PARP Inhibition as Neoadjuvant Therapy in Breast Cancer

Transcript: Joyce A. O’Shaughnessy, MD: Han and colleagues brought a clinical trial in progress, abstract and poster, to San Antonio showing the design whereby women with newly diagnosed breast cancer, women who have a germline BRCA mutation, received preoperative niraparib for 2 months. And then if they’re responding well, they can continue prior to going to surgery, but if they’re not responding well, of course they would go on to standard chemotherapy.

And the PARP inhibitors can be so highly synthetically lethal—hypothetically better than any chemotherapy, even DNA-damaging agents such as platinum—because inhibition of PARP in the context of a germline BRCA mutation, where homologous combination is deficient, in those cancers causes synthetic lethality in all of our preclinical work. The PARP inhibitors are arguably the best therapy, and we should move them into the curative setting and have the highest degree of cell kill.

So Han and colleagues are doing that now in a small cohort, it’s a pilot trial, to get a signal of single-agent niraparib in patients, and they can go from 6 months up to their surgery. And then they may have a surgery, they may have a pathologic complete response. What percentage of patients have that happen? Most of those women will probably go on to get some chemotherapy afterwards, but everything we know shows that no matter how you get there, if you get a pathologic and complete response, the prognosis is excellent. And it’s becoming less and less clear that you actually need to give any more chemotherapy, or any chemotherapy, if you achieve a pathologic complete response.

Of course, the goal would be to identify patients with a germline mutation in BRCA 1 or 2, who are newly diagnosed with breast cancer, and be able to give them just a plain PARP inhibitor, and a certain percentage of those patients will have a pathologic complete response. We actually saw that with Jennifer Litton. She provided data at ASCO [American Society of Clinical Oncology] this year using preoperative talazoparib in newly diagnosed germline BRCA patients. Most patients were triple negative. There were 3 who were ER-positive, a mixture of BRCA 1 and BRCA 2, and the pathologic complete response rate was in the neighborhood of 60%, with 6 months of preoperative talazoparib. So those are small numbers, but it’s exceedingly impressive to have that with just a PARP inhibitor. So larger studies are ongoing now with Dr. Litton at MD Anderson on this. Olaparib is being evaluated in the preoperative setting as well. So this is a very, very compelling hypothesis.

Transcript Edited for Clarity