The magnitude of the currency headwinds in Roche’s first-quarter earnings report caught many off guard, but the company’s earnings call also featured a lot of discussion about oral SERD drug Gylidestrant, which remains a key pipeline prospect. The drug has blockbuster ambitions, but incomplete clinical data cloud its path to commercialization.
In a high-profile Phase 3 failure, diredetrant recently failed in first-line HR-positive, HER2-negative breast cancer, casting doubt on Roche’s multibillion-dollar ambitions for oral SERD.
But on a conference call Thursday, Roche Pharmaceuticals CEO Teresa Graham dismissed the impact of the front-line setbacks and said there was still a good chance Giledetrant would become Roche’s biggest-selling product in history.
The patient population of HR-positive, HER2-negative breast cancers is much larger, accounting for about 70% of all breast cancers, compared to only 15% of HER2-positive breast cancers, Graham noted.
Roche estimates that HR+/HER2- breast cancer represents a $20 billion to $30 billion annual market across all treatment areas. There, adjuvant therapy for early-stage cancer is “by far the biggest part, with three times as many patients receiving drug treatment as first-line metastatic patients, and the duration of treatment is much longer, about five years,” Graham said.
“It’s very important to remember that the first-line metastatic breast cancer setting represents only about 10% of the total opportunity for diredestrant,” she said, adding that adjuvant use accounts for about 70%.
In adjuvant therapy, Roche recently reported positive Phase 3 results from the lidERA study, showing that diredestrant reduced the risk of invasive disease recurrence or death by 30% compared to standard endocrine therapy.
Mr Graham said the lidERA data was “powerful and convincing”. One weakness of this data, however, is that giledestrant was not compared with CDK4/6 inhibitors such as Novartis’ Kisqari and Eli Lilly’s Verzenio, which have been established as the new standard of care for some adjuvant patients. Furthermore, first-line failure could undermine physician confidence in diredestrant in the adjuvant setting, especially given the lack of overall survival wins to date with Lidecera.
“Tumor biology differs depending on the treatment, especially in early-stage versus late-stage breast cancer,” Graham said. “[In early breast cancer]the tumor burden is low compared to the metastatic setting. The later in the treatment the tumor burden increases, the environment becomes more genetically complex, and resistance mechanisms become more prevalent.”
If approved as an adjuvant therapy, Roche expects the fastest uptake will occur among patients at intermediate risk of recurrence, for whom no CDK4/6 inhibitors have been approved. But because of tolerability issues with CDK4/6 inhibitors, there is “a pretty reasonable belief” that diredestrant will penetrate high-risk populations, Graham said.
“We plan to generate additional data in these areas as well in terms of combination therapy,” Graham said. “However, it is very difficult to maintain these regimens long-term, and given the safety profile we have seen with glidetrant, we believe there will be a large number of patients who will want to switch, even in that high-risk population.”
competitive environment
Although it may have great potential for adjuvant treatment of breast cancer, diredestrant is not the only candidate for oral SERD. Additionally, lidERA was not designed to answer that question, even though there is a possibility among physicians to use diredestrant after an adjuvant CDK4/6 inhibitor.
Meanwhile, AstraZeneca’s Cambria-1 and -2 trials are evaluating the British drugmaker’s oral SERD camizetrant in HR+/HER2- early-stage breast cancer, with initial results expected in 2027. Cambria-1 is essentially a switch trial comparing camizetrant to endocrine therapy in patients who have already received standard endocrine therapy for two to five years, with or without a CDK4/6 inhibitor. Cambria-2 is a combination trial comparing adjuvant camizetrant and endocrine therapy, allowing initial treatment with Lilly’s Verzenio in both treatment arms.
Similarly, Lilly plans to specifically demonstrate the value of its competitive oral SERD Inluliyo in the post-CDK4/6 adjuvant setting.. The Indianapolis drug company’s Ember-4 trial is being conducted in patients who received 2 to 5 years of adjuvant therapy, including a CDK4/6 inhibitor.
During Thursday’s conference call, Graham also noted that Gylidetrant “demonstrated the highest preclinical efficacy of any SERD.”
Roche is not giving up on the first-line setting, as Graham pointed out that the failed persevERA study showed a numerical improvement in progression-free survival. The Phase 3 pionERA study is testing giledestrant in combination with a CDK4/6 inhibitor in patients with first-line endocrine-resistant HR+/HER2- breast cancer, which represents approximately 40% of first-line patients. A trial is expected to be handed down next year, Graham said.
The company expects 40% of patients in the new study to carry the ESR1 mutation, for which oral SERD is known to be highly effective, compared to just 5% in persistentERA, which was conducted in patients with endocrine hypersensitivity.
Roche has applied to the FDA for ziridestrant in an adjuvant setting using a priority review voucher, and the FDA expects to make a decision on the second-line application by December 18, 2026.
“Overall, we believe we are very well positioned to capture a significant share of this important market and are confident in GiriDetrant’s overall commercial potential,” Graham said. “This means that our peak sales will be well over 3 billion (Swiss Francs). And in fact (…) as I’m sure you’ve heard before, this could be our biggest selling product, and certainly that possibility still seems very high.”
