Combining Pi3K, PARP Inhibitors May Expand Treatment Options for Triple-Negative Breast Cancer

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(ChemotherapyAdvisor) – Combining a phosphoinositide 3-kinase (PI3K) and a poly-ADP-ribose-polymerase (PARP) inhibitor may provide a new treatment option for women with triple-negative breast cancer (TNBC)—for whom treatment options are limited—two studies concluded in the November issue of Cancer Discovery.

While early-phase clinical studies have shown some benefit of PARP inhibitors in women with TNBC and BRCA1 gene mutations, this activity has been short lived.

In the first study, José Baselga, MD, PhD, of Massachusetts General Hospital Cancer Center, Boston, and colleagues used TNBC patient-derived primary tumor xenografts and found that PI3K blockade with BKM120 resulted in sensitization of DNA homologous recombination impairment and sensitization to PARP inhibition with olaparib.

These results provide “a rationale to combine PI3K and PARP inhibitors in this indication,” they stated. “Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors.” A clinical trial with BKM120 and olaparib is being initiated in patients with TNBC.

In the second study, Lewis C. Cantley, PhD, of Beth Israel Deaconess Medical Center, Boston, and colleagues used an endogenous mouse model of BRCA1-deficient breast cancer. When mice were treated with a PI3-kinase inhibitor, tumor doubling was delayed from 5 to 26 days; however, when BKM120 was combined with a PARP inhibitor, tumor doubling was delayed to >70 days.

The investigators are working with Novartis, which manufactures the PI3K inhibitor, BKM120, and AstraZeneca, which makes the PARP inhibitor, olaparib, to initiate a clinical trial combining the two drugs in humans.

Dr. Cantley noted it is extremely unusual for two unapproved drugs to be combined in a cancer clinical trial, especially when produced by separate companies. Yet, the preclinical results were sufficiently compelling to accelerate the initiation of this trial, which is being led by Ursula Matulonis, MD, Dana-Farber Cancer Institute, Boston. The trial is now enrolling patients with TNBC or ovarian cancer.

“This is truly an amazing story, where essentially the same week that the paper is coming out showing an observation, the clinical trial is starting,” Dr. Cantley said. “This type of bench-to-bedside process typically takes 5 to 10 years but was dramatically accelerated by the collaborative efforts of the Stand Up To Cancer-funded PI3-Kinase Dream Team.”

Both studies received funding from Stand Up To Cancer Dream Team Translational Research Grants.

Baselga et al article (free)

Cantley et al article (free)

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