Veru/Lilly Aim to Fill Gap in Second-Line Metastatic Breast Cancer Therapy

Breast Cancer Exam

Veru Inc.’s new Phase III trial in collaboration with Eli Lilly could be a landmark step in the treatment of AR+ER+HER2- metastatic breast cancer. Veru is introducing a novel non-masculinizing hormone to patients who have progressed after nonsteroidal AI, fulvestrant and CDK 4/6 inhibitor therapy. As a second-line therapy, it has the potential to treat approximately 40% of all breast cancers.

Enobosarm may be the first new hormone treatment in a decade for breast cancer. “AR is the last of the hormone receptors to be exploited,” Mitchell Steiner, M.D., chairman, president and CEO of Veru Inc., told BioSpace.

The collaborative trial with Lilly, dubbed ENABLAR-2 (ENobosarm ABemaciLib Androgen Receptor 2nd line) evaluates Veru’s enobosarm administered in combination with Lilly’s Verzenio® (abemaciclib) as a second-line breast cancer therapy. Verzenio® is a CDK4/6 inhibitor that is widely prescribed as a first-line therapy for patients with this particular type of metastatic breast cancer.

Enobosarm is an oral, first-in-class, new chemical entity, selective androgen receptor targeting agonist that activates the androgen receptor (AR), a tumor suppressor. It is both an agonist and an antagonist, depending on the tissue type. It works by binding to the AR in the breast tissue and inhibiting AR+ and ER+ cancer cells from proliferating. It has been shown, in preclinical studies, to build muscle and improve physical function and to promote and heal cortical and trabecular bone. Consequently, it also has the potential to treat osteoporosis and breast cancer metastases that invade the skeleton.

Veru CEO Mitchell Steiner/courtesy Veru Inc.It cannot be aromatized to estrogen. As Steiner explained, “If you give natural testosterone, it gets converted to estrogen by the aromatase enzyme and stimulates the growth of breast cancer. Enobosarm cannot be converted to estrogen, so you get only the tumor suppressor effects.”

“The FDA said that if enobosarm has the best anticancer activity in breast cancers that express AR, then we need to also develop a companion diagnostic test to measure the androgen receptor accurately,” Steiner said. Therefore, Veru partnered with Roche/Ventana Diagnostics (which performs approximately 80% of the molecular analyses for breast cancer patients globally) to develop a diagnostic to identify women who had enough AR (those with 40% or more AR nuclei staining in breast cancer tissue) to benefit from the therapy. “This is big,” Steiner said.

“With a diagnostic test in place, we wanted to partner with a powerhouse to commercialize enobosarm globally. CDK 4/6 inhibitors, such as Lilly’s drug, Versenio®, have changed the landscape of breast cancer therapy perhaps more than any other type of therapy,” Steiner said. This is the standard of care for first-line metastatic breast cancer therapy, conferring 24 to 30 months of progression-free survival.

“That’s incredible,” he said, but once that period ends, “there is silence.” There are no approved comparably effective second-line treatments.

Enobosarm, however, has the potential to fill that gap in second-line therapies. It shows good proof of concept data even when 90% of patients have failed first-line therapies. “Preclinical models show enobosarm works nicely, but when it’s given after CDK 4/6 inhibitors, it works even better,” Steiner said. More specifically, independent proof of concept preclinical studies using human breast cancer models show that combining enobosarm with a CDK4/6 inhibitor enhanced antitumor activity in tumor samples from patients who previously were treated with palbociclib, a CDK4/6 inhibitor and estrogen-blocking agent.

“That’s what excited Lilly,” he added. Enobosarm potentially enables Lilly or other drug developers to offer a second-line therapy by combining their CDK4/6 inhibitors with enobosarm. For this Phase III collaboration, Lilly reviewed the clinical protocol and supplied its drug, Verzenio®. Veru and Lilly are engaged in continual dialog regarding the trial and the data. Notably, Veru retains full exclusive, global rights to enobosarm.

The ENABLAR-2 combination trial is scheduled to begin this quarter, with data anticipated by the second half of 2023. The trial is an open-label, randomized, active control pivotal study that is expected to involve 35 clinical sites throughout the U.S. and 186 breast cancer patients who have received an estrogen-blocking agent in combination with palbociclib. Progression-free survival is the primary endpoint. Secondary endpoints are overall response rate, change in short physical performance battery and change in DEXA-2 body composition muscle and bone.

Assuming the outcome is positive, Veru expects to submit a new drug approval (NDA) application with the U.S. Food and Drug Administration to use enobosarm as a second-line therapy.

A Phase IIb “sister” study of sabizabulin for AR+ER+HER2- metastatic breast cancer is also planned for the first quarter of this year for patients in a third-line metastatic setting with greater than 40% AR expression in their breast cancer tissue.

In January, the FDA granted Fast Track designation to enobosarm’s Phase III ARTEST registration program to treat “AR+ER+HER2- metastatic breast cancer patients who have shown previous disease progression on a nonsteroidal AI, fulvestrant, and CDK 4/6 inhibitor therapy, and who have AR% nuclei staining ≥40% in breast cancer tissue (third-line metastatic setting).” This evaluates enobosarm alone, as a third-line therapy. It currently is enrolling.

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