Has PARP Inhibition Finally Arrived in Breast Cancer?

Kimberly L. Blackwell, MD

The recent report that olaparib (Lynparza) improved progression-free survival (PFS) versus standard chemotherapy in patients with BRCA-positive breast cancer in the phase III OLYMPIAD trial likely indicates that PARP inhibitors have arrived at last in breast cancer.

Anti-PARP agents have been explored for over a decade in breast cancer; however, after initial success, several PARP inhibitors flamed out. At the 34th Annual Miami Breast Cancer Conference, Kimberly Blackwell, MD, discussed how the olaparib news and recent data for other emerging agents have reversed the PARP narrative in breast cancer.

“The fact that we are seeing agents emerge on the scene that have demonstrated better activity than ‘old-fashioned, suboptimal’ standard chemotherapy is really exciting and I think that this is going to be this year’s major breakthrough in the way that we manage breast cancer, particularly BRCA-driven breast cancer,” said Blackwell, professor of Medicine, assistant professor in Radiation Oncology, Duke University School of Medicine.

The phase III multicenter OLYMPIAD trial included 302 patients with HER2-negative metastatic breast cancer who harbored germline BRCA1 or BRCA2 mutations. The study was conducted in 19 countries across Europe, Asia, North America, and South America.

Patients were randomized to olaparib (300 mg twice daily) or physician’s choice of standard chemotherapy (capecitabine, vinorelbine, or eribulin). The primary endpoint of the trial was PFS per a blinded independent review.

AstraZeneca, the manufacturer of olaparib, is continuing to evaluate the study data and plans to present the full results at an upcoming medical meeting, as well as communicate with regulatory authorities regarding the findings. The initial safety data are consistent with previous olaparib studies, according to the company.

Beyond olaparib, veliparib has also shown promise in BRCA-positive patients, said Blackwell. Findings from the phase II BROCADE trial presented at the 2016 San Antonio Breast Cancer Symposium showed that adding veliparib to carboplatin/paclitaxel chemotherapy induced a response rate of 77.8% in patients with advanced BRCA-positive breast cancer.

The BROCADE study included 290 women with histologically or cytologically confirmed locally recurrent or metastatic breast cancer who harbored a deleterious BRCA1 or BRCA2 germline mutation.

The 3-arm trial randomized patients in a 1:1:1 ratio to veliparib (120 mg twice daily on days 1-7) plus carboplatin (AUC 6)/paclitaxel (175 mg/m²) every 3 weeks (n = 97); the same chemotherapy regimen plus placebo (n = 99); or veliparib (40 mg twice daily on days 1-7) plus temozolomide (150-200 mg/m² each day on days 1-5) every 4 weeks (n = 94).

The findings at SABCS were from the first 2 arms of the trial. Tumor response was assessed in patients with measurable disease, which included 72 patients in the veliparib arm and 80 patients in the placebo arm.

The complete and partial response rates in the veliparib versus placebo arms were 5.6% (n = 4) versus 3.8% (n = 3) and 72.2% (n = 52) versus 57.5% (n = 46), respectively. The clinical benefit rate (progression-free rate at 18 weeks) was 90.7% versus 87.0%, respectively. The median duration of response was 11.7 months (95% CI, 8.5-14.1) in the veliparib arm and 11.1 months (95% CI, 9.5-15.7) in the placebo arm.

The median PFS was 14.1 months (95% CI, 11.5-16.2) for the veliparib arm and 12.3 months (95% CI, 9.3-14.5) for the placebo group (HR, 0.789; 95% CI, 0.536-1.162; P = .231). The median overall survival (OS) was 28.3 months (95% CI, 26.9-NR) versus 25.9 months (95% CI, 20.4-31.8) with veliparib versus placebo, respectively (HR, 0.750; .503-1.117; P = 0.157). The OS data are not fully mature yet.

The study did miss its primary endpoint, noted Blackwell, as the PFS improvement was numerically but not statistically significant; however, she still considers the trial to be a success.

The third PARP inhibitor Blackwell highlighted was talazoparib. Results of a pilot study of neoadjuvant talazoparib for patients with BRCA-positive, early-stage breast cancer were presented at the 2016 Annual ESMO Congress. The study included 13 patients with a median age of 40 years (range, 25-55). Following 2 months of single-agent talazoparib, all 13 patients had decreases in their tumor volume, with an average volume loss of 78% (range, 30%-98%).

Blackwell said that beyond the phase III OLYMPIAD trial examining olaparib, there are 3 key ongoing phase III studies of PARP inhibitors in BRCA-positive breast cancer that are recruiting patients. The phase III randomized BROCADE-3 trial is assessing the addition of veliparib to carboplatin and paclitaxel. The phase III EMBRACA trial (NCT01945775) is comparing talazoparib with physician’s choice of chemotherapy. The third trial, the phase III BRAVO study (NCT01905592), is comparing niraparib with physician’s choice of chemotherapy.

Blackwell said that thus far, there are no data available for PARP inhibitors in patients with breast cancer who do not harbor BRCA mutations, but that physicians should “stay tuned.” She sees hope for these patients in results from the phase III ENGOT-OV16/NOVA ovarian cancer trial that were published in The New England Journal of Medicine.

The trial examined maintenance niraparib in patients with platinum-sensitive, recurrent ovarian cancer who had achieved a complete or partial response to platinum-based chemotherapy. Among patients without BRCA mutations, the median PFS was 9.3 months with niraparib maintenance versus 3.9 months with placebo (HR, 0.45; 95% CI, 0.34-0.61; P <.001).

Based on these data, Blackwell anticipates that platinum sensitivity may emerge as a biomarker. “I think that platinum sensitivity is going to be the ‘poor-man’s’ test of whether or not a tumor is going to be sensitive to PARP inhibition.

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“I give the investigators credit in that this combination is being moved forward. I think they stayed true to the mission of a phase II trial, which is really to look at toxicity and maybe get a hint of activity and then decide which of the regimens to move forward with in a larger phase III study,” said Blackwell.