One of the most frequently diagnosed cancers in women globally, breast cancer, is a leading cause of cancer mortality in women worldwide. Up to two million new breast cancer cases were diagnosed in 2019, representing 11.6% of all cancers. Despite progress with drug therapies, 626,679 deaths were reported in 2018, representing 6.6% of all cancer deaths. Of these cancer cases, approximately 80% of them are determined to be what is known as hormone receptor-positive. Enter AstraZeneca, the UK-based global pharmaceutical company and its oncology research teams, working tirelessly to lead a revolution in oncology precision therapy. Confidence is building within the organization in a next-generation oral selective-estrogen-receptor degrader (SERD) known as AZD9833. Unfortunately for many breast cancer patients today, treatments for those patients with estrogen receptor-positive breast cancer endure invasive procedures. But importantly, this breakthrough endocrine therapy, developed internally by AstraZeneca scientists, offers precise and targeted treatment that, if proven to be safe and effective throughout the clinical trials process, will materially improve breast cancer treatment. To learn more about this promising drug development initiative, TrialSite’s Daniel O’Connor spoke with Teresa Klinowska, Global Product Leader in Late Stage Oncology Research & Development at the global pharmaceutical company. Thanks to Dr. Klinowska’s insights, TrialSite summarizes the positive findings of the recent SERENA-1 clinical trial presented at the 2020 San Antonio Breast Cancer Symposium. A considerable breakthrough for hormone receptor-positive breast cancer patients could be on the horizon.
TrialSite was founded a couple of years ago to break down, distill, and translate important biomedical research information into easier-to-read, consumable chunks, all part of an effort to empower patients and health care professionals alike as medicine moves into the value-based, consumer-driven paradigm. The summaries presented below were inspired by a productive dialogue between TrialSite’s founder, Daniel O’Connor, and Dr. Klinowska.
Earning her Ph.D. in cell biology and embryonic development at the University of Manchester, and then working in academia and biotech startups, Dr. Teresa Klinowska joined AstraZeneca to leverage the company’s global resources and help as many patients as she possibly could. She currently works as Global Product Leader in Late-Stage Oncology Research & Development. As TrialSite’s O’Connor learned, Dr. Klinowska has developed a notable track record of success, having participated in successful drug development initiatives for lung cancer and now breast cancer. The latter is especially close to home for the scientists, as she has had multiple family members receive that diagnosis. The mission is both personal and professional.
What is Hormone Receptive-Positive? What is SERD?
Approximately 80% of all breast cancer patients are classified as “ER-positive.” This means that the cancer cells grow due to the influence or direction of estrogen. Nearly 65% of all of these cases are also deemed “PR-positive,” meaning another hormone also triggers growth—progesterone. Selective estrogen receptor degraders (SERD) are a class of drugs that bind to the estrogen receptor (ER) and eventually lead to a “downregulated” status of said receptor. Used in the treatment of estrogen receptor-sensitive or progesterone receptor-sensitive breast cancer, the only currently-marketed SERD is AstraZeneca’s fulvestrant. According to a recent scholarly report, “SERDS are a novel class of compounds capable of reducing the ERα protein level and blocking ER activity. Considered a significant therapeutic approach in the treatment of ER+ breast cancer in both early-stage and more advanced drug-resistant cases.”AstraZeneca has been a pioneer drug developer with this class of treatment, with their fulvestrant approved by the US FDA for breast cancer patients whose cancer has progressed on antihormonal agents. Due to the limited number of effective drugs for the treatment of breast cancer, a race is now on for compelling SERD’s with superior activity and bioavailability.
What is AZD9833?
This is a drug in development (currently Phase 2) for advanced breast cancer, meaning the cancer has come back in the same place after treatment and has metastasized. The movement toward more precision-based therapies is in part for those patients whose breast cancer cells are in fact sensitive to the hormone receptor positive effect and lack receptors for a protein called HER2—a condition known as HER2 negative. Endocrine resistance is a common problem in ER-positive breast cancer, and presently the only approved SERD is fulvestrant, but one of a number of issues or challenges is that not only must it be administered intramuscularly (in the buttocks), but that it has poor bioavailability.
Therefore, the idea behind this novel oral SERD is that first and foremost, it would be far more convenient for the patient (orally administered), but also would be able to potentially achieve higher blood levels and increase ER degradation with the aim of improving overall clinical benefit. The experimental compound represents a next-generation, based on continuous investment, commitment, and learning.
Dr. Klinowska emphasized the importance of continuous commitment to advance and improve the condition of the patient. To offer individuals combatting advanced breast cancer the possibility for an oral alternative with greater levels of effectivity, for example, represents not only a path to a higher quality of life but also, given the early performance signals, promise for other cancer patients.
Relevance of the SERENA-1 Phase 1 clinical trial
SERENA-1 (NCT03616587) is a multicenter, dose-escalation and expansion, first-in-human study designed to investigate the safety and tolerability of AZD9833, both as monotherapy and also in combination with fulvestrant. The patients enrolled in this study were required to have at least one prior line of endocrine therapy and no more than two lines of chemotherapy for the advanced-disease setting. The study team was able to enroll 98 patients on to the monotherapy cohort, and approximately 48 patients on to the combination cohort. Again, these patients were pretreated for their metastatic hormone receptor-positive breast cancer, with the median number of treatments associated with the monotherapy arm of the study at three and those in the combination arm had two prior treatments. Slightly over 50% of each study arm cohort (again monotherapy or combination therapy) had already progressed on prior Fulvestrant. Approximately 70% of the patients in the combination arm of this study had received a CDK4/6 inhibitor.
Safety Reports from SERENA-1
Notably, the majority of the events identified were grade 1. TrialSite reminds that adverse events are an important way to identify the safety of a novel drug. They describe the patient/event outcome or action criteria associated with the events that pose a threat to a patient’s life or functioning (mild, moderate, severe, or life-threatening). Grade 1 events are the mildest on the measurement scale. There were some visual disturbances, but in both cohorts, this didn’t affect daily living (98% in the monotherapy cohort and 94% in the combination cohort).
Efficacy Reports Look Promising
Monotherapy clinical benefit rate 35%, with combination just over 50%. Clinical benefit CDk4/6 combination 71% clinical-benefit rate. As was presented recently at the 2020 San Antonio Breast Cancer Symposium, AZD9833 evidence encouraging efficacy and a dose-dependent safety profile as both monotherapy and/or in combination with Palbociclib. Key takeaway: AZD9883 is a new oral SERD that is well tolerated, and early data suggest good clinical efficacy even among pretreated metastatic hormone receptor positive disease. The hope: this could be a breakthrough new treatment option for patients with metastatic hormone receptor positive disease. AstraZeneca will continue to invest, mobilizing its talented scientists and researchers in partnership with CROs and trial site organizations to continue the investigational program.
Other Studies Involving AZD9833
Due to the positive takeaways from SERENA-1, AstraZeneca now invests in Phase 2 clinical trials with plans on expanding to include comprehensive Phase 3 studies involving more patients. This would lead to the chance for FDA approval and commercialization, hence access on the market. What follows is a summary of studies disclosed in Clinicaltrials.gov.
Other Phase 1 studies
In addition to SERENA-1 AstraZeneca disclosed other Phase 1 studies involving AZD9833. In an AstraZeneca-sponsored Phase 1 study (NCT04541433) that just started in Sept. 2020, the investigators seek to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of AZD9833 in Japanese women with endocrine-resistant ER+HER2-breast cancer that is not amenable to treatment with curative intent. In another Phase 1 study (NCT04546347) AstraZeneca partners with the contract research organization (CRO) Quotient Sciences to identify and compare how much of the investigational product formulation (recipes) are taken up in the blood when given as a tablet, a solution, and as an injection directly into the vein. As part of this study the dose is radiolabeled, meaning that it contains a radioactive component that helps the investigators track where the drug has traveled in the body. The investigators her also seek to evaluate the effect of food when taking the investigational product in the form of the tablet. Safety and tolerability are also assessed in this endeavor that started om September 2020 and runs till December 2020.
Phase 2 Studies
AstraZeneca now sponsors two important Phase 2 clinical trials comparing the efficacy and safety of three doses of the investigational product known as AZD9833 versus fulvestrant and a Phase 2 study involving a pre-surgical ‘window of opportunity study is ongoing.
AstraZeneca has commenced SERENA-2 (NCT04214288), including 288 patients with Advanced ER-Positive HER2-Negative Breast Cancer. The study was initiated in the spring, and it involves post-menopausal women with histologically or cytologically confirmed metastatic (or loco-regionally recurrent ER-positive HER2-negative breast cancer) before randomization and fulfilling the inclusion criteria. Once patients are screened, confirmed, and deemed eligible, they will be randomly assigned in a 1:1:1:1 ratio to receive one of the following four treatments, consisting of four-week treatment cycles. The dosage groups for AZD9833 include Dose A, B, C and Fulvestrant (500mg). The study is now underway at trial site centers in the United States, Belgium, Poland, Germany, Hungary, Mexico, and Israel. The study started on April 22, 2020, and its estimated primary completion target is March 23, 2022.
As of November 2020, AstraZeneca also sponsors SERENA-3 (NCT04588298), a Phase 2 clinical trial occurring in approximately 20 trial centers located in three countries and including two stages. This randomized, open-label, parallel-group, pre-surgical trial investigates the biological effects, safety, tolerability, and pharmacokinetics (PK) of different doses of oral AZD9833 in post-menopausal (and possibly pre-menopausal) women with primary breast cancer. Once patients are deemed eligible, they are enrolled across treatment groups. In state one, up to 24 evaluable participants across two treatment groups are enrolled. AstraZeneca has set up a Safety and Data Monitoring Committee that will convene to review stage 1 data and determine if further treatment groups are required for stage 2. This latter stage would include up to 60 evaluable patients across up to 5 treatment groups. The study’s estimated primary completion date is targeted for October 2022.
Teresa Klinowska, Global Product Leader in Late State Oncology Research & Development
Call to Action: For those who are diagnosed with advanced breast cancer (or have a loved one that has been), meaning the cancer has come back and metastasized, and who are identified as hormone receptor-positive, there are now current clinical trials associated with this investigational drug to monitor. Ask your oncologist/physician about these studies and the implications for the future.