For Roche, the Phase 3 failure in first-line breast cancer does not eliminate the blockbuster potential of its oral SERD drug gylidestrant, despite increased competition.
Indeed, the results from the failed PerseverERA trial for primary treatment of HR-positive, HER2-negative metastatic breast cancer give Roche confidence in a new study testing giledestrant in combination with a CDK4/6 inhibitor as an adjuvant treatment for early-stage breast cancer, Roche Deputy Chief Medical Officer Stephen Frings, MD, told Fierce in an interview.
“What we’re still seeing is a very attractive separation of the curves (…) that clearly shows there is a therapeutic effect,” Frings said of persevERA’s progression-free survival (PFS) data. “This convinces us, because in the adjuvant setting, if you treat for five years and move up a few percentage points, you already have a positive treatment effect in the adjuvant setting.”
Frings declined to provide further details about the new adjuvant research, saying it was still in the design stage.
Prior to the persevERA results, Roche had already reported positive results from the lidERA trial of diredestrant monotherapy in adjuvant therapy.
Surprising failure on the first line
After lidERA was a hit in November, perseverERA’s miss was a big surprise.
The combination of diredestrant and Pfizer’s CDK4/6 inhibitor Ibrance (palbociclib) showed an 11% improvement in PFS in physician analysis compared with Novartis’ aromatase inhibitor Femara (letrozole) and Ibrance, but this did not meet statistical significance, according to results presented at the 2026 American Society of Clinical Oncology Annual Meeting.
Median PFS with Giledetrant therapy was 33.1 months, 4.9 months longer than the control group. Patients with metastatic disease are treated until their disease is advanced, which means half of them are treated for less than three years, or about half of the five-year duration of early-stage treatment.
The separation in the PFS curves discussed by Frings began to appear around 16 months of age. After 2 years, 59.7% of patients in the Giledestran group and 57.3% of the control group remained progression-free. After 3 years, the PFS rates were 45.8% and 41.9%, respectively.
persevERA Primary Endpoint: Investigator-assessed PFS (Nicholas Turner, et al./ASCO 2026)
In contrast, diredetrant struggled to show an overall survival benefit, as the hazard ratio was recorded at 1.03, meaning the risk of death was slightly higher for the Roche drug, despite median follow-up of about 52 months and immature data. The 3-year OS rate was the same in the two arms, 74.1%, and the median OS was not reached in either arm.
“The reason this hasn’t worked is because certainly CDK4/6 (inhibitors) are very potent agents, and we don’t know early on what the actual effects of endocrine manipulation are. Dead cells are dead, and you can’t kill any more cells if they’re already dead,” Dr. Frings said.
In terms of safety, adverse events (AEs) were similar between the two treatment arms, but were more frequent with diredestrant. Serious AEs were recorded in 23.9% of diredestrant patients compared with 18.8% in the control group. Treatment-related adverse events resulted in 1 (0.2%) and 2 (0.4%) deaths in each group, respectively.
Roche is conducting a second first-line study, pionERA, testing giledestrant alongside CDK4/6 inhibitors in endocrine-resistant populations. Patients enrolled in the study would have relapsed if they received adjuvant endocrine therapy. or have not received treatment for less than 1 year. Frings said Roche had much more confidence in this trial because most of these patients had ESR1 mutations and oral SERD is known to be more effective.
Roche’s initial FDA submission for diredestrant, with a target date of December 18, 2026, is for second-line ESR1-mutant HR+/HER2- breast cancer. The limited pursuit of the ESR1 subgroup was to some extent expected, reflecting past verbal recognition of SERD. However, it was still disappointing given that Roche was touting its benefits to a wide range of all-comers.
“We purposely filed for ESR1 variant (patients) because we knew that[the intent-to-treat label]would be a struggle,” Frings said. However, Roche added that it is “leaving the door open as the data evolves” and may explore broader labels regardless of ESR1 status, especially if more mature OS data is strong.
Pay attention to the prize
Roche announced on Monday that the FDA has approved Giredesrant for HR+ early breast cancer. The FDA set a target date of Nov. 30 after the company exhausted its priority review vouchers.
At ASCO 2026, a subgroup analysis of the lidERA trial demonstrated the benefit of zilidestrant as adjunctive therapy, regardless of the patient’s menopausal status. Compared to standard endocrine therapy, diredestrant improved invasive disease-free survival (iDFS) by 35% in premenopausal women and 26% in postmenopausal patients.
During an investor conference call in April, Roche Pharmaceuticals CEO Teresa Graham defended GiriDetrant’s potential, with top sales forecasts “far north” of CHF 3 billion, despite the setbacks at frontline persevERA. That’s because adjuvant therapy is a much larger market, with “three times more patients treated with drugs than first-line metastatic patients, and treatment durations are much longer, about five years,” she said.
However, critics point out that the LID ERA study does not answer how giledesrant works on or in combination with CDK4/6 inhibitors. CDK4/6 inhibitors have recently become standard treatment for some patients with early-stage HR+/HER2- breast cancer.
Comparisons between trials showed that Giledetrant’s 30% improvement in iDFS was comparable to CDK4/6 drugs, although the study populations were different. While the adjuvant use of Verzenio and Kiscali (which must be combined with endocrine therapy) covers patients at high risk of recurrence, single-agent diredestrant may be an attractive option for low- and intermediate-risk patients, Frings said.
For patients who want to maximize efficacy, diredetrant may be the best backbone for the combination because it is a more potent oral SERD, Frings argued.
Roche is currently conducting a 100-patient substudy with lidERA to evaluate the safety of diredestrant in combination with Eli Lilly’s CDK4/6 drug Verzenio in an adjuvant setting. It also recently launched another 200-patient study to evaluate the safety of giredestrant using Novartis’ Kisqali.
Other companies, including Lilly, AstraZeneca and Menarini, are also conducting Phase 3 trials testing oral SERDs in patients who have received several years of adjuvant therapy containing CDK4/6 drugs.
Dr Frings argued that the trial design was “complex” and “close to a 2×2 design” because not all patients would be exposed to CDK4/6 inhibitors.
Additionally, lidERA showed early therapeutic efficacy against oral SERD, while competitors’ designs eliminated the opportunity for early intervention, Roche executives said. She added that participants in these trials had previously received two to five years of adjuvant therapy, so adherence could also be a challenge when continuing treatment.
Roche’s future adjuvant trials “must be properly planned and have regulatory buy-in,” Frings said. “And once we’re able to talk about it, we’ll announce exactly what we’re going to do.”
