Future Role of PARP Inhibition in BRCA+ Breast Cancer
Looking to future therapeutic approaches and combinations, Joyce A. O’Shaughnessy, MD, reflects on the potential role of poly ADP ribose polymerase (PARP) inhibition for BRCA-positive breast cancer management.
PUBLISHED December 04, 2018
Joyce A. O’Shaughnessy, MD: If I have a woman with metastatic breast cancer and we have found that she has a BRCA1 or BRCA2 germline mutation that she’s inherited, it’s very important that we have a conversation about the PARP inhibitors because in the clinical trials that have been done with olaparib [Lynparza], and talazoparib [Talzenna], they were compared with standard chemotherapy. These women, if they were estrogen receptor–positive, had already received hormonal therapy, so the question was if they should go on to chemotherapy or a PARP inhibitor. Thankfully, the PARP inhibitors had better efficacy. They’re more effective. They had a higher chance of the woman benefiting than chemotherapy in getting a response. Also important was staying without progression of disease or staying with the cancer in control for a longer period of time, which, of course, is extremely important. On that count, they won hands down over chemotherapy.
Another analysis was done in the OlympiAD trial with olaparib and this is for women with a metastatic breast cancer, BRCA1- or BRCA2-positive, who were receiving olaparib as their first treatment for metastatic breast cancer versus chemotherapy. Not only were the response rates higher, but the progression-free survival—that is staying without progression of cancer—was better. Most importantly, survival was also substantially higher with the PARP inhibitors compared to chemotherapy. What that told me is, if at all possible, utilize the PARP inhibitor in the first line of treatment for metastatic breast cancer. If you can’t use it in the first line, then use it as soon as you can in metastatic breast cancer to get the greatest effectiveness of therapy for the woman.
I think the future is really bright for women with a BRCA1 or BRCA2 mutation that they have inherited because the PARP inhibitors are going to be a big advance in the curative setting for these patients. I think that we’ll be utilizing the PARP inhibitors as a standard of care over the next 3 to 5 years in the preoperative setting before a woman has had surgery, to really see whether utilizing olaparib or talazoparib can completely eradicate the breast cancer such that by the time a patient goes to surgery, there is no cancer left. She won’t need any chemotherapy after that. That would be great, and we await the results of the OlympiAD trial. This for women who have already had their surgery; they’ve had chemotherapy if that was indicated for them. And then, half of the women got olaparib and half got placebo for 1 year to see if that will further improve the cure rate. Of course, if it does, it’ll become a standard of care. That’s very exciting.
The other thing that’s going to happen over the next few years is the opportunity in standard practice to combine the PARP inhibitors with immune checkpoint inhibitors, which are also developing and becoming available to us clinically. These make a lot of sense to combine, and some of the early data look like the safety profile is very good. We expect that’s going to be another excellent advance in therapy for women with metastatic BRCA1- or BRCA2-positive breast cancer. That’s going to move quickly into the curative setting as well. We really think the immune agents and PARP inhibitors are going to be a very important combination.
Treating women with BRCA1 or BRCA2 mutations that they’ve inherited is the tip of the iceberg for the PARP inhibitors. Many important questions remain about how else we can use the PARP inhibitor. Who else will benefit? What about women with other inherited mutations that lead to an increased risk of breast cancer, ovarian cancer, or other cancers such as PALB2, CHEK2, or ATM? There is a large number of other mutations that can be inherited. Will the PARP inhibitors benefit those women?
What if a woman does not have an inherited mutation of BRCA1 or BRCA2, but let’s say her breast cancer itself has developed a mutation in BRCA1 or BRCA2? Is there a group of those women who may also benefit from PARP inhibitors? What if her cancer has one of the other mutations that can be inherited, but she didn’t inherit it, such as PALB2? Will the PARP inhibitors also help her?
Lastly, what about in women whose breast cancers don’t even have a BRCA1 or BRCA2 mutation where they didn’t inherit it, for example? We think it’s the kind of breast cancer such as triple-negative breast cancer that might really benefit from a platinum agent such as carboplatin [Paraplatin] or cisplatin [Platinol]. Could the PARP inhibitors be a much safer and better-tolerated way to give the woman platinum without giving her platinum? Giving her a PARP inhibitor instead? These are very important questions for the future.