Promising Debut for PARP Inhibitors Spurs Excitement for Future Therapy

Anita T. Shaffer @Shaffer1
Published: Friday, Mar 08, 2019

Mark E. Robson, MD
Mark E. Robson, MD
The introduction of PARP inhibitors into the breast cancer treatment paradigm is a clinically meaningful advance for patients with germline BRCA1/2 mutations but much more research must be conducted to optimize their use, according to leading investigators in the field.

A panel of experts discussed the integration of olaparib (Lynparza) and talazoparib (Talzenna) into clinical practice during a breakfast symposium Friday at the 36th Annual Miami Breast Cancer Conference®. The FDA approved both drugs last year for patients with HER2-negative advanced or metastatic breast cancer whose tumors test positive for germline BRCA1/2 mutations on companion diagnostics (Table).1,2

Findings from the pivotal trials that led to the approvals show similar progression-free survival (PFS) improvements of approximately 3 months over standard chemotherapy, the panel members noted, adding that the mission now is to discover how to improve outcomes.

“There’s a whole host of different approaches that can be taken to try to extend the benefits of the very promising early findings,” said Mark E. Robson, MD, who chaired the discussion. “We do have to be cautious in our optimism but I would point out that if you go back and look at the original [trastuzumab] Herceptin trial, the PFS advantage was only about 4 or 5 months, so I think it’s just a question of trying to find how well we can make this work and can we extend the benefits.”

Robson, who was the lead investigator on the pivotal olaparib study, is chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College, both in New York City.

He said that the next steps in the research include testing combinations of PARP inhibitors with therapies that target PIK3CA mutations, VEGF, DNA replication stress (ATM and ATR inhibitors), and BET and TOPO1 inhibitors. Additionally, PARP inhibitors will be evaluated in combination with immunotherapy agents.

However, combining PARP inhibition with chemotherapy is not a promising strategy, Robson said. “It’s extremely challenging, largely because of overlapping myelosuppression,” he said. “It’s very difficult to get full-dose PARP inhibition and full-dose myelosuppressive therapy despite the fact that there are potentially advantages to doing that.”

Other areas to be explored include testing PARP inhibitors in the neoadjuvant and adjuvant settings, trying the agents against other genes and somatic mutations, and learning from PARP research in other cancers, particularly emerging information in pancreas and prostate cancers.

Table. PARP Inhibitors in Breast Cancer1,2

Table. PARP Inhibitors in Breast Cancer

Key Findings in Pivotal Trials

The olaparib approval was based on the results of the phase III OlympiAD study, in which patients were randomized 2:1 to receive olaparib at 300 mg twice daily or standard therapy with single-agent chemotherapy of the physician’s choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). Progression-free survival (PFS), the primary endpoint, was 7.0 months with olaparib versus 4.2 months with standard therapy. That translated into a hazard ratio (HR) for disease progression or death favoring olaparib of 0.58 (95% CI, 0.43-0.80; P <.001).3

In the phase III EMBRACA trial, patients were randomized 2:1 to receive talazoparib at 1 mg once daily or physician’s choice of the same single-agent chemotherapy agents offered in OlympiAD. The median PFS was 8.6 months with talazoparib versus 5.6 months with chemotherapy. The hazard ratio for disease progression or death favoring talazoparib was 0.54 (95% CI, 0.41-0.71; P <.001).

Notably, both drugs performed well when health-related quality of life was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). The median time to a clinically meaningful decrease in QLQ-C30 score (≥10 points) was not reached among patients who received olaparib compared with 15.3 months for those who had chemotherapy (HR, 0.44; 95% CI, 0.25-0.77; P = .004).3

For talazoparib, investigators reported a statistically significant delay in the time to clinically meaningful deterioration on the QLQ-C30. The median time to deterioration was 24.3 months with talazoparib (95% CI, 13.8-not reached) compared with 6.3 months (95% CI, 4.9-12.2) for with chemotherapy (HR, 0.38; 95% CI, 0.26-0.55; P <.0001).5

Panel members said those findings are further evidence that the drugs are improving the lives of patients.

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