PARP/AKT Inhibitor Combination Active in Multiple Tumor Types


The combination of the PARP inhibitor olaparib and the investigational AKT inhibitor AZD5363 resulted in durable responses in patients with solid tumors, with and without BRCA mutations.

The combination of the PARP inhibitor olaparib and the investigational AKT inhibitor AZD5363 resulted in durable responses in patients with solid tumors, with and without BRCA mutations, according to a phase I trial reported at the 2016 AACR Annual Meeting.

Overall, 27% of evaluable patients across multiple tumor types had complete or partial responses to two different schedules of the combination of olaparib and AZD5363. Duration of response approached 2 years in some cases.

“The combination of olaparib and AZD5363 is feasible and well tolerated,” said Vasiliki Michalarea, MBBS, a researcher in the drug development unit at the Royal Marsden Hospital in London, who presented the data at AACR. “Antitumor activity has been observed in BRCA-mutated and non-BRCA-mutated tumors as well as in patients who previously received PARP inhibitors, as well as AKT-pathway inhibitors.”

The trial included 53 patients, including 21 patients with germline BRCA mutations. The BRCA representation in the trial consisted of nine of 19 patients with ovarian cancer, eight of 16 with breast cancer, three of four patients with prostate cancer, and one of two patients with bile duct cancer.

All patients received olaparib at 300 mg twice daily and AZD5363 by one of two administration schedules. Twenty-three patients received AZD5363 at a dose of 400 mg twice daily for 4 days, followed by 3 days off treatment (4/3), and 30 patients received AZD5363 at 640 mg twice daily for two days, followed by 5 days off treatment (2/5).

The 37 patients evaluable for response included 15 patients with BRCA mutations. The results showed 10 objective responses by RECIST criteria: four patients with BRCA-mutated breast cancer; two patients with platinum-resistant, BRCA-mutated ovarian cancer; one patient with BRCA wild-type triple-negative breast cancer; two patients with BRCA wild-type ovarian cancer; and one patient with BRCA-unknown.

In general, the combination was well tolerated, as a single case of grade 3 rash was the only dose-limiting toxicity associated with either AZD5363 administration schedule.

Some patients had stable diseases or responses that did not conform to RECIST criteria, Michalarea noted. As an example, she described a 78-year-old man with BRCA-mutated, castration-resistant prostate cancer who had received two prior lines of therapy and was treated with the 4/3 AZD5363 schedule. He had an ongoing MRI and PSA response at 23 months of follow-up.

Other examples of patients that had promising response included a patient with PI3K/mTOR-resistant peritoneal mesothelioma, who had a significant, persistent reduction in levels of the CA125 antigen and stable disease by RECIST criteria that lasted for 21 months.

One of the responding patients had BRCA-mutated high-grade serous ovarian cancer and previously had a partial response by RECIST criteria to olaparib monotherapy, persisting for 11 months. Treated again with olaparib in combination with the 4/3 AZD5363 schedule, the 72-year-old woman had another RECIST partial response that was ongoing at 18 weeks.

The one dose-limiting toxicity occurred in a patient on the 4/3 schedule. Other non-dose limiting toxicities associated with the schedule were three cases of grade 3 anemia, and one case each of grade 3 diarrhea, vomiting, and proteinuria. Grade 3 toxicities associated with the 2/5 schedule consisted of two cases each of transaminitis, nausea, fatigue, and anemia; and one case each of rash, hyperglycemia, and diarrhea. With both of the dosing schedules, common grade I/II toxicities included nausea, fatigue, anemia, diarrhea, anorexia, mucositis, and vomiting.

A phase I dose-escalation trial had previously demonstrated the safety of daily olaparib in combination with two different schedules of AZD5363: 4 days on, 3 days off; or 2 days on, 5 days off. The trial demonstrated the feasibility and safety of the combination and the dose-escalation schedules, leading to the follow-up study reported by Michalarea.

Preclinical studies had suggested therapeutic synergy between PARP-inhibitors and agents that inhibit the PI3K pathway, including AKT. Robust activity was observed in both BRCA-mutated tumors and sporadic cancers.

Investigators performed next-generation sequencing of 160 cell-free DNA samples obtained from 38 of the 53 patients. Driver mutations were identified and tracked from baseline in 28 of the 38 patients, and Michalarea and colleagues found 100% concordance in mutation status between tumor and cell-free DNA. Changes in cell-free DNA concentrations appeared to correlate with treatment response in 72% of patients.

Michalarea V, Roda D, Drew T, et al. Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations. Presented at: AACR Annual Meeting 2016, New Orleans; April 16-20, 2016. Abstract CT010.


View more from the 2016 AACR Annual Meeting

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