

Arvinas/Pfizer’s vepdegestrant (ARV-471) claims some uniqueness too, being described as a Protac (heterobifunctional) molecule, though it seems to act purely as a SERD. The phase 3 Veritac-2 trial started in March, measuring PFS versus Faslodex and also mandating prior CDK4/6 blockade.

Such moves have gone on against the backdrop of big pharma’s mixed track record in SERD development, as Sanofi’s amcenetrant and Roche’s giredestrant scored notable failures in the Ameera-3 and Acelera trials respectively. Astra succeeded in the Serena-2 study of its camizestrant, though it has apparently not yet filed this with regulators.

The biggest win so far belongs to the private company Menarini, which succeeded with the Radius Health-partnered elacestrant in the Emerald trial, on the back of which this drug, trademarked Orserdu, in January became the first US-approved oral SERD. Meanwhile, the Ember-3 trial of Lilly’s imlunestrant remains a key 2023/24 catalyst.

A comparison of selected SERD studies in 2nd-line ER-positive HER2-negative breast cancer

Source: clinicaltrials.gov & company reports.

The successes and failures have raised not only the question of prior CDK4/6 inhibitor use, but also the importance of the ESR1 mutation, a resistance mechanism to endocrine therapy. The Emerald trial worked largely because it had enriched for ESR1-positive patients, something Ameera-3 and Acelera had not done; Serena-2 did show an all-comers PFS benefit, but this was clearly driven by ESR1-positives.

So how have palazestrant and vepdegestrant done so far? Not brilliantly. At SABCS ARV-471 managed just two partial remissions among 71 patients in the phase 1/2 Veritac trial, while the latest cut of palazestrant’s monotherapy study showed only eight responses, four of these unconfirmed, in 54 evaluable patients.

Neither asset seems especially differentiated in practice, and the best that can be said is that their activity likely correlates with the ESR1 mutation. For vepdegestrant tumour shrinkage was meaningfully greater in ESR1 mutant versus wild-type patients, while three of four of palazestrant’s confirmed PRs occurred in subjects with the ESR1 mutation.

Opera-01’s co-primary PFS endpoints are split between all-comers and ESR1 mutants, and though it is not apparent from clinicaltrials.gov the Veritac-2 study has been said to use the same approach. If there is a saving grace for both projects it might lie in the ESR1 biomarker.