Next-generation SERD camizestrant significantly improves progression-free survival vs. fulvestrant in advanced ER+ HER2- breast cancer

• Presented at the 45^th annual San Antonio Breast Cancer Symposium® (2022 SABCS®), results of the phase II SERENA-2 randomized, multi-dose clinical trial show that the next-generation oral selective estrogen receptor degrader (SERD) camizestrant significantly improves progression-free survival versus fulvestrant in patients with estrogen receptor-positive, HER2-negative breast cancer.

• SERENA-2 is the first phase II study to evaluate a next-generation SERD at several dose levels compared with fulvestrant in post-menopausal women with advanced ER+ HER2- breast cancer with disease recurrence or progression after first-line endocrine therapy for advanced disease.

• Data presented by Mafalda Oliveira, a Senior Consultant at the Vall d’Hebron University Hospital’s Medical Oncology Department and Clinical Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Breast Cancer Group, show that in the overall population, camizestrant significantly reduced the risk of disease progression or death by 42% at the 75mg dose and by 33% at 150mg compared to fulvestrant.

• Fulvestrant, which has been used to treat patients with ER-positive breast cancer for almost twenty years, is currently the only SERD clinically approved for the treatment of postmenopausal patients with ER+ metastatic breast cancer after progression on prior therapy. Its intramuscular route of administration, low bioavailability, and eventual cancer drug resistance represent clinical limitations.

• Selected for inclusion in the 2022 SABCS® media program, results of the phase II SERENA-2 study point to oral camizestrant as a promising contender in improving currently available endocrine therapies for patients with ER-driven breast cancer.

Selected as late breaking data and featuring in the meeting’s media program, results of the randomized, multi-dose phase II SERENA-2 trial ⁽¹⁾ were presented by Mafalda Oliveira, a Senior Consultant at the Vall d’Hebron University Hospital’s Medical Oncology Department and Clinical Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Breast Cancer Group, at the 2022 San Antonio Breast Cancer Symposium® (SABCS®), December 6-10, San Antonio, Texas (USA). Findings show that camizestrant, an oral next generation selective estrogen receptor degrader (ngSERD), significantly improves progression-free survival versus fulvestrant in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer.

According to recent statistics ⁽²⁾ female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases in 2020. Nearly 80% of all breast cancers are ER+, the majority of which are HER2-.Therapies targeting the estrogen signaling axis, including aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders/down-regulators (SERDs) continue to be the cornerstone of therapy for patients diagnosed with ER+ breast cancer.

Despite their significant impact on the management of this disease, cancer drug resistance to existing treatments remains a major obstacle in achieving more durable responses. These tumors commonly acquire a mutation in the ER gene, ESR1. SERDs such as fulvestrant can block ER activity in these cases. Fulvestrant is the only SERD approved to date for breast cancer treatment and must be administered by injection in a physician’s office.

“ESR1-mutated cancers have constitutive activation of ER and worse prognosis. Seeking out more effective treatment options for these patients represents an unmet clinical need. Orally bioavailable SERDs that can antagonize and degrade ER are currently under development, including camizestrant. Our data show that this next-generation SERD is stepping up in improving patient outcomes,” says Mafalda Oliveira, a Senior Consultant at the Vall d’Hebron University Hospital’s Medical Oncology Department and Clinical Investigator of VHIO’s Breast Cancer Group, Vall d’Hebron Barcelona Hospital Campus.

Phase II SERENA-2: pointing to the promise of camizestrant

Led by Mafalda Oliveira, the randomized, multi-dose SERENA-2 study is the first phase II trial to evaluate a next-generation SERD at several dose levels versus fulvestrant in post-menopausal women with advanced ER+ HER2- breast cancer with disease recurrence or progression after prior endocrine therapy.

“Results of this study show that treatment with oral camizestrant at both 75 and 150 milligram dose levels achieves statistically significant and clinically meaningful benefit in progression free survival in patients with and without ESR1 mutations, and was well tolerated,” observes Mafalda Oliveira, international coordinator of this present study and co-developer of this new drug.

In the overall study population, camizestrant significantly reduced the risk of disease progression or death by 42% at the 75 mg dose (median PFS of 7.2 vs 3.7 months) and by 33% at the 150 mg dose (median PFS 7.2 vs 3.7 months), compared with fulvestrant. Among patients with an ESR1 mutation at baseline, camizestrant showed a 67% reduction in the risk of disease progression or death with a 75 mg dose and a 45% reduction with 150 mg compared to those patients who received fulvestrant. Efficacy was also observed in patients without a detectable ESR1 mutation, with a 22% and 24% reduction in the risk of disease progression or death with 75 mg and 150 mg, respectively.

Camizestrant also demonstrated improved disease control in patients with lung or liver metastases, showing a 67% and 45% reduction in the risk of disease progression or death at 75mg and 150mg doses, respectively. In those patients who had received prior treatment with a CDK4/6 inhibitor, camizestrant showed a 51% reduction in the risk of disease progression or death at the 75 mg dose (with a median PFS of 5.5 vs 2.1 months) and a 32% reduction in the risk of disease progression or death with 150 mg (from 3.8 vs 2.1 months).

“These positive results and compelling safety profile highlight the potential of this next-generation SERD, support its continued development in treating hormone receptor-positive breast cancer, and could reignite enthusiasm for the development of oral SERDs in breast cancer,” concludes Oliveira.

Encouraged by these data, the investigators are now following up on these results with two phase III clinical trials, both in combination with a CDK4/6 inhibitor.  One study is assessing the efficacy of camizestrant versus an aromatase inhibitor, in combination with palbociclib, as first-line therapy in the advanced setting, and the other is evaluating the benefit of treatment acceleration to camizestrant when ESR1 mutations are detected in circulating tumor DNA (ctDNA).

This study was funded by AstraZeneca. Oliveira has received personal funding from AstraZeneca, Guardant Health, Roche, Merck Sharp & Dohme, Pfizer, Seagen, iTeos Therapeutics, Eisai, Novartis, Relay Therapeutics, and Gilead.

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1. GS3-02: Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial. Oliveira M, Pominchuk D, Nowecki Z, Hamilton E, Kulyaba Y, Andabekov T, Hotko Y, Melkadze T, Nemsadze G, Neven P, Semegen Y, Vladimirov V, Zamagni C, Denys H, Forget F, Horvath Z, Nesterova A, Bennett M, Kirova B, Klinowska T, Lindemann JPO, Lissa D, Mathewson A, Morrow CJ, Traugottova Z, van Zyl R, Arkania E. 

Session details:

San Antonio Breast Cancer Symposium®

GENERAL SESSION #3 – Hall 3

Date: Thursday 8 December 2022
Moderators: Carey K. Anders, William M. Sikov

Session time: 08:30am – 11:00am CT.

2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. 

About the San Antonio Breast Cancer Symposium®

Since 1977, the San Antonio Breast Cancer Symposium® (SABCS®) has been the leading scientific conference for basic scientists, physician-scientists, clinical investigators and breast care providers, and advocates seeking an exchange of new information in experimental biology, etiology, prevention, diagnosis, and therapy of premalignant breast disease and breast cancer. Founded, owned, and operated by UT Health San Antonio, the symposium has grown to a five-day event attended by an international audience of academic investigators and private physicians from over 80 countries to attain information through abstract presentations, panel discussions, research findings, and state-of-the-art educational sessions. UT Health San Antonio, with co-sponsor the American Association for Cancer Research, supports SABCS, which provides education and accessibility to the latest information regarding the prevention, diagnosis, and treatment of premalignant breast cancer and breast disease. For more information on SABCS, visit www.sabcs.org.