While the scale of the currency headwinds in Roche’s first-quarter financial update caught many off guard, the company’s earnings call still featured much discussion on a pivotal pipeline prospect: the oral SERD drug giredestrant. The drug carries blockbuster ambitions, yet its commercial path has been clouded by imperfect clinical data.
In a high-profile phase 3 flop, giredestrant recently flunked in first-line HR-positive, HER2-negative breast cancer, raising questions about Roche’s multibillion-dollar ambition for the oral SERD.
But on Thursday’s call, Teresa Graham, CEO of Roche Pharmaceuticals, brushed off the impact from the first-line setback, saying it’s still very much possible for giredestrant to become the largest-selling product in Roche’s history.
HR-positive, HER2-negative breast cancer is a much larger patient population, accounting for about 70% of all breast cancers, versus only 15% for HER2-positive disease, Graham pointed out.
By Roche’s estimates, HR+/HER2- breast cancer represents a market of between $20 billion and $30 billion annually across all lines of therapy. There, adjuvant treatment of early-stage cancer is “by far the largest piece, with three times more drug-treated patients than in first-line metastatic and a much longer treatment duration [of] around five years,” Graham said.
“It is really important to remember that the first-line metastatic breast cancer setting only represented around 10% of the overall giredestrant opportunity,” whereas the adjuvant use accounts for about 70%, she added.
In the adjuvant setting, Roche recently reported positive phase 3 readout from the lidERA trial, showing that giredestrant reduced the risk of invasive disease recurrence or death by 30% versus standard endocrine therapy.
Graham called the lidERA data “strong and compelling.” However, one weakness in the data is that giredestrant was not compared against CDK4/6 inhibitors such as Novartis’ Kisqali and Eli Lilly’s Verzenio, which have been established as the new standards of care for some adjuvant patients. Besides, the first-line flop could undermine physicians’ confidence in giredestrant in the adjuvant setting, especially given the absence of an overall survival win so far in lidERA.
“Tumor biology differs across lines of treatments, especially in early breast cancer versus later line setting,” Graham said. “In [early breast cancer], tumor burden is low versus the metastatic setting. The tumor burden increases, the environment becomes more genetically complex, resistance mechanisms are more prevalent, the later line in therapy that you go.”
If approved for adjuvant treatment, Roche expects the quickest uptake will occur among patients at medium risk of recurrence, for whom the CDK4/6 inhibitors are not approved. But “there’s quite a reasonable belief” that giredestrant will penetrate into the high-risk population because of tolerability issues with CDK4/6 inhibitors, Graham said.
“We’ll have additional data that we will generate in these areas as well in terms of combination therapy,” Graham said. “But it is very tough to remain on these regimens over time. And given the safety profile that we saw with giredestrant, we would believe that there will be a number of patients even in that high-risk population that will want to make the switch.”
Competitive landscape
The adjuvant breast cancer opportunity may be large, but giredestrant is not the only oral SERD contender. And despite a willingness among doctors to potentially use giredestrant after adjuvant CDK4/6 inhibitors, lidERA wasn’t designed to answer that question.
Meanwhile, AstraZeneca’s Cambria-1 and -2 trials are evaluating the British pharma’s oral SERD camizestrant in HR+/HER2- early breast cancer, with the first expected to read out in 2027. Cambria-1 is essentially a switch study comparing camizestrant versus endocrine therapy in patients who have already received two to five years of standard endocrine therapy, with or without CDK4/6 inhibitors. Cambria-2 is a combination trial comparing adjuvant camizestrant with endocrine therapy, with initial treatment with Lilly’s Verzenio permitted in both treatment arms.
Similarly, Lilly plans to specifically prove the worth of its rival oral SERD Inluriyo in a post-CDK4/6 adjuvant setting. The Indianapolis pharma’s Ember-4 trial is being conducted in patients ho have previously received two to five years of adjuvant therapy, including a CDK4/6 inhibitor.
And Menarini Group’s Orserdu, the first oral SERD to reach the market, is undergoing its own adjuvant switch study. Called Elegant, the study is evaluating Orserdu following two to five years of prior adjuvant therapy, which may include a CDK4/6 inhibitor.
On Thursday’s call, Graham also spotlighted that giredestrant has “demonstrated the highest preclinical potency among the SERDs.”
Roche has not given up on the first-line setting, as Graham noted that the failed persevERA study showed a numerical progression-free survival improvement. The phase 3 pionERA study is testing giredestrant, combined with a CDK4/6 inhibitor, in patients with first-line, endocrine-resistant HR+/HER2- breast cancer, who represent about 40% of the first-line population. The trial is expected to read out next year, according to Graham.
The company expects 40% of patients in the new study will carry ESR1 mutations, for whom oral SERDs are known to work better, versus just 5% in persevERA conducted in endocrine-sensitive patients.
Roche has filed giredestrant with the FDA in the adjuvant setting using a priority review voucher, and the agency is set to decide on its second-line application by Dec. 18, 2026.
“Overall, we see ourselves very well positioned to capture a meaningful share of this significant market, giving us confidence in the overall commercial potential on giredestrant,” Graham said. “This means peak sales well north of 3 billion [Swiss francs]. And I think in fact, you’ve heard […] before, this could be our largest-selling product, and that certainly does seem to still appear to be very possible.”
Editor's Note: The story was updated to include an adjuvant trial information from Orserdu.