Olaparib Plus Neratinib Shows Early Potential in HER2+ Ovarian Cancer

Combination use of olaparib (Lynparza) and neratinib (Nerlynx) may represent a novel therapeutic option for chemotherapy-resistant patients with HER2-positive, homologous recombination—proficient ovarian cancer tumors, according to preclinical findings presented at the 2019 SGO Annual Meeting.

Ovarian cancer remains the most lethal gynecologic tumor and the development of effective targeted treatments in ovarian cancer remains an unmet medical need,” Chan H. Han, MD, Yale New Haven Hospital, said during her presentation.

The FDA has approved olaparib for the treatment of ovarian cancer and neratinib for early-stage HER2-positive breast cancer; while studies in breast cancer models have shown that high HER2 expression resulted in sensitization of breast cancer to PARP inhibitors regardless of BRCA status. Therefore, the investigators evaluated the efficacy of the combination of olaparib and neratinib in HER2-positive, BRCA—wild-type ovarian cell lines and xenografts.

Cell viability experiments with olaparib, neratinib, and the combination were performed using flow-cytometry—based assays in 4 primary BRCA1/2-proficient ovarian cancer models overexpressing HER2, and drug synergy was assessed using CompuSyn software.

In addition, immunoblotting and real-time polymerase chain reaction (RT-PCR) experiments were performed to elucidate the mechanism of drug activity, while the efficacy of single-agent olaparib, neratinib, and the combination was evaluated in HER2-positive ovarian cancer xenograft models.

In the in vitro models, olaparib and neratinib as single agents were both effective in suppressing primary ovarian tumor cell line growth. However, neratinib had more prominent tumor suppression activity than olaparib in HER2-positive ovarian cancer cell lines. Of note, the combination regimen demonstrated synergy in all 4 primary ovarian cancer models that were tested and appeared superior to olaparib or neratinib as monotherapy in vivo and in vitro.

Mice treated with the combination regimen demonstrated a significantly longer overall survival when compared to control mice (P = .0005), mice treated with olaparib (P = .0005), and mice treated with neratinib (P = .0013).

Lastly, RT-PCR and immunoblotting of ovarian cancer cells treated with neratinib showed decreased BRCA1/2 and increased PARP activity.

During the in vivo study, the side effects from treatment was evaluated by measuring weight gain change in mean, from which the investigators saw no significant side effects in the mice.

“Our study demonstrated the synergism between olaparib and neratinib in HER2-overexpressing ovarian cancer. This combination may represent a novel therapeutic option for chemotherapy-resistant HER2-expressing, BRCA wild-type ovarian cancer cells,” Han said.

Olaparib has multiple FDA-approved indications for ovarian cancer, including 2 maintenance indications and an indication for the treatment of adult patients with BRCA-positive advanced ovarian cancer following ≥3 lines of chemotherapy.

Neratinib is currently being explored across multiple HER2-positive gynecologic malignancies, including cervical cancer. Data also presented at the 2019 SGO meeting showed that treatment with neratinib led to a clinical benefit rate of 54.5% in patients with HER2-mutant cervical cancer, according to results from the ongoing phase II SUMMIT basket trial.

References

1. Han C, Altwerger G, Menderes G, et al. The combination of olaparib (Poly ADP-ribose polymerase inhibitor) with neratinib (pan-HER inhibitor) is synergistic in epithelial ovarian carcinoma overexpressing HER2. Presented at: 2019 SGO Annual Meeting. March 16-19, 2019; Honolulu, HI. Abstract 69.
2. D’Souza A, Roman LD, Saura C, et al. Neratinib in patients with HER2-mutant, metastatic cervical cancer: findings from the phase 2 SUMMIT ‘basket’ trial. Presented at: 2019 SGO Annual Meeting. March 16-19, 2019; Honolulu, HI. Abstract 18.

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