On The Horizon for Ovarian Cancer: Potentially Promising Treatments

Most patients with ovarian cancer present with late-stage, bulky, and metastatic disease.^1,2Surgery and platinum-based chemotherapies are the mainstay of treatment for patients with newly diagnosed disease, but recurrence and resistance to therapy are common.²In addition, while other cancers have benefited from large-scale initiatives, such as The Cancer Genome Atlas (TCGA), and the development of targeted therapies for specific mutations, progress in ovarian cancer has been slower.

“Ovarian cancer is a disease of genetic instability;BRCA1and2encode DNA repair enzymes, and they predispose to ovarian cancer, because DNA repair cannot occur; this is the hallmark of high-grade serous ovarian cancer,” said Bradley J. Monk, MD, FACOG, FACS, 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.

Jyoti D. Patel, MD, on Cediranib Versus Olaparib in Recurrent Platinum-Sensitive Ovarian Cancer

Patel is an associate professor at Northwestern University Feinberg School of Medicine.

Monk also emphasizes the importance of distinguishing among histologic subtypes of ovarian cancer. “Epithelial ovarian cancer (EOC) is the most common type, and even within this subgroup, there are different kinds such as stromal and germ cell cancers, and we do not treat them the same.”

Within the EOC group, the main subtypes are high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous.²“When we discuss ovarian cancer and genetic instability, we really mean the high-grade serous subtype—unlike other cancers, there are so many damaged oncogenes in ovarian cancer, you cannot identify one as a single therapeutic target, suchHER2,BRAF, etc,” Monk stated.

Despite these challenges, Richard T. 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, noted that there are essentially 4 groups of therapies under investigation for ovarian cancer: vaccines, immunologic therapies designed to inhibit targets like programmed cell death receptor (PD-1), or its ligand, PD-L1, inhibitors of poly ADP-ribose polymerase (PARP), and anti-angiogenic therapies, such as those designed to target vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), anti-angiopoietins, and antibody drug conjugates (ADCs).

PARP Inhibitors

PARP inhibitors are among the most promising agents currently under investigation for ovarian cancer.^1-3These agents exploit the sensitivity of cells containing a defect in homologous recombination pathways to PARP inhibition (eg, those withBRCAmutations), which results in a so-called synthetic lethality that effectively targets tumor cells while sparing normal cells.^2,3

Anti-Angiogenesis Agents

“The PARP inhibitors forBRCAmutant [ovarian cancers], either acquired or inherited, is a big thing,” said Penson. “We think 8% are predisposition mutations that you inherit, 10% are acquired in tumors, and another 20% to 25% are epigenetic phenomena (eg,FANCD1) or other mutations that disrupt homologous recombination; all of those are potentially exploitable by PARP inhibitors, so this is the hottest topic. Maybe half of the patients with high-grade serous and endometrioid ovarian cancer could benefit from PARP inhibitors.” Penson notes that several PARP inhibitors are either in or have planned registration trials. Krishnansu S. Tewari, MD, FACOG, FACS, 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.“VEGF inhibitors are also a big deal,” Penson noted, citing the activity that has been observed with cediranib, an oral inhibitor of VEGFRs 1, 2, and 3, and c-kit, in the setting of recurrent epithelial ovarian cancer.⁴The AURELIA trial has also evaluated the use of standard single-agent chemotherapy with or without the addition of an antiangiogenic agent, in patients with platinum-resistant disease (N = 361 patients).

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.5 The results showed that the addition of bevacizumab was associated with a significant benefit in progression-free survival (PFS) when compared with chemotherapy alone (hazard ratio [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.⁵Overall 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.

&ldquo;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,&rdquo; Penson said. &ldquo;It really shows that when you add [bevacizumab] to any agent for recurrent ovarian cancer, you significantly improve progression free survival, and that&rsquo;s likely to impact overall survival.&rdquo;

Other Targeted Therapies

Clinical Pearls

• There are 4 groups of therapies under investigation for ovarian cancer: vaccines, immunologic therapies designed to inhibit targets like PD-1 or its ligand, PD-L1, PARP inhibitors, and anti-angiogenic therapies, such as those designed to target VEGF and its receptors.
• It is estimated that as much as half of the patients with high-grade serous and endometrioid ovarian cancer could benefit from PARP inhibitors.
• The results from the AURELIA trial showed that the addition of bevacizumab was associated with a significant benefit in PFS compared with chemotherapy alone.
• Although the ODAC reached a negative decision for the leading PARP inhibitor, olaparib, in June 2014, there are a number of other PARP inhibitors in clinical trials.
• Other areas of promise include emerging immunotherapies for cervical cancer, such as CVac and antibody-drug conjugates, such as investigational agents targeting the folate receptor and CA-125/MUC 16.

Looking Forward

Also in the angiogenesis realm, Monk cited the activity of trebananib, an antibody 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 also appears to differ from VEGF-targeted agents in terms of some important side effects, such as bowel perforation or hypertension.¹Trebananib has been associated with clinically meaningful improvements in PFS in patients with recurrent EOC.⁶Tewari added that &ldquo;both the VEGF-dependent, and Ang1/Ang2-Tie2-dependent angiogenesis pathways are active in ovarian cancer,&rdquo; and findings of these randomized phase 3 trials have been summarized in a recent review from his group.⁷As to the assessment of ovarian cancer within initiatives such as TCGA, Penson noted &ldquo;I think [ovarian cancer] is distinctly different from other cancers, because there are so many genetic abnormalities.&rdquo; He explained that ovarian cancer is &ldquo;driven by loss of p53, which results in huge chunks of DNA being amplified, rather than specific oncogene drivers; and so it has benefited less from TCGA than other diseases.&rdquo; Regarding the more global role of targeted therapies in ovarian cancer, Penson suggested that the tumor is &ldquo;initially very chemo-responsive, but resistance develops, and there has been less impressive benefits from targeted therapy. Patients can live for a long time, and it is hard to get drugs approved in the field. Proving a survival advantage in recurrent disease is hard, and initial benefit can get diluted out with subsequent treatment.&rdquo;Commenting on some recent developments in the field, Monk noted that, although the Oncology Drug Advisory Committee (ODAC) reached a negative decision for the leading PARP inhibitor, olaparib, in June 2014, there are a number of other PARP inhibitors in clinical trials, as noted earlier. He also expressed continued enthusiasm for exploiting the role of the microenvironment in ovarian cancer (angiogenesis), citing at least 8 different trials that have reported positive results for anti-angiogenesis agents in ovarian cancer, as recently summarized by Tewari&rsquo;s group.⁷Monk pointed out that results from AURELIA have been filed with the US Food and Drug Administration (FDA), with an FDA action (Prescription Drug User Fee Act) date of November 19, 2014.⁸Monk also sees promise in emerging immunotherapies for cervical cancer, including treatments such as CVac.⁹

In terms of what he sees as the future of ovarian cancer therapy, Penson reflected that, &ldquo;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,&rdquo; he said, citing some investigational agents targeting the folate receptor and CA-125/MUC 16. Lastly, Tewari recognizes the potential for immunotherapy approaches such as anti-PD-1—directed therapies (ie, nivolumab), either with or without anti cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody (ie, ipilimumab), currently in development through the NCI and the NRG Oncology cooperative group. He also sees potential for targeted therapies such as MEK inhibitors for low-grade serous cancers, and possibly mTOR inhibitors, for clear cell cancers of the ovary. He adds, however, that these therapies have not yet changed treatment paradigms in the US. &ldquo;The US FDA has not yet approved any of these novel targeted therapies for the management of ovarian cancer&rdquo; he said.

References

1. Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of advanced-stage epithelial ovarian cancer.Nat Rev Clin Oncol. 2013;10(4):211-224.
2. Banerjee S, Kaye SB. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential.Clin Cancer Res. 2013;19(5):961-968.
3. Eskander RN, Tewari KS. PARP inhibition and synthetic lethality in ovarian cancer.Expert Rev Clin Pharmacol. 2014;7(5):613-622.
4. Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer.J Clin Oncol. 2009;27(33):5601-5606.
5. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial.J Clin Oncol. 2014;32(13):1302-1308.
6. Monk BJ, Poveda A, Vergote I, et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase III trial.Lancet Oncol. 2014;15(8):799-808.
7. Eskander RN, Tewari KS. Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—mechanistics, review of phase III randomized clinical trials, and regulatory implications.Gynecol Oncol. 2014;132(2):496-505.
8. BioTechnology Events. FDA grants Roche&rsquo;s Avastin priority review for recurrent platinum-resistant ovarian cancer. http://www.biotechnologyevents.com/node/8965. Accessed September 22, 2014.
9. Prima BioMed. CVac&trade;. http://www.primabiomed.com.au/products/cvac.php. Accessed September 22, 2014