The Evolving Role of PARP Inhibitors in Ovarian Cancer - Episode 11
Whitney S. Graybill, MD, MS: When I’m trying to decide what I’m going to treat a patient with in the recurrent setting, I usually consider first whether it’s a platinum-sensitive recurrence or a platinum-resistant recurrence. If it’s platinum sensitive, I try to treat with a platinum doublet, usually carboplatin with Taxol (paclitaxel). Now if a patient has had a significant problem with neuropathy, then I’ll consider other agents along with carboplatin such as gemcitabine or Doxil (doxorubicin). I also have some patients who really don’t want to lose their hair again, and in that setting I’ll also tend to avoid Taxol and retreat with a gemcitabine/carboplatin or Doxil/carboplatin doublet. So, I really try to individualize it to toxicity, quality of life, and what the patient desires.
The other area is the platinum-sensitive recurrence setting. I am now tending to offer patients a PARP inhibitor maintenance treatment after their second recurrence, or after their first recurrence, if they’ve had a partial response or complete response to platinum-based chemotherapy. If a patient has platinum-resistant disease, then I tend to go with single-agent therapy, typically Taxol, or a single-agent weekly regimen of topotecan, gemcitabine, or Doxil. And that is usually plus or minus Avastin (bevacizumab) in the recurrent platinum-resistant setting. Also in the recurrent setting, I’m now evaluating patients for eligibility to be treated with PARP inhibitors. If I have a patient who is BRCA-positive, after their third-line treatment, I discuss putting them on olaparib. For my patients who are BRCA-positive or HRD-positive, I consider rucaparib if there have been greater or equal to 2 lines of prior treatment.
Oliver Dorigo, MD, PhD: The treatment of recurrent ovarian cancer is certainly very challenging and, in my opinion, has to be individualized to the patient. We do include, at least in my practice, information about germline and somatic mutation testing. We also include, as a very important factor, prior history in terms of treatment for the patient. In general, I like to consider patients who have long disease-free intervals, at least 6 months or more after completion of the prior chemotherapy, as being platinum-sensitive. I tend to treat those patients with another platinum-containing regimen.
In the recurrent setting, platinum can be combined with Taxol or doxorubicin, which in the latest setting has less effects with similar efficacy. I do also use, in a number of my patients, bevacizumab as an antiangiogenic agent, which has shown to really increase progression-free survival. I use it as maintenance therapy after completion of the combination treatment with chemotherapy and bevacizumab. We have data from the Gynecologic Oncology Group that suggests even the overall survival might actually be prolonged. So, bevacizumab as a maintenance therapy is certainly something I would strongly consider.
Those patients who have BRCA1 and BRCA2 mutations and have had more than 3 lines of prior chemotherapy are excellent candidates for treatment with a PARP inhibitor. Olaparib or rucaparib are approved in this space here. If patients become platinum resistant or refractory, meaning they either do not respond to a platinum-containing chemotherapy regimen or they recur or progress with disease within 6 months after completion of prior treatment, those are the patients I consider for a different agent. I like to use, as one of my first choices, doxorubicin in combination with Avastin again. I also choose topotecan as a third or fourth-line agent, particularly in those patients who are platinum resistant.
Patients who have platinum resistance should be advised on considering a clinical trial. At my institution, which is a large academic center, we do run a number of very innovative clinical trials that focus on PARP inhibitors, targeted therapies, and immunotherapies. I think these areas are where we will make advances in ovarian cancer treatment that will be very meaningful going forward in the future.
Matthew Powell, MD: When we look at sequencing, it’s really hard to use a specific algorithm. I think understanding what tools we have to treat our patients, how they did with their prior therapy, what their goals are for schedule, and then the need for travel, the need for other features, all play into that. There’s no 1 single method we use for these patients, but I would say maximizing platinum seems to be important. And then, adding in our targeted therapies early on in the disease course makes sense.
Oliver Dorigo, MD, PhD: We also get information about microsatellite instability. When this is high in ovarian cancers, we can potentially use immune checkpoint inhibitors. Pembrolizumab is approved in this space at this point. We also get information about what’s called tumor mutational burden, which, when high, could predict response to other immune therapies. But immune checkpoint inhibitors could be an option for the patient.
I think one has to greatly individualize the treatment. A lot of the treatment choices are based not only on what the patient responded to prior, but also much on genomic mutation testing, germline testing, and the ability of the patient to tolerate certain drugs. There are chemotherapies that are highly bone marrow suppressive. Those might not be adequate or appropriate to choose at the point in treatment when we consider that the patient won’t tolerate this.
Transcript Edited for Clarity