The combination of the PARP inhibitor olaparib with an mTORC1/2 inhibitor known as vistusertib was tolerable and had promising activity across endometrial, ovarian, and triple-negative breast cancers, according to a phase I trial. Results of the trial (abstract 5504) were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago.
“There are a number of different mechanisms of action for PARP inhibitors in gynecologic malignancies,” said Shannon N. Westin, MD, of the University of Texas MD Anderson Cancer Center in Houston. “Specifically, synthetic lethality seems to occur in those cancer cells that are deficient in homologous deficient pathways. What we’ve been wondering is, how can we get efficacy from PARP inhibition in more cancer types and more patients?”
A number of combination approaches are under investigation. Westin said that there is evidence of synergy between PARP inhibition and targeting of the PI3K pathway, which led to this phase I trial combining an mTORC1/2 inhibitor with olaparib.
A total of 74 patients were enrolled. All patients included had recurrent endometrial adenocarcinoma (32%), recurrent triple-negative breast cancer (27%), or recurrent high-grade serous or deleterious BRCA-mutant ovarian/primary peritoneal/fallopian tube carcinoma (41%). About three-quarters of the patients were white, and the median age was 60 years. Most patients (84%) were BRCA mutation–negative, and the median number of prior therapies was four.
There were two separate dose-escalation schedules, one using continuous dosing and another using an intermittent approach for vistusertib. Dose-limiting toxicities with the continuous dosing included grade 3 rash, mucositis, grade 4 thrombocytopenia, and allergic reaction; the third dose level—olaparib 200 mg twice daily and vistusertib 50 mg twice daily—was considered the recommended phase II dose.
In the intermittent group, dose-limiting toxicities included grade 3 neutropenia, hyperglycemia, and fatigue. A recommended phase II dose of olaparib 300 mg twice daily and vistusertib 100 mg twice daily in a 2-days-on/5-days-off schedule was selected.
Of 64 evaluable patients, the overall response rate was 19%, with a clinical benefit rate of 47%. The median duration of benefit was 14 months. The response rate was highest in the 22 endometrial cancer patients, at 27%, compared with 20% in the ovarian cancer patients, and 6% in the triple-negative breast cancer patients.
“We were able to successfully combine olaparib with the mTORC1/2 inhibitor vistusertib,” Westin concluded. “We did see durable anticancer activity across all cancer types, with really particularly promising response seen in both histologies of endometrial cancer.”
Gini F. Fleming, MD, of the University of Chicago, was the discussant for the session. She agreed that the response rate, especially in endometrial cancer, is very promising. “The combination still appears moderately toxic, and one question is whether a more traditional mTOR inhibitor would work as well,” she said. “However, further development of this and similar combinations are clearly warranted.”