New Concepts Emerging in Treatment of Advanced Ovarian Cancer

James Tate Thigpen, MD

Although ovarian cancer remains a formidable challenge in the United States, therapeutic advances achieved during the past several years have provided specialists in gynecologic malignancies with more options than ever for treating patients.

These options were explored by a panel of experts in a recent OncLive Peer Exchange discussion entitled “Emerging Concepts in Advanced Ovarian, Fallopian, Peritoneal, and Cervical Cancers.” The discussion was moderated by James Tate Thigpen, MD, a leader in the field whose work has helped define the most effective uses of chemotherapy for patients.

“I think this is a great time for us in the GYN oncology sphere for the development of new drugs and integration of these drugs into practice,” said panelist Robert L. Coleman, MD. “I’m very excited. The precision medicine field is just exploding. We’re excited to see it develop.”

Angeles Alvarez Secord, MD, noted that the FDA drug approvals for patients with ovarian cancer in 2014—the PARP inhibitor olaparib (Lynparza) and the antiangiogenic antibody bevacizumab (Avastin)—marked the first new agents in the malignancy since 2006.

BRCA and Other Biomarkers

“We’ll see how these agents can improve care for our patients clinically,” she said. “Biomarkers are going to help us identify patients who are most likely to benefit from these agents and improve survival, and that’s really what this is all about.”The category of ovarian cancer encompasses malignancies of the fallopian tubes, peritoneum, and ovaries, and is comprised of five histologic subtypes, explained Bradley J. Monk, MD. These subtypes consist of clear cell, endometriod, mucinous (rare subtypes unresponsive to chemotherapy), and low- and high grade serous (the most common subtype).

Robert L. Coleman, MD

These histologies are further classified as type I or II based on whether or not they display high-grade characteristics in either clinicopathologic or molecular features. Low-grade serous tumors in the fallopian tubes, peritoneal, and ovaries have molecular perturbations in the mitogen-activated protein (MAP) kinase pathway, while high-grade tumors are characterized by TP53 mutations, said Monk. In addition, there are multiple subtypes within each subtype.

Thus, ovarian cancer represents a very heterogeneous disease with “a lot of genomic chaos” in these tumors, noted Coleman. One consequence of the existence of these subtypes, he explained, is that while the current indication for olaparib specifies patients with more than three lines of prior therapy who are germline positive for BRCA mutations, study findings potentially open up the PARP class of agents to other populations.

High-grade tumors can be bifurcated based on the BRCA gene alterations or genes related to BRCA, said Monk. The National Comprehensive Cancer Network recommends that women with ovarian cancers, regardless of family history, age of onset, and histologic subtype, should be tested for BRCA mutations. Newer data show that women with non-serous cancers also express a high prevalence of BRCA1 mutations and other homologous recombination defects, noted Alvarez Secord.

Bradley J. Monk, MD

At present, testing for everything other than BRCA mutations may yield information that is not immediately clinically useful, Thigpen pointed out. Even within the realm of BRCA mutations, however, there are complexities.

Platinum-Resistant Disease

For predicting response to PARP inhibition, the ARIEL2 study¹ showed that rucaparib demonstrated robust clinical activity in patients with BRCA-negative relapsed ovarian cancer, marking the first study to suggest a possible clinical benefit with PARP inhibitors in BRCA-negative patients, said Coleman, who was the lead investigator on the trial.Patients with ovarian cancer who have progressed after first-line platinum-based chemotherapy within 6 months of treatment are classified as having platinum-resistant or refractory disease, Coleman explained. Four chemotherapy options might reasonably be selected for these patients, according to the panel: weekly paclitaxel, pegylated liposomal doxorubicin (PLD), and two topotecan regimens.

Bevacizumab was approved for the treatment of women with platinum-resistant, recurrent ovarian cancer in combination with chemotherapy on the basis of findings of the phase III AURELIA trial.² This study randomized 361 individuals to receive physician’s choice of chemotherapy or chemotherapy with bevacizumab, with the primary endpoint being progression-free survival (PFS).

PFS nearly doubled with bevacizumab, the median PFS being 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. There was no measurable change in overall survival, but many symptomatic patients saw significant resolution of symptoms, noted Coleman.

Platinum-Sensitive Recurrent Disease

Panelists were divided over which chemotherapy approach they combine with bevacizumab. “I think it’s all about individualization,” said Monk.Patients who progress after 6 months of receiving first-line therapy are classified as having platinum-sensitive disease, while those who progress between 6 and 12 months fall into a gray zone of pseudosensitive disease, Coleman said.

GOG213 SGO was a phase III trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary, and fallopian tube cancer, with 674 patients randomized and a primary endpoint of overall survival.3

Thomas Herzog, MD

The trial arm that included bevacizumab improved the stratified estimated treatment hazard ratio (HR) of death by 18.6%, (HR, 0.827 (95% CI: 0.683—1.005); P = .056), while bevacizumab was associated with greater toxicity.

Findings, “did not achieve statistical significance” yet are “clinically meaningful, which we rarely ever say,” Alvarez Secord stated. “I think it’s an important study because in the big picture it’s the fifth study with bevacizumab now showing activity and now this hint of a signal of improved overall survival.”

At the same time, Alvarez Secord said doctors should discuss the “trade-offs” of bevacizumab-containing regimens with patients. “You have to individualize your therapies,” while ensuring that patients understand potential adverse events and are willing to take the medication for the necessary duration, she said.

Frontline Treatment

Thomas Herzog, MD, also tries “to individualize a bit,” based on whether the recurrence period is 6 to 12 months or greater than 12 months after treatment, whether there is neuropathy, where the patient lives, and her personal schedule. “But all things being equal, I’ve done pretty much what the rest of the panel has done.” If the patient is “out over 12 months, I tend to go with carboplatin/paclitaxel and in light of the recent data I have a strong discussion about adding bevacizumab to those patients.”The panel did not reach consensus on the therapy most appropriate in the frontline setting after suboptimal cytoreductive surgery. Paclitaxel, carboplatin, and bevacizumab are the key agents in the frontline setting, said Thigpen. In this setting, he treats with 6 cycles of paclitaxel/carboplatin/bevacizumab and then follows that with bevacizumab maintenance until progression.”

In suboptimally bulk-reduced patients, Coleman uses weekly paclitaxel/carboplatin while Alvarez Secord favors Q3 week paclitaxel/carboplatin.

Intraperitoneal (IP) chemotherapy can be used in patients with small-volume disease, as long as they are good candidates, suggested Herzog. Alvarez Secord would select “optimal surgical cytoreduction and IP therapy” as frontline therapy and would “take IP therapy all the way up to 2 cm.”

Olaparib in Ovarian Cancer

The appropriate duration of bevacizumab therapy in the frontline setting is “an unsettled issue,” explained Thigpen. For him, current data indicate that stopping bevacizumab yields degradation of the difference between the bevacizumab and non-bevacizumab clinical trial arms, suggesting bevacizumab should be continued “indefinitely.” Monk noted that “bevacizumab starts in cycle 2,” since “the first cycle is without bevacizumab to allow healing.”The FDA approved the PARP inhibitor olaparib in December 2014 for patients with germline BRCA-positive advanced ovarian cancer following treatment with 3 or more prior lines of therapy. This decision was based on a similar subpopulation of patients who experienced an objective response rate of 34% in a single-arm phase II.

The phase II trial, which had a primary endpoint of PFS, enrolled 265 patients and assessed olaparib as maintenance therapy for patients with platinum-sensitive, relapsed ovarian cancer. Although this is not the approved indication, results from this study were positive. In patients with BRCA-mutant ovarian cancer, the median PFS was 11.2 months with olaparib and 4.3 months with placebo (HR, 0.18; P <.0001).⁴

The panel’s discussion focused in part upon how long to use the drug, for although it is labeled for use until progression, toxicities may become too great for a patient to tolerate. “The Achilles’ heel is GI toxicity—so the dyspepsia, the nausea, and then the diarrhea,” said Monk. He acts proactively to provide supportive care, treating with Protonix or an H2 blocker for the dyspepsia and ensures that patients possess supportive medications for diarrhea and nausea. If necessary, he considers dose reduction. “I treat them until they progress or until they have symptoms that I can’t handle,” he said.

Similarly, Coleman prepares patients ahead of time “so they understand that this is going to happen and do not to freak out about it.” Importantly, he explains to patients in advance that the most severe symptoms frequently appear during the first cycle of olaparib therapy, while symptoms may moderate later.

Recent studies have investigated combinations of olaparib with chemotherapeutic agents and combinations of olaparib with biologic therapies, including antiangiogenic agents and immunotherapies. “I think the future here is combinations that don’t include cytotoxic chemotherapy,” said Monk, noting that this would permit oncologists to better manage toxicities.

Although data about PARP-targeting agents have focused on the serous population, Coleman noted that PARP inhibitors might potentially find a place within therapy for non-serous, ovarian/fallopian tube/peritoneal cancers.

Managing Platinum-Resistant Ovarian Cancer

Since BRCA repairs double-stranded DNA breaks, a genome with many DNA breaks provides a type of “surrogate biomarker” for PARP sensitivity, Monk said. The new terminology for this is “genomic scarring,” Alvarez Secord noted.For platinum-resistant patients, especially individuals who have been heavily pretreated, therapeutic decisions depend largely on knowledge of prior therapy and toxicities incurred, explained Herzog.

In evaluating ovarian cancer therapies, the FDA has permitted advances in quality of life and PFS to assume considerable importance, Herzog said. To demonstrate survival benefit would require enrolling thousands of patients, continuing the study for many years at a great expense to produce information that would “be irrelevant by the time it reports out,” Herzog said.

“None of the agents that we’ve talked about today has a clear survival benefit,” noted Monk. Thus, PFS has become the optimal primary endpoint for clinical trials in ovarian cancer, which he accepts so long as the therapy achieves “a sufficient prolongation of tumor stabilization and disease control to be clinically meaningful. It has to be associated with a level of adverse events and toxicities that we can stand, and ideally, even associated with improvement in patient-reported outcomes,” he said.

References

1. McNeish IA, Oza AM, Coleman RL, et al. Results of ARIEL2: A phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. J Clin Oncol. 2015;33 (suppl; abstr 5508).
2. 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.
3. Coleman RL, Brady RF, Herzog TJ, et al. A phase III randomized controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer. Presented at: Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer 2015; March 28-31, 2015; Chicago, IL. Abstract 3 (late breaking).
4. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-861.