Roche flunks its first-line degrader test

Roche last year surprised with success for its oral SERD giredestrant, but now the project has stumbled in the front line. The company announced on Monday that the Persevera study, in treatment-naive, ER-positive, HER2-negative breast cancer, had failed to meet its primary endpoint, progression-free survival.

The result is puzzling after giredestrant’s victories in second-line all-comers – albeit driven by ESR1 mutants – and in the adjuvant setting. On paper, these results made a win in Persevera look likely, as in the front line tumours are still ER dependent and haven’t yet developed resistance via ESR1 mutations.

Still, Roche is still holding out some first-line hope. The company noted a “numerical improvement” in PFS in Persevera with giredestrant plus Pfizer’s CDK4/6 inhibitor Ibrance, versus Ibrance plus letrozole. And the company has another first-line phase 3 ongoing; while Persevera enrolled endocrine-sensitive patients, the upcoming Pionera study focuses on those with endocrine therapy resistance.

Results from Pionera are due next year, and if these are positive it’s possible that Roche might try to bundle the two studies and argue for a benefit across first-line disease.

Adjuvant questions

However, for now a filing looks out of the question, and the Persevera failure could also raise questions about whether the adjuvant result, which came from the Lidera trial, was just a case of Roche getting lucky.

Lidera found a 30% reduction in the likelihood of a patient developing invasive disease with adjuvant giredestrant monotherapy versus standard-of-care endocrine therapy. One potential flaw was that the control arm didn’t include CDK4/6 inhibitors, but the study started before these became approved. On a cross-trial basis giredestrant looked similar to the likes of Novartis’s Kisqali and Lilly’s Verzenio.

Roche expects to file the Lidera data with the FDA “in the coming weeks”.

The Swiss group also believes that, in the adjuvant setting there’s “a path forward” for a combination of giredestrant and a CDK4/6 inhibitor. An adjuvant investigator-sponsored trial, Mirador, is under way testing giredestrant plus Verzenio, as well as alongside the PI3Kα inhibitor Itovebi.

Second line

Meanwhile, Roche is awaiting an FDA decision by 18 December in second-line disease, based on the Evera trial. The company touted a benefit in all-comers last year, but the study was enriched for ESR1m, and ultimately Roche's filing was accepted by the FDA only in this subgroup of patients – setting giredestrant up to compete with the other approved oral SERDs, Menarini’s Orserdu and Lilly’s Inluriyo.

A win in first-line disease could have opened up a much broader market. Roche has said it expects giredestrant sales to peak at over CHF3bn, but this could be in doubt if the first-line setting is off the table. The group has another shot here, but this now looks a lot riskier.

Giredestrant phase 3 trials in ER-positive HER2-negative breast cancer

Source: OncologyPipline & company statements.