Pfizer and Arvinas gamble to shift breast cancer treatment paradigm
Breast cancer (BC) is the most prevalent cancer among women globally with two million diagnosed cases each year. Oestrogen receptor (ER) is expressed in most invasive BC cases (70 to 80%). Many therapies have therefore been developed to target this receptor, including fulvestrant, and more recently the CDK4/6 inhibitors, which act synergistically with endocrine therapies. But following exposure to endocrine and CDK4/6 inhibitor therapy, many patients quickly acquire ER mutations (ESR1m), leading to treatment resistance and leaving a significant unmet need.
Pfizer's and Arvinas' vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) ER degrader. The drug exploits the ubiquitin-proteasome system, degrading the mutant ER complex and greatly slowing growth and increasing tumour survivability. As the drug drives degradation and more specific targeting than small-molecule ER inhibitor receptors in preclinical studies, this class could leave a more profound effect with a tolerable safety profile. In the Phase II VERITAC trial, the drug was well-tolerated in a heavily CDK4/6 inhibitor pre-treated BC patient setting. Of 35 patients receiving 200mg of vepdegestrant, there was only one discontinuation and no dose reductions.
A press release by Arvinas announced the results from the Phase III trial, VERITAC-2. Significant improvements to progression-free survival were seen with a hazard ratio of 0.60 in the ESR1m patient subpopulation for patients receiving vepdegestrant monotherapy compared to fulvestrant. This improvement was not seen in the overall population, including non-ESR1m patients. These patients had previously experienced progression following CDK4/6 inhibitor treatment. The full trial results are to be announced on 31 May at the 2025 American Society of Clinical Oncology conference.
While initial safety and efficacy results are positive, the recent controversy surrounding the efficacy of CDK4/6 inhibitors in improving overall survival for breast cancer patients will hurt sales and the growth of the market share accessible to vepdegestrant. Regardless, the projected impact of vepdegestrant is suspected to be strong for the ESR1m population, which currently affects up to 39% of endocrine-resistant metastatic BC cases. GlobalData's analyst consensus forecasts estimate the drug to reach $1.64 billion in sales for metastatic breast cancer by 2031.
"Pfizer and Arvinas gamble to shift breast cancer treatment paradigm" was originally created and published by Clinical Trials Arena, a GlobalData owned brand.
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HR was estimated using the Cox proportional hazard model adjusted for stratification Assessments were conducted at baseline, weeks 4, 8 and 12 and then every 8 weeks until PFS2. Analysis conducted in patients with a baseline score and at least one post-baseline assessment. TTD in global health status/quality of life, an exploratory endpoint, was defined as the time from randomization to first deterioration that was confirmed at a subsequent timepoint measured using the European Organization for Research and Treatment of Cancer 30-item quality-of-life questionnaire (EORTC QLQ-30). Deterioration was defined as a decrease from baseline ≥16.6. HR was estimated using the Cox proportional hazard model stratified by time of ESR1 mutation detection (one test vs more than one test), and time from initiation of AI + CDK4/6i to randomization (<18 months vs. ≥18 months).iii HR was estimated using the Cox proportional hazard model adjusted for stratification factors. 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No new safety signals were identified and discontinuation rates were very low and similar in both arms, with 1% patients discontinuing camizestrant and 2% patients discontinuing an AI. Discontinuation of the CDK4/6 inhibitor occurred in 1% of patients in both arms of the trial. SERENA-6 is the first global, double-blind, registrational Phase III trial to use a circulating tumor DNA (ctDNA)-guided approach to detect the emergence of endocrine resistance and inform a switch in therapy before disease progression. The novel trial design used ctDNA monitoring at the time of routine tumor scans to identify patients for early signs of endocrine resistance and the emergence of ESR1 mutations. Following detection of an ESR1 mutation without disease progression, the endocrine therapy of patients was switched to camizestrant from ongoing treatment with an AI, while continuing combination with the same CDK4/6 inhibitor. Based on the results of the SERENA-6 Phase III trial, camizestrant in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) has been granted Breakthrough Therapy Designation (BTD) in the US by the Food and Drug Administration for the treatment of adult patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer upon emergence of ESR1 mutation during first-line endocrine-based therapy. Notes HR-positive breast cancer Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.1 More than two million patients were diagnosed with breast cancer in 2022, with more than 665,000 deaths globally.1 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.2 HR-positive breast cancer, characterized by the expression of estrogen or progesterone receptors, or both, is the most common subtype of breast cancer with 70% of tumors considered HR-positive and HER2-negative.2 ERs often drive the growth of HR-positive breast cancer cells.3 Globally, approximately 200,000 patients with HR-positive breast cancer are treated with a medicine in the 1st-line setting; most frequently with endocrine therapies that target estrogen receptor (ER)-driven disease, which are often paired with CDK4/6 inhibitors.4-6 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.6 Once this occurs, treatment options are limited and survival rates are low with 35% of patients anticipated to live beyond five years after diagnosis.2,6,7 Mutations in the ESR1 gene are a key driver of endocrine resistance and are widely tested for in clinical practice at time of disease progression on 1st-line therapies.8,9 These mutations emerge during treatment of the disease, becoming more prevalent as the disease progresses and are associated with poor outcomes.8,9 Approximately 30% of patients with endocrine sensitive HR-positive disease develop ESR1 mutations during 1st-line treatment without disease progression.4 The optimization of endocrine therapy and overcoming resistance to enable patients to continue benefiting from these treatments, as well as identifying new therapies for those who are less likely to benefit, are active areas of focus for breast cancer research. SERENA-6 SERENA-6 is a Phase III, double-blind, randomized trial evaluating the efficacy and safety of camizestrant in combination with a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) versus treatment with an AI (anastrozole or letrozole) in combination with a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) in patients with HR-positive, HER2-negative advanced breast cancer (patients with either locally advanced disease, or metastatic disease) whose tumors have an emergent ESR1 mutation. The global trial enrolled 315 adult patients with histologically confirmed HR-positive, HER2-negative advanced breast cancer, undergoing treatment with an AI in combination with a CDK4/6 inhibitor as 1st-line treatment. The primary endpoint of the SERENA-6 trial is PFS as assessed by investigator, with secondary endpoints including OS, and PFS2 by investigator assessment. Camizestrant Camizestrant is an investigational, potent, next-generation oral selective estrogen receptor degrader (SERD) and complete ER antagonist that is currently in Phase III trials for the treatment of HR-positive breast cancer. AstraZeneca's broad, robust and innovative clinical development program, including the SERENA-6, SERENA-4, CAMBRIA-1 and CAMBRIA-2 trials, is evaluating the safety and efficacy of camizestrant when used as a monotherapy or in combination with CDK4/6 inhibitors to address a number of areas of unmet need in HR-positive, HER2-negative breast cancer. Camizestrant has demonstrated anti-cancer activity across a range of preclinical models, including those with ER-activating mutations. In the SERENA-2 Phase II trial, camizestrant demonstrated PFS benefit versus fulvestrant irrespective of ESR1 mutation status or prior treatment with CDK4/6 inhibitors in patients with ER-positive locally advanced or metastatic breast cancer, previously treated with endocrine therapy. The SERENA-1 Phase I trial demonstrated that camizestrant is well tolerated and has a promising anti-tumor profile when administered alone or in combination with palbociclib, ribociclib and abemaciclib; three widely used CDK4/6 inhibitors. AstraZeneca in breast cancer Driven by a growing understanding of breast cancer biology, AstraZeneca is challenging, and redefining, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death. AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumor environment. With fam-trastuzumab deruxtecan-nxki, a HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive, HER2-low and HER2-ultralow metastatic breast cancer, and are exploring its potential in earlier lines of treatment and in new breast cancer settings. In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines fulvestrant and goserelin and aims to reshape the HR-positive space with first-in-class AKT inhibitor, capivasertib, the TROP-2-directed ADC, datopotamab deruxtecan-dlnk and next-generation oral SERD and potential new medicine camizestrant. PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with Merck & Co., Inc. (MSD outside the US and Canada) continue to research olaparib in these settings and to explore its potential in earlier disease. AstraZeneca is also exploring the potential of saruparib, a potent and selective inhibitor of PARP1, in combination with camizestrant in BRCA-mutated, HR-positive, HER2-negative advanced breast cancer. To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is collaborating with Daiichi Sankyo to evaluate the potential of datopotamab deruxtecan-dlnk alone and in combination with immunotherapy durvalumab. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca's innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit and follow the Company on social media @AstraZeneca. References Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4. doi: 10.3322/caac.21834. National Cancer Institute. Cancer Stat facts: Female breast cancer subtypes. Available at: Accessed June 2025. Scabia V, et al. Estrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor. Nat Commun. 2022; 10.1038/s41467-022-30898-0. Cerner CancerMPact database. Accessed June 2025. Lin M, et al. Comparative Overall Survival of CDK4/6 Inhibitors Plus Endocrine Therapy vs. Endocrine Therapy Alone for Hormone receptor-positive, HER2-negative metastatic breast cancer. J Cancer. 2020; 10.7150/jca.48944. Lloyd M R, et al. Mechanisms of Resistance to CDK4/6 Blockade in Advanced Hormone Receptor–positive, HER2-negative Breast Cancer and Emerging Therapeutic Opportunities. Clin Cancer Res. 2022; 28(5):821-30. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines). Available at: Accessed June 2025. Brett O, et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor‑positive breast cancer. Breast Cancer Res. 2021; 23:85. Zundelevich, A, et al. ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis. Breast Cancer Res. 2020; 22:16. US-101612Last updated 06/25 View source version on Contacts Media Inquiries Fiona Cookson +1 212 814 3923Jillian Gonzales +1 302 885 2677 US Media Mailbox: usmediateam@
