Palbociclib

The ink was barely dry on the FDA approval letter for AstraZeneca’s Etcamah before the oral SERD suffered a key clinical setback. Etcamah failed to significantly improve patients’ time before tumor progression or death compared with the aromatase inhibitor anastrozole for the first-line treatment of ER-positive, HER2-negative breast cancer, AZ said Friday. The readout comes from the Serena-4 phase 3 trial, in which all patients also received Pfizer’s CDK4/6 inhibitor Ibrance. AZ noted a numerical progression-free survival improvement for the Etcamah regimen, but the outcome didn’t meet statistical significance on that trial’s primary endpoint. Etcamah now joins Roche’s rival oral SERD, giredestrant, in missing the mark in first-line HR+/HER2- breast cancer. Previously, in the phase 3 persevERA trial, giredestrant plus Ibrance only showed a numerical 11% improvement over Novartis’ aromatase inhibitor letrozole and Ibrance. Trying to infuse confidence into Serena-4 on AZ’s second-quarter earnings call back in July, AZ’s oncology and hematology R&D chief, Susan Galbraith, Ph.D., pointed to the study’s larger patient pool than persevERA, as well as a population enriched for endocrine sensitivity. Because oral SERDs exert their therapeutic effect through estrogen receptor signaling, they need tumors that remain vulnerable to endocrine manipulation to work. The two failures now spell trouble for other oral SERD efforts in the first-line setting, such as Olema Oncology’s Opera-02 trial that combines its palazestrant with Ibrance. The Serena-4 announcement came merely a week after the FDA’s surprise approval for Etcamah in another first-line setting. Rather than giving Etcamah from the outset, the accelerated approval allows the AZ drug to be used in combination with a CDK4/6 inhibitor upon detection of ESR1 mutation during first-line aromatase inhibitor and CDK4/6 therapy—prior to traditional radiographic disease progression. In a Friday statement, Galbraith said the Serena-4 readout “reinforces the importance of ESR1 testing for patients on first-line therapy.” The FDA had initially resisted that novel first-line switch approach because of a design flaw in AZ’s Serena-6 trial, but the agency came around to overrule a similarly negative advisory committee opinion. However, there’s a twist: In clearing Etcamah, the FDA has required AZ to run a separate randomized trial, essentially asking the company to re-do Serena-6 but with an optimal design. The agency specifically asked that AZ compare changing therapy to Etcamah during first-line treatment to using the oral SERD upon progression in the second-line setting, according to the FDA’s approval letter. That trial, along with the final overall survival results from Serena-6, form the FDA’s accelerated approval requirements to verify Etcamah’s benefit in its current indication. According to the FDA’s letter, AZ plans to finalize the new study’s protocol by April 2027. That means at least the current Serena-4 flop will not affect Etcamah’s accelerated approval status. Prior to Etcamah, oral SERDs have been approved as second-line HR+/HER2- breast cancer treatments but only for those whose tumors carry ESR1 mutations, as they’ve shown no clear benefit in those without the abnormalities. Untreated HR+/HER2- breast cancers rarely carry ESR1 mutations that could give oral SERDs a biological advantage over standard therapies. Over time, cancer cells adapt to anti-estrogen treatment by developing ESR1 mutations, making standard aromatase inhibitors ineffective. Existing CDK4/6 inhibitors are already very potent, and “you don’t see early on what is really an effect of an endocrine manipulation,” Roche’s deputy chief medical officer, Stefan Frings, M.D., Ph.D., told Fierce when explaining giredestrant’s first-line fail during ASCO 2026. Despite the first-line setback, Roche’s pharma chief, Teresa Graham, has argued that giredestrant’s multibillion-dollar peak sales potential remains intact by pointing to its opportunity as an adjuvant therapy for early-stage cancer. Similarly, Eli Lilly’s oncology chief, Jake Van Naarden, has also called the adjuvant setting what “this entire class of medicines was ever resourced” for. The Indianapolis pharma has its oral SERD, Inluriyo, currently approved as a second-line option. In its press release on Friday, AZ also highlighted its two phase 3 trials, Cambria-1 and -2, designed for patients at both intermediate and high risk of recurrence in the adjuvant setting. The two studies together encompass roughly 10,000 patients and are evaluating Etcamah as a monotherapy, in combination with CDK4/6 inhibitors and following CDK4/6 treatment in early HR+/HER2- breast cancer. The content above comes from the network. if any infringement, please contact us to modify.

AstraZeneca's Etcamah (camizestrant) has fallen short in a Phase III study testing whether the oral selective oestrogen receptor degrader (SERD) could outperform an aromatase inhibitor when used as an upfront treatment for advanced ER-positive, HER2-negative breast cancer.In the SERENA-4 trial, AstraZeneca said Etcamah plus Pfizer's Ibrance (palbociclib) produced a "numerical improvement" on the primary endpoint of progression-free survival versus anastrozole plus Ibrance, but the difference wasn't statistically significant.The result comes a week after the FDA granted Etcamah accelerated approval for use as part of biomarker-triggered switching strategy in which patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer are given the drug when an ESR1 mutation emerges during aromatase inhibitor (AI) plus CDK4/6 inhibitor therapy (see – Physician Views Preview: Can AstraZeneca's Etcamah carve out a new treatment paradigm in breast cancer?). That decision was based on data from the Phase III SERENA-6 study."Whilst we are disappointed by the SERENA-4 outcome, it sharpens our focus on maximising the number of patients who can benefit from Etcamah today based on SERENA-6 and reinforces the importance of ESR1 testing for patients on first-line therapy," said Susan Galbraith, EVP for Oncology Haematology R&D at AstraZeneca, in a release Friday."Early breast cancer represents an important opportunity, and we remain confident in the long-term potential of Etcamah in the early setting as we advance our broader programme," she added.Echoes of Roche rivalSERENA-4 enrolled 1371 adult patients with newly diagnosed Stage IV de novo or recurrent disease who had not received systemic treatment for advanced disease. The trial was testing whether replacing the AI component of standard first-line treatment with Etcamah could improve outcomes, with all patients also receiving Ibrance. Secondary endpoints include overall survival and PFS2.AstraZeneca said the safety profile was consistent with the known profiles of the individual drugs, with no new safety concerns, and that full data would be shared in due course.The result puts Etcamah in similar territory to Roche's rival oral SERD giredestrant, which also failed to significantly improve PFS in the Phase III persevERA trial toplined in March. That study compared giredestrant plus Ibrance with letrozole plus Ibrance in 992 patients receiving first-line treatment; it had also shown a numerical PFS improvement, but missed statistical significance.At this year's American Society of Clinical Oncology meeting, Roche reported median PFS was 33.1 months with giredestrant versus 28.2 months with letrozole, corresponding to a PFS benefit of 11% in favour of giredestrant (see – KOL Views Q&A: Breast cancer at ASCO – first take on AZ and Roche oral SERD debates, Gilead's Trodelvy TNBC data).'Manageable setback'RBC Capital analyst Trung Huynh called the SERENA-4 results a "manageable setback" that largely removes a near-term uncertainty without fundamentally altering the long-term investment case for Etcamah.James Gordon of Barclays likewise described the update as "well anticipated by the market," citing the earlier Roche failure as well as AstraZeneca's cautious commentary on SERENA-4.Earlier this year, Galbraith had highlighted a number of factors that could favour SERENA-4 over persevERA, including a first-line population enriched for endocrine sensitivity and a much larger patient population "sized for an effect size that will still be clinically meaningful in that population." For more, see – Spotlight On: First-line and adjuvant opportunities still beckon for AstraZeneca's camizestrant despite FDA setback.Meanwhile, AstraZeneca is also continuing to test Etcamah in earlier-stage disease in the Phase III CAMBRIA-1 and CAMBRIA-2 trials, which together are enrolling about 10,000 patients. The trials are designed for patients at both intermediate and high risk of recurrence in the adjuvant setting, evaluating Etcamah as monotherapy, together with CDK4/6 inhibitors and following CDK4/6 inhibitor treatment.According to Jefferies analysts, AstraZeneca estimates the drug could generate more than $5 billion in peak annual sales, with early breast cancer expected to account for most of that opportunity.