The Promise of PARP Inhibitors for BRCA-Mutated Breast Cancer
Published Online: 12:36 PM, Mon March 16, 2015
Mark E. Robson, MD
“It is an exciting time. We have an approval for olaparib (Lynparza) in ovarian cancer and there are active phase III studies for olaparib and other PARP inhibitors in metastatic breast cancer for patients with BRCA1/2 mutations,” said Robson (Table).
Robson is leading the phase III OlympiAD trial that is evaluating olaparib in patients with metastatic breast cancer with germline BRCA1/2 mutations.1 The trial, which is seeking to recruit 310 participants, is open to men and women. Patients will be randomized to receive either olaparib at 300 mg twice daily or physician’s choice chemotherapy of either capecitabine (2500 mg/m2 for 14 days, then repeated every 21 days), vinorelbine (30 mg/m2 on days 1 and 8, then repeated every 21 days), or eribulin (1.4 mg/m2 days 1 and 8, then repeated every 21 days).
PARP inhibitors capitalize on the Achilles’ heel of BRCA1/2-mutated cells whose DNA repair mechanisms are already impaired. Researchers know that the action of a PARP (poly ADP-ribose polymerase) inhibitor serves to fully disable the tumor cell’s ability to repair its damaged DNA, leading to what is known as synthetic lethality, while normal cells suffer little-to-no effect on their ability to survive.
Enough has been accomplished in trials to signal that PARP inhibitors have acquired credibility and traction in breast cancer, Robson said. “I think the message out there is one of cautious optimism,” he said in an interview in advance of his presentation.
In December, the FDA approved olaparib as monotherapy for the treatment of patients with germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication calls for patients to be tested with an FDA-approved test, and the agency gave its nod the BRACAnalysis CDx as the companion diagnostic.
Nevertheless, it remains unclear whether a positive test for BRCA1/2 mutations can lead to a reliable determination about which patients will benefit from PARP inhibitor therapy, Robson said.
“The technological ability to detect sequence variations in BRCA1/2 is not trivial, but certainly well within the tech- nological capabilities of a number of different laboratories,” Robson said. “Assigning meaning to different variations is a little bit more complicated because certainly protein truncating mutations are relatively straightforward, but other types of sequence variations can be a little bit more difficult to determine whether or not they are likely associated with response.”
In part, it comes down to generating a sufficient evidence base that regulators agree can set the boundaries for those types of determinations, Robson said.
“The FDA and others are certainly trying to figure out what the rules of engagement are here–what’s the right level of regulation so that the clinician can be comfortable that the result he or she has obtained will indeed be tied to an increased likelihood of response,” said Robson. “That’s a tough conversation.”
Many Questions Unanswered
Knowing who will and will not respond to PARP inhibitors and better understanding the mechanisms of resistance are among the crucial questions in ongoing research, as is knowing what other gene mutations might signal efficacy in the use of this class of therapy, Robson said.
“PALB2 is the next most obvious target, but it is going to be more challenging because those mutations are probably tenfold less common than BRCA mutations, and so getting enough patients together to show PARP inhibitors work in PALB2 carriers is going to be very challenging,” Robson said. “It is going to require a lot of collaboration and a lot of effort.”
Researchers believe that up to 10% of breast cancers may be caused by inherited mutations in breast cancer susceptibility genes, including BRCA1/2 and PALB2.2 Mutations in either BRCA gene are associated with a 50% to 80% elevated lifetime risk of developing breast cancer.2 For female carriers of the PALB2 mutation, the risk of developing breast cancer has been estimated at 14% by age 50 years and 35% by 70 years of age.3
Olaparib’s approval by the FDA is contingent upon satisfactory results from either of two ongoing studies of the drug, and as a therapy it is not without adverse events (AEs), the FDA noted. AEs can include nausea, fatigue, vomiting, diarrhea, cold-like symptoms and various types of pain, including joint, musculoskeletal and abdominal. Serious AEs include myelodysplastic syndrome, acute myeloid leukemia, and lung inflammation.4
Robson said such risks are especially a concern for those considering olaparib as a preventive therapy or for early stages of cancer treatment. But he said there may be other factors involved for patients who experience AEs, such as effects of prior medications, and more study is needed. He said most of the events have occurred in people who have been fairly heavily pretreated.
“The numbers are not, to my knowledge, high enough to signal that there is a definitive association. It is an important theoretical concern—it needs to be monitored very, very carefully, but I do think that we have to be careful not to allow a theoretical concern to get in the way of doing the research that needs to be done,” said Robson.
While PARP inhibitors have already shown merit as an important new class of cancer fighters, the breadth of their potential and their strength against particular types of cancer have yet to be determined, he said.
“You have an approved agent, so I think it is important,” Robson said. “And if it starts showing benefit in broader groups of population, either people with sporadic mutation versus BRCA pathways that are not necessarily germline, then it could be even more important. Right now, it looks like the impact is going to be greater in ovaries than it is in breast, but that could well change.”
Preventive Role Remains Speculative
The ability of PARP inhibitors to target cells that have acquired at least one defect in a DNA repair pathway has led to speculation that PARP inhibitors could be used as a preventive agent in patients in whom cancer has not yet developed. While current preventive surgical options for women with BRCA1/2 mutations include prophylactic bilateral mastectomy and bilateral salpingo-oophorectomy, some researchers believe PARP inhibitors may one day offer a more desirable solution.5
Robson said such an option should first be backed up by thorough research and analysis. “I think that the idea of having a pharmacologic prevention approach is sort of aspirational right now. Yes, we know that PARP inhibitors are effective in people with advanced-stage cancer that’s linked to BRCA mutations, but we really don’t have any data regarding the utility in the setting of an unaffected woman,” he said. “We don’t even yet have data about use in the adjuvant setting.”
There are studies on the preventive value of PARP inhibitors under way, but there is no understanding of how these agents may affect otherwise healthy people over the long term, he said. “There are reasons to be slightly hesitant about prolonged use of an agent that impairs DNA damage repair in a healthy population. Now, those concerns are all theoretical. There are no real data to tell you that it is unsafe, but I think the bar has to be pretty high before we start using it.”
Therefore, PARP inhibitors are likely to remain a distant goal as a preventive measure and surgical intervention must be recognized for its value as a means of forestalling the development of cancer, Robson said.
“You know, people say we are going to find these mutation carriers and we are going to prevent their cancers. What we are actually saying is we are going to find these mutation carriers and they have to undergo prophylactic mastectomy and oophorectomy if they want to prevent their cancers,” said Robson.
“We have to be mindful of what it is that we are offering people for prevention,” he continued. “Now, that’s not to say that people won’t choose to do that, but we have to be very honest about what the downstream decisions will be for people who are found to have mutation.”
- NIH Clinical Trials Registry. www.ClinicalTrials.Gov. Identifier NCT02000622.
- Drost R, Jonkers J. Opportunities and hurdles in the treatment of BRCA1-related breast cancer [published online August 19, 2013]. Oncogene. 2014;33(29):3753-3763.
- Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497-506.
- FDA approves Lynparza to treat advanced ovarian cancer [news release]. Silver Spring, MD: US Food and Drug Administration; December 19, 2014.
- Vinayak S, Ford JM. PARP inhibitors for the treatment and prevention of breast cancer. Curr Breast Cancer Rep. 2010;2(4):190–197.