BRCA+ Breast Cancer: The Advent of PARP Inhibitors
Joyce A. O’Shaughnessy, MD, provides insight on the available poly ADP ribose polymerase (PARP) inhibitors with regard to their safety profiles and the rationale behind their development for BRCA-positive breast cancer.
PUBLISHED December 04, 2018
Joyce A. O’Shaughnessy, MD: PARP inhibitors are a great advance in breast cancer and ovarian cancer management, and soon to be used for other cancers that are related to a woman or man having inherited a BRCA1 or BRCA2 mutation. And in other cancers — in pancreatic cancer, prostate cancer—they’re very important. The PARP inhibitors are really proving to be beneficial because the cancer cells are very sensitive and susceptible to killing by the PARP inhibitors because they have defective BRCA1 or BRCA2. They become reliant on PARP to repair their DNA. When you knock that out and the cancer doesn’t have BRCA1 or BRCA2, they die very, very well. It’s a very, very specific way of killing the cancer cells. This has been a great advance and has led, in metastatic HER2 [human epidermal growth factor receptor 2]-negative breast cancer, to 2 very important large phase III clinical trials. One is called the OlympiAD trial, looking at olaparib, and the other is called the EMBRACA trial, looking at talazoparib. These are 2 oral PARP inhibitors.
The PARP inhibitors olaparib and talazoparib, which are fortunately oral agents, have been approved by the FDA for women with metastatic HER2-negative breast cancer that is BRCA1- or BRCA2-mutation positive, based on the woman herself having inherited a BRCA1 or BRCA2 mutation. Right now, that’s where they’re being utilized as standard of care. However, the PARP inhibitors are also in clinical trials in the curative setting. Olaparib is in a very important adjuvant clinical trial called OlympiAD for women with ER [estrogen receptor]-positive or triple-negative breast cancer. They’ve already finished up their chemotherapy if they were going to receive chemotherapy. If they’re ER-positive, they received antiestrogen therapy, endocrine therapy. And then they’re randomized to receive a year of the olaparib or placebo, aimed at curing more women who have BRCA1- or BRCA2-positive breast cancer. Talazoparib is being studied right now in the preoperative setting for women with BRCA1 or BRCA2 germline-positive breast cancer. We’re moving quickly into the curative setting, adjuvant or neoadjuvant. So far, it fortunately looks like whether a woman’s breast cancer is triple-negative or estrogen receptor-positive, there’s equal efficacy or equal effectiveness for olaparib and talazoparib as long as the breast cancer has a mutation in BRCA1 or BRCA2 that the woman has inherited.
The side effects of the PARP inhibitors, olaparib and talazoparib, are fortunately not that bad. There is some suppression of the bone marrow, particularly some anemia. For example, sometimes there’s a little bit of decrease in the white cells or of the platelets, but nothing that we really call clinically significant. There can be some fatigue. There can initially be a little bit of nausea or a little bit of GI [gastrointestinal] upset. But fortunately it’s quite safe, and women, in my experience, tolerate them really quite well. As with so many of our medications in cancer treatment, women’s bodies adjust to it very readily and sometimes women require a little bit of dose adjustment, if you will, but the body gets readily used to it. Talazoparib has a low chance of causing some thinning of the hair: not complete hair loss, but a low chance of some thinning of the hair. But otherwise, they’re quite similar.