A key goal of breast cancer research is to translate laboratory findings to doctors in the clinic. Clinical trials playing a vital role in this process. Conferences such as the San Antonio Breast Cancer Symposium (SABCS) provide a venue for researchers to share results, including from these trials.
Here BCRF reports several important developments from breast cancer clinical trials that have the potential to improve patient care and outcomes.
EMBER3
Results from the EMBER3 (NCT04975308) clinical trial suggest that while oral imlunestrant alone may offer benefits for patients with specific genetic profiles, combining it with abemaciclib (Verzenio®) could prove a more effective treatment option for a broader group of patients. This combination therapy could address limitations associated with current treatments like fulvestrant (Faslodex®), which are delivered by injection and may be less effective in patients with ESR1 mutations.
Dr. Komal Jhaveri of Memorial Sloan Kettering Cancer Center presented the results of this phase III trial evaluating oral imlunestrant, a next-generation selective estrogen receptor degrader (SERD) in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer previously treated with endocrine therapy. The study assessed this SERD as a monotherapy and in combination with CDK4/6 inhibitor.
The trial demonstrated that imlunestrant monotherapy significantly improved progression-free survival (PFS) compared to standard endocrine therapy in patients with ESR1 mutations, with a median PFS of 5.5 months with imlunestrant alone versus 3.8 months for chemotherapy—a 38 percent reduction in risk of progression or death. In the overall patient population, imlunestrant monotherapy did not show a statistically significant benefit.
Notably, the combination of imlunestrant and abemaciclib enhanced PFS to 9.4 months across all patients, representing a 43 percent reduction in the risk of progression or death, regardless of ESR1 mutation status. Furthermore, imlunestrant as a monotherapy or in combination with abemaciclib yielded PFS benefit across subgroups where breast cancer had metastasized to the lungs or liver, prior CDK4/6 inhibitors were used, or PI3K pathway mutations were present.
PATINA
The investigators from the phase 3 PATINA trial (NCT02947685) reported that incorporating palbociclib (Ibrance®) into the treatment regimen for hormone receptor (HR)–positive, HER2-positive metastatic breast cancer can significantly delay disease progression, potentially offering a new standard of care for this patient population.
Dr. Otto Metzger of the Dana-Farber Cancer Institute presented this study which evaluated the efficacy and safety of adding the CDK4/6 inhibitor palbociclib to standard anti-HER2 therapy and endocrine therapy in patients with HR-positive, HER2-positive metastatic breast cancer.
The study enrolled 518 participants who had completed chemotherapy without disease progression and were randomized to receive standard-of-care therapy alone or in combination with palbociclib.
The trial demonstrated a greater than 15-month improvement in PFS for patients receiving palbociclib (the median PFS was 44.3 months in the palbociclib arm compared to 29.1 months in the control arm). This benefit was observed despite the control arm median PFS exceeding initial expectations and translates to a 26 percent reduction in the risk of progression.
Codifying the risk-reducing benefit of surgeries for BRCA-mutated breast cancers
Dr. Matteo Lambertini of University of Genova-IRCCS Policlinico San Martino Hospital presented findings from an international, multicenter study examining the impact of risk-reducing surgeries on survival outcomes in BRCA mutation carriers diagnosed with early-onset breast cancer. The study analyzed data from 5,290 patients ages 40 or under who were diagnosed with BRCA1- or BRCA2-mutated, stage 1 to 3 invasive breast cancer. Among these patients, 2,911 underwent risk-reducing mastectomy, 2,782 underwent risk-reducing salpingo-oophorectomy, and 1,804 underwent both procedures.
Patients who underwent mastectomy experienced a 35 percent reduction in the risk of death and a 42 percent reduction in the risk of breast cancer recurrence or a second primary malignancy. Oophorectomy was associated with a 42 percent reduction in the risk of death and a 32 percent reduction in the risk of breast cancer recurrence or a second primary malignancy. The survival benefit of oophorectomy varied by BRCA mutation type, with a greater reduction in risk of death in patients with BRCA1 mutation (56 percent) compared to the BRCA2-mutated group (15 percent). This procedure also showed varied results by subtype: patients with triple-negative breast cancer derived the greatest benefit (56 percent lower risk of death) followed by HR-positive breast cancer (20 percent lower risk).
These findings underscore the importance of personalized counseling regarding risk-reducing surgical options for younger BRCA mutation carriers with early-onset breast cancer. The demonstrated survival benefits of both risk-reducing procedures provide critical information for patients and healthcare providers when considering comprehensive risk management strategies. The potential impact to a patient’s quality of life, including surgically induced menopause and infertility associated with these procedures, should be weighed carefully to make informed decisions specific to the patient.
OlympiA results and its implications for genetic counseling
BCRF Scientific Director Dr. Judy E. Garber presented updated results from the phase III OlympiA trial (NCT02032823), which evaluated the efficacy of olaparib (Lynparza®) as adjuvant therapy in patients with germline BRCA1/BRCA2 pathogenic variants and high-risk stage 2-3 HER2-negative breast cancer. The study involved 1,836 participants who, after completing standard treatments—including surgery, chemotherapy, and radiation—were randomized to receive either olaparib or placebo for one year.
After a median follow-up of 6.1 years, olaparib reduced the risk of death by 28 percent. In addition, olaparib reduced both the risk of invasive breast cancer recurrence and the risk of distant disease recurrence by 35 percent, compared to placebo.
The consistent benefits of olaparib observed across subgroups, including for patients with high-risk hormone receptor–positive disease, highlight the importance of genetic testing at the time of diagnosis to identify those who may benefit from the treatment as early as possible.
BCRF investigator Dr. Mafalda Oliveira of Vall d’Hebron Institute of Oncology presented primary results of SOLTI-VALENTINE (NCT05569811), a phase 2 study testing a first-in-class anti-HER3 antibody-drug conjugate (HER3-deruxtecan, HER3-Dxd) alone or in combination with letrozole (Femara©) in previously untreated , high-risk HR-positive/HER2-negative early breast cancer.
Multi-agent chemotherapy improves survival outcomes in this subset of patients but there is a need for more effective and tolerable treatment strategies. Dr. Oliveira reported that treatment with HER3-DXd, both with and without letrozole, had similar overall response rate and pathological complete response as chemotherapy. Compared to multi-agent chemotherapy, however, HER3-DXd demonstrated lower incidence rates of grade 3 adverse events with fewer dose reductions, treatment interruptions, and treatment discontinuations. The team also saw evidence of anti-tumor activity from the therapy as indicated by a drop in the Ki67 biomarker. SOLTI-VALENTINE supports the effectiveness of HER3-DXd in early breast cancer and its potential for the treatment of high-risk HR-positive/HER2-negative early breast cancer.
BCRF investigator and Scientific Advisory Board member Dr. Eric Winer led the session detailing the clinical trial results behind recent FDA approvals.
NATALEE
The NATALEE trial (NCT03701334) results led the FDA to grant expanded approval treating early, high-risk breast cancer with ribociclib (Kisqali®). Ribociclib was initially approved by the FDA in March 2017 for treatment of HR-positive/HER2-negative advanced or metastatic breast cancer.
NATALEE tested the CDK4/6 inhibitor ribociclib in combination with an aromatase inhibitor (AI) to reduce the risk of recurrence in patients with HR-positive, HER2-negative, high-risk early breast cancer. The main outcome measured was invasive disease-free survival (iDFS), defined as the first occurrence of local or regional invasive breast cancer recurrence, distant recurrence, death from any cause, contralateral invasive breast cancer, or secondary primary non-breast invasive cancer. Final analysis showed the iDFS at 36 months was 90.7 percent with ribociclib plus an AI versus 87.6 percent with AI alone.
The success of the NATALEE trial extends the clinical utility of ribociclib, now offering a therapeutic option for patients with early-stage breast cancer at elevated risk of recurrence. Further, this provides patients with more opportunities for effective intervention when the disease is detected early.
INAVO
The INAVO120 (NCT04191499) trial investigated the efficacy and safety of inavolisib (Itovebi®), a PI3Kα-selective inhibitor, in combination with palbociclib and fulvestrant for patients with endocrine-resistant, HR-positive, HER2-negative locally advanced or metastatic breast cancer with PIK3CA mutations—known drivers of breast cancer. Further, the patients in the study experienced disease progression during treatment or within 12 months of completing adjuvant endocrine therapy and had not received prior systemic therapy. The trial demonstrated that inavolisib improved PFS: by 15 months with inavolisib, palbociclib, and fulvestrant compared to 7.3 months with placebo, palbociclib, and fulvestrant.
With this approval, inavolisib is now a targeted therapeutic option for patients with PIK3CA-mutated breast cancer and clinicians can provide more personalized treatment strategies tailored to the molecular profile of their specific cancer.
The NATALEE and INAVO120 trials are clearcut examples of how clinical trials accelerate treatments to patients. They not only expand treatment options for patients, but they also provide valuable information and clarity on a myriad of questions as investigators work to bring laboratory findings to the clinic. As researchers rely on the results of clinical trials to improve outcomes for patients, they also rely on meetings such as SABCS to learn about the newest developments that, in turn, can spark ideas to inform future trials.
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