Lynparza Plus Investigational Alpelisib Is Promising for Epithelial Ovarian Cancer

A combination of Lynparza (olaparib) and the investigational PI3K inhibitor alpelisib is safe for the treatment of recurrent epithelial ovarian cancer and induces at least stable disease in more than 80% of patients, results from a Phase 1 trial show.

Importantly, the combination was effective in women without any BRCA mutations and with platinum-resistant cancers, a population that PARP inhibitors such as Lynparza often fail to benefit.

The study, “Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial,” was published in the journal The Lancet Oncology.

Over the past decade, physicians have been successful in treating advanced ovarian cancer with inhibitors of an enzyme called oral poly (ADP-ribose) polymerase (PARP), which is involved in repairing damage to DNA.

Repairing damage to DNA allows the cancer cells to continue to grow. Therefore, PARP inhibitors are effective at stopping cancer growth.

To date, three PARP inhibitors are approved for ovarian cancer treatment: Lynparza (by AstraZeneca), Rubraca (rucaparib, by Clovis Oncology), and Zejula (niraparib, by Tesaro, now acquired by GSK).

But ovarian cancer cells often acquire new mutations that allow them to regain a functional DNA repair mechanism, leading to PARP inhibitor resistance.

Therefore, researchers hypothesize that combining PARP inhibitors with other inhibitors of DNA repair can benefit patients with this disease.

The DNA repair process requires the involvement of several different types of enzymes aside from PARP. Hence, there are several strategies that can be used to overcome resistance to PARP inhibitors.

A group of drugs known as PI3K inhibitors increase the deficiency in DNA repair by reducing the amount of BRCA proteins. Treating cells with PI3K inhibitors sensitizes them to treatment with PARP inhibitors.

Therefore, researchers set out to investigate the synergistic effect between Lynparza and Novartis‘ PI3K inhibitor alpelisib in a Phase 1 study (NCT01623349).

Researchers enrolled 34 patients — 30 with recurrent epithelial ovarian cancer and four with recurrent breast cancer — and divided them into two groups: the dose-escalation cohort (28 patients) and the dose-expansion cohort (six patients).

The primary objective of the study was to identify the maximum tolerated dose and the recommended Phase 2 dose for the combination treatment. This was defined as a once-a-day 200 mg dose of alpelisib and a twice-daily 200 mg dose of Lynparza.

At all dose levels, the most common serious treatment-related adverse events were high blood sugar levels in 16% of patients, nausea in 9% of patients, and increased alanine aminotransferase concentrations (a marker for liver injury) in 9% of patients. There were no treatment-related deaths.

Of the 28 patients with epithelial ovarian cancer included in the analysis, 36% achieved a partial response to therapy, while 50% had stable disease. Of the four breast cancer patients, three had their disease stabilized after treatment.

Interestingly, while PARP inhibitors often show the best responses among patients with mutations in their BRCA genes, responses to the combination were similar in patients with and without these mutations. Responses were also high among those resistant to platinum-based chemotherapy — a population that usually has acquired resistance to PARP inhibitors.

Thus, “our study showed that the combination of alpelisib and olaparib produced no unexpected toxic effects or safety signals, and exhibited preliminary clinical evidence of synergism” in patients with no BRCA mutations and in tumors enriched for PARP inhibitor resistance, researchers said.

“The activity of the olaparib and alpelisib combination in this setting appears to be higher than expected from either olaparib or alpelisib monotherapies, and warrants further investigation,” they concluded.