Results from the Phase 2 SERENA-2 trial shows that camizestrant (previously known as AZD9833), a next-generation oral selective estrogen receptor degrader (ngSERD) and and pure ERα antagonist, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) at both 75mg and 150mg dose levels versus fulvestrant (Faslodex®; AstraZeneca) 500mg in post-menopausal patients with estrogen receptor (ER)-positive locally advanced or metastatic breast cancer, previously treated with endocrine therapy.

Selective estrogen receptor degraders or SERDs are a type of drugs which bind to the estrogen receptor (ER) and, in the process, cause the ER to be degraded or down-regulated. Generally, SERDs are used to treat estrogen receptor-sensitive or progesterone receptor-sensitive breast cancers, along with older classes of drugs like selective estrogen receptor modulators (SERMs) and aromatase inhibitors.

The results of the SERENA-2 study were presented in an oral presentation at the 2022 San Antonio Breast Cancer Symposium (SABCS), held December 6 – 10 in San Antonio, Tx.

HR-positive breast cancer
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.[1] More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.[1] HR-positive breast cancer (expressing estrogen or progesterone receptors, or both) is the most common subtype of breast cancer with approximately 70% of breast cancer tumors considered HR-positive and HER2-low or negative.[2]

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The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER), [3] and endocrine therapies that target ER-driven disease are widely used as firts-line treatment in the advanced setting, and often paired with cyclin-dependent kinase (CDK) 4/6 inhibitors.[4][5]

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However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.[5] Once this occurs, the treatment options are limited [5] – with chemotherapy being the current standard of care [6] – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.[2]

Optimizing endocrine therapy and overcoming resistance for patients with ER-driven disease at all stages of treatment as well as identifying new therapies for those who no longer have ER-driven disease are active areas of focus for breast cancer research.

SERENA-2 trial
Camizestrant, which is being developed by AstraZeneca, is in investigated the SERENA-2 study. This study is a randomized, open-label, parallel group, multicenter Phase 2 trial evaluating camizestrant in advanced ER-positive, HER2-negative breast cancer.

The primary endpoints in the study include progression free survival (PFS) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 for 75mg camizestrant versus fulvestrant and for 150mg camizestrant versus fulvestrant. 240 patients were randomized to receive camizestrant or fulvestrant until disease progression. Secondary endpoints include safety, objective response rate and clinical benefit rate at 24 weeks.

Study results
In the overall population, camizestrant significantly reduced the risk of disease progression or death by 42% at a 75mg dose (based on a hazard ratio [HR] of 0.58, 90% confidence interval [CI] 0.41-0.81; p=0.0124; median PFS of 7.2 versus 3.7 months) and 33% at a 150mg dose (HR 0.67, 90% CI 0.48-0.92; p=0.0161; median PFS of 7.7 versus 3.7 months) compared to fulvestrant, the current SERD standard of care.

Mafalda Oliveira MD, PhD, is a medical oncologist at the Medical Department of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO) in Barcelona since 2011. She has completed a Master in Clinical Research in June 2013 and a PhD in Medicine in July 2017, both at the Universidad Autònoma de Barcelona. Oliveira’s research interest focuses on the study of the molecular alterations and evolution of metastatic breast cancer, the clinical development of new drugs (especially by designing clinical trials with innovative biological hypotheses), and on the application of liquid biopsies as diagnostic, predictive, and prognostic tools in breast cancer. She is involved as Principal Investigator in multiple phase I, phase II, and phase III clinical trials in breast cancer, with drugs that target the PI3K/AKT/mTOR pathway, CDK4/6 inhibitors, oral SERDs, new epigenetic drugs, ADCs, and cancer immunotherapy drugs.

Among the prespecified subgroup of patients with ESR1 mutations – comprising 36.7% of the trial population – camizestrant showed a 67% reduction in the risk of disease progression or death at a 75mg dose (HR 0.33, 90% CI 0.18-0.58; median PFS of 6.3 versus 2.2 months) and a 45% reduction at a 150mg dose (HR 0.55, 90% CI 0.33-0.89; median PFS of 9.2 versus 2.2 months) compared to fulvestrant. Efficacy was also seen in patients without a detectable ESR1 mutation, with a 22% and 24% reduction in the risk of disease progression or death (HR 0.78, 90% CI 0.50-1.22 and HR 0.76, 90% CI 0.48-1.20) respectively for the 75mg and 150mg dose levels.

Clinically meaningful
A clinically meaningful PFS benefit was also observed across other prespecified subgroups, including in patients with previously treated with prior cyclin-dependent kinase (CDK) 4/6 inhibitors, those with lung and/or liver metastases and those with ER-driven disease.

Safety and tolerability
Camizestrant was generally well tolerated, and its safety profile was consistent with that observed in previous trials with no new safety signals identified. The most frequent treatment-emergent adverse events (TEAEs) were photopsia (12.2%, 24.7%, 35.0% and 0%) and bradycardia (5.4%, 26.0%, 40.0% and 0%), for 75mg, 150mg or 300mg camizestrant or fulvestrant, respectively, all of which were Grade 1 or 2. TEAEs at Grade 3 or higher occurred in 1.4%, 2.7%, 5.0% and 1.4% of patients in the 75mg, 150mg and 300mg camizestrant or fulvestrant arms, respectively, with only two patients in the 75mg camizestrant arm and no patients in the 150mg, 300mg camizestrant or fulvestrant arms discontinuing therapy due to TEAEs.

Cristian Massacesi, MD, Chief Medical Officer & Oncology Chief Development Officer, Oncology R&D, AstraZeneca.

A new treatment option
“These data reflect an important step toward a potential new treatment option for patients with advanced ER-positive disease,” explained Mafalda Oliveira, MD, Ph.D., Vall d’Hebron Hospital and Vall d‘Hebron Institute of Oncology in Barcelona, Spain, and lead investigator for the SERENA-2 Phase II trial.

“Based on the SERENA-2 results, camizestrant was well tolerated at both doses and significantly improved patient outcomes, nearly doubling median progression-free survival in this setting compared with the current SERD standard of care,” Oliveira added.

“SERENA-2 showed a meaningful improvement over fulvestrant, demonstrating the potential of camizestrant, our next-generation SERD, to optimize outcomes for patients with advanced ER-driven breast cancer, irrespective of ESR1 mutation status and prior treatment with CDK4/6 inhibitors,” noted Cristian Massacesi, MD, Chief Medical Officer & Oncology Chief Development Officer, Oncology R&D, AstraZeneca.

“Our focus on bringing new medicines to patients across the breast cancer spectrum is unwavering and we look forward to additional findings from our ongoing Phase 3 development program for camizestrant including SERENA-4 and SERENA-6,” Massacesi concluded.

Summary of results of the phase 3 SERENA-2 study

Efficacy measureCamizestrant (75mg) Camizestrant (150mg)Fulvestrant (500mg)
Primary endpoint
Overall population (n)747373
Median PFS (months)7.27.73.7
Adjusted HR (90% CI)0.58 (0.41-0.81)0.67 (0.48-0.92)
P-value0.0124*0.0161*
Prespecified sub-populations of interest
ESR1m detected (n)222635
Median PFS (months)6.39.22.2
Adjusted HR (90% CI)0.33 (0.18-0.58)0.55 (0.33-0.89)
ESR1m not detected (n)514637
Median PFS (months)7.25.87.2
Adjusted HR (90% CI)0.78 (0.50-1.22)0.76 (0.48-1.20)
Prior treatment with CDK4/6 inhibitors (n)383737
Median PFS (months)5.53.82.1
Adjusted HR (90% CI)0.49 (0.31-0.75)0.68 (0.44-1.04)
Presence of lung and/or liver metastasis (n)434343
Median PFS (months)7.25.62.0
Adjusted HR (90% CI)0.43 (0.28-0.65)0.55 (0.37-0.82)
Evidence of ER-driven disease (n)505353
Median PFS (months)7.412.03.2
Adjusted HR (90% CI)0.53 (0.35-0.79)0.58 (0.39-0.86)

*Statistically significant; HR, hazard ratio (adjusted for stratification factors [prior use of CDK4/6i and presence of lung and/or liver metastases]); CI, confidence interval; PFS, progression free survival; ESR1m, ESR1 mutation.

Ongoing studies
In addition to the SERENA-2 study, camizestrant is investigated in a number additional clinical studies in advanced breast cancer, including:

  • the Phase 1 SERENA-1 trial demonstrated that camizestrant is well tolerated and has a promising anti-tumor profile when administered alone or in combination with the CDK4/6 inhibitor palbociclib (Ibrance®, Pfizer).
  • the Phase 3 SERENA-4 trial is evaluating camizestrant in combination with the CDK4/6 inhibitor palbociclib for the first-line treatment of patients with HR-positive, locally advanced or metastatic breast cancer.
  • the Phase 3 SERENA-6 study is assessing camizestrant in combination with CDK4/6 inhibitors for the firstst-line treatment of patients with HR-positive metastatic breast cancer who have developed detectable ESR1 mutations during treatment with aromatase inhibitors;

The indication sought for SERENA-6 has been granted Fast Track Designation by the US Food and Drug Administration.

Clinical trials
Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer. (SERENA-1) – NCT03616587
A Comparative Study of AZD9833 Versus Fulvestrant in Women With Advanced ER-Positive HER2-Negative Breast Cancer (SERENA-2) – NCT04214288
A Trial to Find Out How Well Camizestrant Together With Palbociclib Works in Participants With a Type of Advanced Breast Cancer That Has ER Proteins But no Overexpression of HER2 Protein. (SERENA-4) – NCT04711252
Phase III Study to Assess AZD9833+ CDK4/6 Inhibitor in HR+/HER2-MBC With Detectable ESR1m Before Progression (SERENA-6) – NCT04964934

Highlights of Prescription Information
Fulvestrant (Faslodex®; AstraZeneca) [Prescribing Information]
Palbociclib (Ibrance®, Pfizer) [Prescribing Information]

References
[1] Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.
[2] National Cancer Institute. Surveillance, Epidemiology and End Results Cancer Stat Facts: Female Breast Cancer Subtypes. Online. Last accessed December 7, 2022.
[3] 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.
[4] 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.
[5] 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.
[6] National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines). Online. Last accessed on December 7, 2022.

Featured image: Attendees at the San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX, December 6 – 10, 2022. Photo courtesy: © 2022 AACR/SABCS MedMeetingImages/Todd Buchanan. Used with permission.

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