Promising Treatments on Horizon in Ovarian Cancer

Richard T. Penson, MD

The treatment of women with advanced ovarian cancer is set to undergo a substantial transformation, due to an explosion of clinical trials exploring promising novel treatment options. At this point, there are 4 main groups of therapies under investigation for patients with ovarian cancer: PARP inhibitors, vaccines, anti-PD-1/PD-L1 therapies, and anti-angiogenic therapies.

For further perspective on the evolving field, OncLive interviewed Richard T. Penson, MD, Bradley J. Monk, MD, and Krishnansu S. Tewari, MD, on the changing landscape in the treatment of ovarian cancer. These experts identified PARP inhibitors as the most promising agents currently under investigation for ovarian cancer. These agents exploit the sensitivity of cells containing a defect in homologous recombination pathways to PARP inhibition (eg, those with BRCA mutations), which results in a so-called synthetic lethality that effectively targets tumor cells while sparing normal cells.

“The PARP inhibitors for BRCA mutant [ovarian cancers], either acquired or inherited, is a big thing,” said Penson, an associate professor in the department of medicine at Harvard Medical School and clinical director of medical and gynecological oncology at Massachusetts General Hospital. “We think 8% are predisposition mutations that you inherit, 10% are acquired in tumors, and another 20% to 25% are epigenetic phenomena or other mutations that disrupt homologous recombination; all of those are potentially exploitable by PARP inhibitors, so this is the hottest topic."

Penson explained that several PARP inhibitors are either in or have planned registration trials. Tewari, a professor and director of research and principal investigator at NRG Oncology and GOG Legacy at University of California Irvine Medical Center, also noted the importance of PARP inhibition in ovarian cancer, citing this approach as the subject of 3 ongoing studies: ARIEL, SOLO, and NOVA.

“When we discuss ovarian cancer and genetic instability, we really mean the high-grade serous subtype," stated Monk, a professor and director of the division of gynecologic oncology and vice chair of the department of obstetrics and gynecology at the University of Arizona Cancer Center. "Unlike other cancers, there are so many damaged oncogenes in ovarian cancer, you cannot identify one as a single therapeutic target, such HER2, BRAF, etc.”

In June 2014, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11-2 against the accelerated approval of the PARP inhibitor olaparib as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer with germline BRCA mutations.

Through this vote, the committee recommended waiting for the FDA to make a decision on olaparib until results were available from the phase III SOLO-2 trial, which began enrolling in 2013. The primary endpoint of this study is progression-free survival (PFS) by RECIST criteria. Overall survival (OS) will be a secondary endpoint, as was the case in earlier phase II trials.

Monk noted that although ODAC reached a negative decision for olaparib there are a number of other PARP inhibitors in clinical trials. He also expressed continued enthusiasm for exploiting angiogenesis in ovarian cancer.

The FDA assigned a priority review designation to the angiogenesis inhibitor bevacizumab (Avastin) in combination with chemotherapy for patients with recurrent platinum-resistant ovarian cancer, based on findings from the phase III AURELIA trial. Genentech, the company that markets the drug, announced an FDA action date of November 19, 2014.

The AURELIA trial evaluated the use of standard single-agent chemotherapy with or without the addition of bevacizumab, in patients with platinum-resistant disease (N = 361). Patients in this study had early recurrence (<6 months) following at least 4 cycles of a platinum-based regimen and were randomly assigned to therapy with single-agent chemotherapy (paclitaxel, pegylated liposomal doxorubicin [PLD], or topotecan) with or without the addition of bevacizumab.

The results showed that the addition of bevacizumab was associated with a significant benefit in PFS when compared with chemotherapy alone (HR = 0.48; P <.001), with a median PFS of 6.7 versus 3.4 months in the respective groups; the benefit in PFS was observed across all subgroups examined. Overall response rate (ORR) was also significantly improved (30.9% vs 12.6%; P <.001) and safety profile was consistent with that previously reported for bevacizumab with no new safety signals.

“AURELIA for resistant tumors was really a big splash paper; probably one of the 6 or 7 most important papers of the last year in oncology,” Penson said. “It really shows that when you add [bevacizumab] to any agent for recurrent ovarian cancer, you significantly improve progression free survival, and that’s likely to impact overall survival.”

Also in the angiogenesis realm, Monk cited the activity of trebananib, a therapy designed to block activity of a different set of targets, angiopoietin (Ang) 1 and 2, by preventing their binding to the Tie2 receptor; this agent appears to differ from VEGF-targeted agents in terms of some important side effects, such as bowel perforation or hypertension.

Trebananib has been associated with clinically meaningful improvements in PFS in patients with recurrent epithelial ovarian cancer (EOC). Both the VEGF-dependent, and Ang1/Ang2-Tie2-dependent angiogenesis pathways are active in ovarian cancer.

In terms of what he sees as the future of ovarian cancer therapy, Penson reflected that, “while interest is high in PARP inhibitors, the field has somewhat stalled. The next best thing is hard to predict, but probably the most exciting development at present are antibody-drug conjugates.”

Tewari recognized the potential for immunotherapy approaches such as anti-PD-1—directed therapies (ie, nivolumab), either with or without an anti-CTLA-4 antibody (ie, ipilimumab). He also expressed optimism for targeted therapies, such as MEK inhibitors, for low-grade serous cancers, and possibly mTOR inhibitors, for clear cell cancers of the ovary.

In a small clinical trial, the PD-1 inhibitor nivolumab was well tolerated and demonstrated promising clinical efficacy for patients with advanced or relapsed, platinum-resistant ovarian cancer. In 10 patients treated with 1-mg/kg nivolumab, the response rate was 20%. The 3-mg/kg dose was explored in 3 patients, with a response rate of 33%. A larger study is being formed to look specifically at 3-mg/kg nivolumab in advanced ovarian cancer.

In addition to checkpoint inhibitors, several novel vaccine strategies are also under investigation for patients with ovarian cancer. Researchers at the University of Pennsylvania are currently exploring a novel two-step immunotherapy consisting of an adoptive T-cell therapy and a dendritic cell vaccine. This treatment demonstrated promising activity in a phase I clinical trial for women with advanced ovarian cancer. Additionally, investigators at the University of Connecticut recently reported the discovery of a new method to identify protein mutations in cancer cells, which could lead to the creation of a personalized vaccine to treat patients with recurrent ovarian cancer.