Two-Pronged Strategy With PARP Inhibitor Gains Traction in Breast and Ovarian Cancers

A two-pronged strategy combining the PARP inhibitor Lynparza (olaparib) and the PI3K inhibitor BKM120 proved to be a safe and clinically beneficial regimen for women with triple-negative breast cancer (TNBC) and for patients with high-grade serous ovarian cancer, according to early clinical trial results presented at the 2015 AACR Annual Meeting.

The oral regimen demonstrated partial response (PR) rates of 21 percent among patients with breast cancer and 26 percent among women with ovarian cancer who participated in the phase 1 dose-escalation trial.¹

The findings show that dual inhibition of the pathways is a valid approach that should be pursued with further research for patients with these malignancies, lead author Ursula A. Matulonis, MD, said in presenting the findings at a press conference. Matulonis is director and program leader of Medical Gynecologic Oncology in the Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute in Boston.

Additionally, researchers found that the combination showed activity in certain patients regardless of whether their tumors tested positive for germline BRCA (gBRCA) mutations, which currently is required under the FDA’s approval for administering Lynparza as a treatment for women with advanced, recurrent ovarian cancer.

“It is important that we saw responses against both BRCA-mutant and BRCA wild-type cancers,” Matulonis, who also is an associate professor of Medicine at Harvard Medical School, said in a statement. “We need to do further analysis to identify biomarkers that we can use to more effectively identify the patient population that will be most positively affected by the Lynparza/BKM120 combination.”

Maximum Dose Established

The clinical trial was designed to test the maximally tolerated dose (MTD) of the combination of Lynparza and BKM120 given orally on a continuous daily basis.² The trial also will evaluate the combination of Lynparza and another PI3K inhibitor, BYL719, and those findings will be reported at a later date.

Patients were eligible for the trial if they had a confirmed diagnosis of TNBC or high-grade serous ovarian cancer, or a documented gBRCA mutation in either of those tumor types regardless of tumor histology.

The Lynparza/BKM120 segment enrolled 46 patients with ovarian cancer and 24 patients with breast cancer. Participants in the ovarian cancer cohort were a median age of 60 years, 90 percent had high-grade serous tumors, and 77 percent had a gBRCA mutation. In the breast cancer cohort, the median age was 47.5 years, 63 percent had TNBC, and 58 percent had a gBRCA mutation.

Among the patients with ovarian cancer, the overall response rates (ORRs) were 26 percent (12 patients) with a PR, 48 percent (22 patients) with stable disease (SD), and 15 percent (7 patients) with progressive disease (PD). Five patients (11 percent) were not evaluable.

For patients with breast cancer, the ORRs were 21 percent (5 patients) with a PR, 50 percent (12 patients) with SD, and 17 percent (4 patients) with PD. Three patients (13 percent were not evaluable). Among the responders in the breast cancer group, four patients had triple-negative tumors, including three individuals with gBRCA1 mutations and one with gBRCA wild-type. The fifth responder’s tumor was positive for estrogen and progesterone receptors and harbored a gBRCA2 mutation.

In all, the study tested 10 different dose level combinations of Lynparza and BKM120. Once the MTD was determined, 10 patients each with breast cancer or high-grade serous ovarian cancer entered the expansion phase.

The MTD was found to be 50 mg once per day of BKM120 plus 300-mg tablets twice per day of Lynparza. There were three instances of dose-limiting toxicities (DLTs) of hyperglycemia, transaminitis, and depression, and a grade 4 instance of transaminitis; four patients who each had one toxicity experienced these DLTs.

Overall, the combination was well tolerated, with toxicities primarily of grades 1/2 severity, Matulonis said. The most common nonhematologic toxicities of all grades were nausea (79.4 percent), fatigue (66 percent), and hyperglycemia (40 percent). Anemia (23.5 percent) and neutropenia (12 percent) were the most common hematologic toxicities of all grades.

Rationale for Combination

Matulonis said the trial illustrates that, in order to develop combinations of biologic agents, researchers will have to establish biomarkers to target appropriate patient populations so that sensitivity to novel agents can be predicted and mechanisms of action can be clarified.

“The combinations of these biologics moving forward will point to us understanding the genomic landscape of that particular patient’s tumor and try to decide, as different combinations are developed, where these combinations fit in,” she said.

Matulonis said there was a strong rationale for pairing Lynparza and BKM120 in the two tumor types. She said both tumor types are associated with gBRCA mutations and sensitivity to platinum agents, and that analyses from The Cancer Genome Atlas project show that both malignancies have high copy number alteration rates.

“We thought about this from a genomic commonality standpoint,” she said.

Moreover, preclinical data suggest a synergy with a concurrent attack on the two pathways. PARP proteins are active in DNA transcription and repair, among other cellular processes, while PI3K kinases orchestrate processes such as growth, survival, and metabolism. PARP inhibitors have proved most effective against tumors with mutations in BRCA1/2, tumor suppressor genes whose best-understood role is the repair of double-strand breaks in DNA.

Since the dual inhibition approach appears to benefit some patients with BRCA wild-type tumors, the trial results also point to the need for a deeper understanding of the “genomic landscape” of these tumors, said Matulonis.

Key Sponsors Recognized

Matulonis credited a large team of researchers who collaborated on the clinical trial, with major funding provided through Stand Up to Cancer (SU2C). An SU2C Dream Team was formed to study the PI3K pathway in women’s cancers several years ago. This week, the American Association for Cancer Research, which administers the program, announced that another Dream Team was awarded a $6 million grant to investigate DNA repair therapies for ovarian cancer. Matulonis said that work will help her team and colleagues move forward with their dual inhibition research.

Participating in the trial presented at the 2015 AACR conference were researchers from Beth Israel Deaconess Hospital and Massachusetts General Hospital in Boston; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York, and The University of Texas MD Anderson Cancer Center in Houston.

AstraZeneca, which developed Lynparza, and Novartis, which manufactures BKM120, provided the drugs for the study.

References

1. Matulonis UA, Wulf G, Birrer M, et al. Phase I of oral BKM120 or BYL719 and olaparib for high grade serous ovarian cancer or triple negative breast cancer: Final results of the BKM120 plus olaparib cohort. Presented at: 2015 American Association of Cancer Research Annual Meeting. Abstract 8972.

2. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01623349.