Ursula A. Matulonis, MD, discusses ongoing developments with olaparib, as well as the overall future of PARP inhibitors in ovarian cancer.
Ursula A. Matulonis, MD
Investigators hope a duo of just-opened phase III studies will support expanding the FDA approval of olaparib (Lynparza) in ovarian cancer, according to Ursula A. Matulonis, MD.
Olaparib was approved in December 2014 for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with 3 or more prior lines of chemotherapy.
“With the underlying identification of BRCA mutations and maybe expanding beyond BRCA, PARP inhibitors, for sure, are the next personalized medicine for ovarian cancer,” says Matulonis.
Matulonis, medical director of Gynecologic Oncology at Dana-Farber Cancer Institute, says that the landscape of PARP inhibitors in ovarian cancer is currently changing. This modification stems from genetic testing in women for risks of developing ovarian cancer, as well as identifying different mutations within the disease.
OncLive: Can you tell us about the phase II study1 of cediranib and olaparib versus olaparib alone?
In an interview with OncLive during the 2016 Society of Gynecologic Oncology Annual Meeting, Matulonis discusses ongoing developments with olaparib, as well as the overall future of PARP inhibitors in ovarian cancer.Matulonis: That trial looked at single-agent olaparib versus the combination of cediranib and olaparib. Cediranib is an oral VEGF inhibitor that inhibits VEGFR-1, -2, and -3, and olaparib is an oral PARP inhibitor. One of my junior colleagues and I showed that the median progression-free survival was longer [17.7 vs 9.0 months] for women receiving the combination versus the single agent. The PFS benefit was most notable in patients who did not have an underlying BRCA mutation [16.5 vs 5.7 months]. For those patients who had a germline BRCA mutation, the combination was fairly equivalent to single-agent olaparib [PFS: 19.4 vs 16.5 months].
What are the hopes for NRG-GY004 and NRG-GY005?
The interesting thing now is that this combination is moving into 2 phase III studies—those being NRG-GY004 (NCT02446600) and NRG-GY005 (NCT02502266)—which have just opened as of February 2016.Both of these studies are looking at this combination. NRG-GY004 is looking at platinum-sensitive recurrent ovarian cancer, and NRG-GY005 is looking at the combination in platinum-resistant ovarian cancer.
The hope is that for the sensitive patients, the combination will be either similar or superior to platinum-based chemotherapy. Investigators have a choice as to which doublet they want to use—whether they want carboplatin plus paclitaxel, carboplatin plus gemcitabine, or carboplatin plus liposomal doxorubicin.
Could olaparib move to earlier lines of treatment for ovarian cancer?
In NRG-GY005, the hope is that the combination will do better than single-agent chemotherapy. The purpose of these trials is to test this concept in patients with platinum-resistant cancer, and also patients with platinum-sensitive cancer. It's really a different type of patient and a different subset of patients that we are testing this with.There's a chance that it may, but it is unlikely for that to happen based on data from these 2 trials.
Could these studies result in an expanded approval from the FDA?
How does olaparib fit into the discussion on the evolution of PARP targeting in gynecologic malignancies?
These 2 randomized phase III studies are really in all patients, irrespective of underlying BRCA status. Patients are being stratified for BRCA, but it's also for patients who have wild-type BRCA as well, whereas the FDA approval is really for patients who have germline BRCA-positive ovarian cancer.That would be the goal if the trials turn out to be positive. The FDA would have to make the decision about the approval or not, but yes. It would expand olaparib to be used in women who don't have an underlying BRCA mutation and for oncologists to potentially use it earlier.There are really 3 ways of how to select patients for PARP inhibitor use. One of them is through germline, or somatic, BRCA testing, which has been the olaparib strategy.
There are other strategies looking at homologous recombination deficiencies or measures of homologous recombination deficiencies, usually through something called genomic scarring. Homologous recombination deficiency assays involve loss of heterozygosity, telomeric allelic imbalance, and then large-scale transitions.
Those are measures that are part of the Myriad test that is now being prospectively tested in the NOVA trial (NCT01847274), which is looking at the PARP inhibitor niraparib versus placebo in patients with platinum-sensitive recurrent ovarian cancer on the heels of receipt of platinum-based chemotherapy.
The purpose of expanding the identification of tumors responsive to BRCA is that approximately 20% to 25% of ovarian cancers either have somatic or a germline BRCA mutations. We know that, overall, about 50% of high-grade serious cancers are what we call HR-deficient or have these homologous recombination deficiency properties that would allow it to be sensitive to carboplatin or PARP inhibitors.
The purpose of these other homologous recombination deficiencies tests are to try to capture those patients who will not necessarily have a BRCA mutation, but are also going to be sensitive to carboplatin or a PARP inhibitor.
The purpose of doing these tests is to look at the tumors and see if there has been evidence of DNA-repair problems. There are these genomic scars, where breaks happen in the DNA. However, they don't always get fixed correctly, so there's a scar.
How would that information impact research and practice?
The more scars you have, the more evidence you have that those tumors may be more receptive to a drug such as a PARP inhibitor.With that kind of information, it would allow one to predict the responsiveness of a cancer to a PARP inhibitor, but it also allows that test to be embedded within a clinical trial. This way, you can prospectively not only test the drug, but also use an appropriate biomarker to tell you which patients would be appropriate for this drug or not.
1. Liu J, Barry WT, Birrer MJ, et al. A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. J Clin Oncol. 2014;32: 5s. (suppl; abstr LBA5500).