PARP inhibitors are offering new treatment options for ovarian cancer patients with known mutations, but early-stage diagnosis is still elusive.
Ovarian cancer is the most common cause of cancer mortality from gynecologic tumors in the United States, as treatment options have been limited and diagnosis at an early stage has been a challenge. But while the treatment paradigm has not significantly changed over the past two decades, regimens have evolved and PARP inhibitors have become available to treat a subset of patients.
Most patients are diagnosed with advanced disease, as symptoms tend to be vague and there are no screening strategies similar to those for other cancer types, such as breast or colorectal. “About 85% of patients are diagnosed with extra ovarian disease, unfortunately,” explained Deborah K. Armstrong, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, during the National Comprehensive Cancer Network (NCCN) Annual Conference, held March 22-24 in Orlando, Florida. “We are still not very good at diagnosing ovarian disease when it is surgically curable and limited to the ovaries.”
About 75% of patients also have type II tumors, which are high-grade serous carcinosarcomas, and undifferentiated carcinomas. “These tumors tend to be aggressive and at an advanced stage, and they account for the majority of patients we see and the treatments we give,” she said.
A quarter of patients have type I tumors; endometrioid, clear cell, mucinous, low-grade serous, and low-grade adenocarcinoma. “They tend to be early stage and indolent and are characterized by K-RAS, B-RAF, PTEN, and beta-catenin mutations,” said Armstrong. “We are learning more about the mutation profiles of these cancers.”
Surgery is often the initial treatment of choice for ovarian cancer, although data on the efficacy of neoadjuvant chemotherapy has challenged this strategy. However, the percentage of maximum cytoreductive surgery that can be performed is “really a straight line correlation” with overall survival, she pointed out. Surgical debulking can still be important for patients who are able to undergo the procedure, even in the era of neoadjuvant chemotherapy.
Chemotherapy with paclitaxel combined with cisplatin or carboplatin remains the mainstay of first-line therapy. There has been an increase during the past 5 years in the so-called “dose-dense” paclitaxel, where it is given weekly (days 1, 8, and 15). Studies have demonstrated mixed results, Armstrong explained, as to whether it is superior to the standard regimen.
There are also the bevacizumab-containing regimens, and these remain somewhat controversial, although “we see it across it the guidelines,” she said. “It can be considered in upfront therapy, combined with chemotherapy for platinum-sensitive disease and platinum-resistant disease, or used alone. In the US it has not been approved by the Food and Drug Administration (FDA) for initial therapy but is being considered for that use at this time.”
In terms of recurrent disease, Armstrong explained that it is divided into platinum-sensitive and platinum-resistant, and the regimens vary accordingly. The duration of the progression-free interval will also influence the selection of the nonplatinum chemotherapeutic agents/regimen.
In platinum-sensitive disease, the preferred regimens are a platinum agent combined with gemcitabine, gemcitabine/bevacizumab, liposomal doxorubicin, or paclitaxel/bevacizumab.
For platinum-resistant disease, treatment tends to be with a single agent. “Studies have looked at single agents compared to combinations, but there has been no benefit seen with combination chemotherapy,” said Armstrong.
Treatment for this population includes single-agent regimens of docetaxel, etopside, liposomal doxorubicin, and topotecan, with some combined with bevacizumab. But more research is needed on bevacizumab in this setting, explained Armstrong. “We don’t know if patients who have previously received bevacizumab front-line will still continue to benefit in the platinum resistant setting.”
The most recent advance in ovarian cancer treatment has been the advent of PARP inhibitors, which were initially approved to treat patients with epithelial ovarian cancer who have known mutations (germline or somatic) in BRCA. In addition, there is evidence that they may be effective in the absence of BRCA mutations.
Three PARP inhibitors are commercially available, and while they have received FDA approval for use in different clinical settings, there have been no direct head-to-head studies. The first one to receive approval was olaparib, in 2014, for the treatment of active disease in patients with germline BRCA mutations who have received more than three prior lines of therapy. The second was rucaparib, approved 2 years later in 2016, for treatment of active disease in patients with germline/somatic BRCA mutations who have received more than two prior lines of therapy. The most recent was niraparib, approved last year for maintenance therapy in patients with platinum-sensitive disease who have responded to second-line therapy.
After its initial approval, olaparib received an expanded indication last year as maintenance therapy for patients with platinum-sensitive recurrent disease who achieved a complete or partial response after treatment with platinum-based chemotherapy. This was based on a phase II randomized trial that showed a progression-free survival benefit for maintenance in patients with platinum-sensitive high-grade serous ovarian cancer who had already received previous platinum regimens (8.4 vs 4.8 months; hazard ratio, 0.35; 95% CI, 0.25–0.49; P < .00001).
“All three of these PARP inhibitors have been included in the NCCN guidelines,” said Armstrong. “A rucaparib trial has been completed and reported, so we have included rucaparib for maintenance therapy in the guidelines as well.”