Young-PEARL study’s survival data marks new milestone in premenopausal breast cancer at ASCO 2024

Updated survival data from the Young-PEARL study, a Korean investigator-initiated phase II clinical trial, was once again the subject of an oral presentation at the recent American Society of Clinical Oncology Annual Meeting (ASCO 2024), marking a new milestone in the treatment of premenopausal breast cancer patients.

Professor Park Yeon-hee of the Department of Hematology/Oncology at Samsung Medical Center presented the overall survival (OS) analysis from the Young-PEARL study orally at the world's largest cancer conference, held from May 31 to June 4 in Chicago, Ill.

Having previously presented the primary endpoint of the Young-PEARL study, progression-free survival (PFS), at ASCO in 2019, Professor Park was selected to present the secondary endpoint, OS data.

The Young-PEARL study is an investigator-initiated clinical trial designed by the Korean Cancer Study Group, considering Korean breast cancer patients' epidemiologic and biologic dynamics.

Unlike in the West, about half of Korean and Asian patients are premenopausal, a younger age for breast cancer prevalence. Until now, however, their treatment has run into limitations because all breast cancer treatments have focused on postmenopausal Western women.

For premenopausal patients to receive endocrine therapy, they have been forced to have an oophorectomy.

In the Young-PEARL study, researchers evaluated exemestane and palbociclib (Ibrance in product name) in combination with leuprolide by comparing them with capecitabine in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) premenopausal breast cancer who had relapsed or progressed on previous tamoxifen therapy.

By comparing the gonadotropin-releasing hormone (GnRH) agonist leuprolide, which suppresses ovarian function, with the aromatase inhibitor (AI) and CDK4/6 inhibitor combination, which was expanding in use as a standard of care at the time, to conventional chemotherapy, the trial established the rationale for the use of a new drug without oophorectomy in premenopausal patients.

Data initially presented in 2019 showed that at 17 months of follow-up, the median progression-free survival (mPFS) in the combination arm was 20.1 months, compared to 14.4 months in the capecitabine monotherapy arm. This resulted in a 34 percent reduction in the risk of disease progression or death (HR 0.659).

The data presented this time is survival results analyzed at a median follow-up of 54.0 months, which showed that the PFS benefit of the exemestane + palbociclib combination with a GnRH agonist remained consistent (19.5 months vs. 14.0 months, HR 0.744).

Median overall survival (mOS) was not statistically different in the treatment and control arms (54.8 months vs. 57.8 months, respectively) (HR 1.021).

However, the use of CDK4/6 inhibitors after disease progression was analyzed as the main reason for the lack of OS improvement.

When the researchers analyzed follow-up treatment after disease progression, they found that a higher proportion of patients received endocrine therapy in the treatment arm (80.3 percent) compared to the control arm (28.2 percent), while a higher proportion received chemotherapy in the treatment arm (63.4 percent) compared to the control arm (18.3 percent).

Finally, after disease progression during follow-up, 15.5 percent of patients (11 among 71) in the treatment arm used CDK4/6 inhibitors compared to 49.3 percent (35/71) of patients in the control arm.

Based on the Young-PEARL study, Ibrance won approval from the U.S. Food and Drug Administration (FDA) in 2022 for an expanded indication in combination with an aromatase inhibitor (AI) in “premenopausal” patients, and a year later, in 2023, by the Korean Ministry of Food and Drug Safety.

The Korean investigator-led phase 2 clinical trial led to the expansion of the indication in the global market, helping to improve the treatment of premenopausal breast cancer patients in Korea and worldwide.

In addition, the Young-PEARL study is also considered to have established the position of capecitabine, which had been undervalued in Korea.

At the time, Korean oncologists and even insurance authorities were reluctant to use capecitabine for chemotherapy without first using taxanes or anthracyclines.

However, in the Young-PEARL study, capecitabine was used as a control group for patients who failed tamoxifen treatment, confirming the efficacy of capecitabine, which is used widely overseas in Korean clinical trials.

The Korean researchers’ efforts did not stop there, as they proposed a new treatment for premenopausal breast cancer patients.

In the development of ribociclib (trade name Kisqali), a late-stage drug among CDK4/6 inhibitors, Professor Seock-Ah Im of the Department of Hematology/Oncology at Seoul National University Hospital proposed the MONALEESA-7 study to evaluate its efficacy in premenopausal patients, and as the principal investigator, successfully conducted a global phase 3 clinical trial.

The MONALEESA-7 study was a phase 3 trial that evaluated Kisqali plus endocrine therapy vs. endocrine therapy alone in the first-line treatment of premenopausal HR+/HER2- advanced and metastatic breast cancer patients and demonstrated that Kisqali plus endocrine therapy could reduce the risk of death by 30 percent compared to endocrine therapy alone.

The MONALEESA-7 study is also recognized as the only clinical study to evaluate the combination of a CDK4/6 inhibitor and endocrine therapy compared to endocrine therapy in premenopausal patients.

Through the Young-PEARL and MONALEESA-7 studies, Korean researchers could provide improved treatments for premenopausal breast cancer patients who have been neglected, fulfilling the unmet needs of breast cancer patients in Korea, Asia, and beyond.