Venetoclax may have a role as triple therapy with endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer because of its ability to kill senescent cancer cells, Victorian research suggests.

A research team from the Walter and Eliza Hall Institute of Medical Research (WEHI) say relapse is almost inevitable  for patients with ER+ breast cancer receiving current standard treatment, possibly because CDK4/6 inhibitors put tumour cells into a dormant state rather than kill them.

But in pre-clinical studies they have shown that venetoclax is able to induce cell death in ER+ breast cancer cell lines when combined with fulvestrant and palbociclib.

Dr James Whittle, a clinician PhD student at the Institute and a medical oncologist at the Peter MacCallum Cancer Centre says the findings highlight the potential for targeting BCL2 in combination with CDK4/6 inhibitors and support further trials to investigate venetoclax in combination with the current gold standard therapy in ER+ breast cancer.

“We discovered that venetoclax could indeed kill ER+ breast cancer cells that had been treated with a CDK4/6 inhibitor – even those that were senescent. This was an exciting result as it was the first time that venetoclax has been shown to kill senescent cells,” he said.

The WEHI team’s study, published in Clinical Cancer Research showed that triple therapy was well-tolerated and produced a superior and more durable tumour response compared to single or doublet therapy in ER+ breast cancer cells derived from patients.

The response was associated with marked apoptosis, including of senescent cells, indicative of senolysis. Venetoclax also resulted in Rb dephosphorylation and reduced G1/S cyclins, most notable at high doses, thereby intensifying the fulvestrant/palbociclib-induced cell cycle arrest.

And encouragingly, venetoclax did not abrogate the favourable immunomodulatory effects of palbociclib in a ER+ mammary tumour model and extended tumour response when combined with anti-PD1 therapy.

Co-investigator Professor Geoff Lindeman the results provided a justification for starting clinical trials to look at a ‘triple therapy’ combining venetoclax, endocrine therapy and a CDK4/6 inhibitor in patients with ER+ breast cancer.

“We have initiated the phase 1 PALVEN trial which will, in the first place, look at whether this triple therapy is safe for patients, and will also consider how patients’ tumours respond to the triple therapy,” he said.