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PARP Inhibitors in Front-Line and Maintenance Therapy of Ovarian Cancer: A Changing Standard of Care

October 30, 2019

ColemanAt the European Society of Medical Oncology (ESMO) Annual Meeting (September 26-30, 2019; Barcelona, Spain), Robert L Coleman, MD, The University of Texas MD Anderson Cancer Center (Houston, TX), presented on the potential integration of veliparib with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin.

Journal of Clinical Pathways spoke with Dr Coleman regarding this treatment strategy as well as the larger PARP inhibitor landscape for treatment of ovarian cancer across various histologies and disease stages.

How would you describe the current treatment landscape of front-line and maintenance therapy in patients with high grade serous carcinoma of the ovary?

Dr Coleman: The general primary treatment landscape for ovarian cancer patients includes the consideration of surgery and systemic, multiagent chemotherapy. The contemporary goal for surgery is complete removal of visible disease, or complete gross resection (CGR), so evaluation of how amenable this target is to accomplish informs the strategic approach. Several different modalities of assessment are used but in general, when it is felt there is a reasonably good chance that CGR can be accomplished or there is need for proximate surgical attention (ie, impending bowel obstruction, organ compromise, pain, etc), primary surgery is performed followed by chemotherapy. If CGR is not felt not to be amenable or the patient is at high risk for surgery, chemotherapy can be induced and surgery deferred (usually for three or four cycles) whereby surgery can be attempted.

In late 2013, we reviewed our approach to surgery and available assessment tools and initiated a program modeled after that purported by Anna Fagoti, MD, and her colleagues in Europe, which employed diagnostic laparoscopy as a way to assess tumor volume and tumor distribution to inform the decision as to surgery or chemotherapy first. Currently, patients coming to our clinic with new diagnoses of suspected ovarian cancer will be counseled to consider a diagnostic laparoscopy in order to make this decision. We have found that our ability to achieve CGR in either setting (primary or interval cytoreduction) using laparoscopic assessment is over 80%.

Primary adjuvant chemotherapy for advanced-stage ovarian cancer has changed very little over the past 25 years. Outside of the introduction paclitaxel in 1996, only bevacizumab (2018) and most recently, olaparib (2018, in BRCA-mutated ovarian cancer) have been successfully added to (bevacizumab) or after (olaparib) combination platinum/paclitaxel. Nevertheless, several concepts in treatment—including intraperitoneal chemotherapy, dose-dense paclitaxel, dose dense carboplatin, the addition of non-cross resistant chemotherapy triplets, and sequential doublets—have been studied in the front-line setting. A lot of work has been done, but we did not move the needle much.

The introduction of PARP inhibitors has completely changed how we approach this disease, even to the point where we are starting to consider whether we will be able to avoid chemotherapy altogether for some patients. PARP inhibitors have the potential to change what has been considered the standard of care for almost 25 years.

As far as PARP inhibitors in ovarian cancer are concerned, how is veliparib currently regarded with respect to standard of care? Furthermore, how is it determined which PARP inhibitor should be used for a specific patient?

Dr Coleman: In women with recurrent, platinum-sensitive ovarian cancer who respond to an induction regimen of platinum-based chemotherapy, there are three approved PARP inhibitors that can be used as switch maintenance: niraparib, olaparib and rucaparib. Given their relatively similar efficacy profiles, the choice of a specific PARP inhibitor usually comes down to physician choice and comfort managing their somewhat different adverse event profiles. Rucaparib, olaparib, and most recently niraparib have specific indications as to treatment of recurrent disease, but with efficacy parity in the mix, the choice is generally guided by experience.

In the primary treatment setting, only olaparib is approved in BRCA-mutated ovarian cancer. It is administered, like the recurrent setting, as a single agent following platinum-based chemotherapy. At ESMO 2019, a fourth PARP inhibitor, veliparib, was introduced. Veliparib has been evaluated both as a single agent in BRCA-mutated recurrent ovarian cancer and in combination with chemotherapy. Previous attempts at combining PARP inhibitors with chemotherapy have been challenged by myelosuppression necessitating dose-delays and substantial dose-reductions of both the PARP inhibitor and chemotherapy. Veliparib, likely due to its pharmacokinetic and pharmacodynamic properties, has been able to be combined with full dosages of chemotherapy. The feasibility of this strategy led to the VELIA/GOG-3005 trial presented at ESMO 2019.  

The results of your study suggest that veliparib with carboplatin and paclitaxel, followed by veliparib maintenance, leads to very positive progression-free survival results. Do you believe that this result is enough to lead to a change in standard of care, or is there a need for further follow‑up or validation studies?

Dr Coleman: In short, I do believe the results are strong enough to enable consideration of this approach in women with newly diagnosed, advanced-stage ovarian cancer. Ultimately, the regulatory agencies will drive this decision. However, given the number of positive clinical trials evaluating PARP inhibitors in the primary maintenance setting (as opposed to the primary adjuvant setting), clinicians are now challenged to make decisions based on datasets from trials with different patient populations, controls, agents, and endpoints. Compounded with this are analyses from unstratified, underpowered, hypothesis-generating subgroups, using imperfect biomarkers and assessing the relative merits of treatment across trials. The question of the optimal standard of care for a newly diagnosed patients has to juggle these various concepts. 

VELIA/GOG-3005 was a trial designed to address the common ovarian cancer patient. It allowed both primary and neoadjuvant chemotherapy approaches and it allowed paclitaxel to be given every 3 weeks or weekly. It included patients without restriction on their genotype or tumor homologous recombination deficiency (HRD) status. The primary endpoint of the trial was progression free survival, comparing veliparib given throughout chemotherapy and continued as maintenance (2 years of treatment) to combination chemotherapy alone. Progression-free survival was assessed in three analytical cohorts: BRCA-mutated ovarian cancer, HRD tumors (including BRCA-mutated ovarian cancers), and all patients. The clinical application is one that is in consideration at diagnosis. Frequently at that point, only BRCA status is known, particularly in patients getting NACT. So, the relevant clinical question is based on the information at hand is whether or not to initiate veliparib or bevacizumab – assuming veliparib is approved. If neither is initiated or if bevacizumab is initiated with chemotherapy, then the clinical question reverts to an assessment of tumor HRD status, which includes BRCA status. If bevacizumab was initiated, then a decision to add olaparib or not is entertained based on the results of PAOLA-1. If neither veliparib or bevacizumab is initiated with chemotherapy, then based on BRCA status and HRD status, a decision for switch maintenance olaparib (SOLO-1) or niraparib (PRIMA) would be entertained, as well as consideration for a clinical trial.

The world just got more complex, but the central theme was that VELIA demonstrated that one could safely give a PARP inhibitor with full dose chemotherapy and continuance as maintenance benefit all enrolled patients, particularly those who’s tumors harbored BRCA-mutation/HRD. Since the trial was not predicated on response to induction therapy like the other maintenance trials, the results have broad appeal and potentially capture that small fraction of patients who would have otherwise progressed on primary treatment had they not also received veliparib. Nevertheless, the merit of a PARP inhibitors in patients with tumors harboring HRD is remarkable and reproducible, offering new options for patients deemed most likely to be curable.

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