Leave No One Behind: Optimizing Targeted Therapies in Ovarian Cancer

Bradley J. Monk, MD

The development of targeted therapies, including bevacizumab (Avastin) and 3 PARP inhibitors, is changing treatment paradigms for women with epithelial ovarian cancer. This underscores the need to personalize care and conduct molecular testing, according to experts.

Epithelial ovarian cancer remains the most lethal gynecologic malignancy. Although it is highly sensitive to platinum-based chemotherapy and many patients achieve remission, most will experience disease recurrence. Use of bevacizumab and PARP inhibitors, however, enables more patients with this disease to achieve long-term responses and possibly even cures.

During an OncLive Peer Exchange^® program at the 2019 Society of Gynecologic Oncology Annual Meeting in March, a panel of ovarian cancer experts discussed how they use these agents in their own practices.

A consistent refrain during the discussion: “Leave no one behind.”

“My theme is to try to maximize the opportunity for my patients to be one of these long-term responders with either bevacizumab or PARP or maybe both,” moderator Bradley Monk, MD, FACOG, FACS, said.

Bevacizumab: Where Does It Fit In?

Bevacizumab, a monoclonal antibody against VEGF, was the first targeted therapy approved for epithelial ovarian cancer and currently has 3 FDA-approved combinations for these settings: (1) with carboplatin and paclitaxel, followed by bevacizumab as a single agent, for stage III or IV disease after initial surgical resection; (2) with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease in patients who received ≤2 prior chemotherapy regimens; and (3) with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by bevacizumab as a single agent, for platinum-sensitive recurrent disease.¹

The frontline indication was the most recent approval, added in June 2018, based on the results of the phase III GOG-0218 trial. The findings showed that adding bevacizumab to carboplatin and paclitaxel followed by bevacizumab as a single agent reduced the risk of disease progression or death by 38% compared with chemotherapy alone.²

In the study, the median progression-free survival (PFS) was 18.2 months compared with 12.0 months, respectively (HR, 0.62; 95% CI, 0.522-0.75; P <.0001).² No overall survival (OS) benefit was observed. Because OS is considered the most important clinical endpoint, the appropriateness of using bevacizumab in the frontline setting remains the subject of debate.

“I don’t agree with overall survival as an endpoint in frontline ovarian cancer,” Monk said. The panelists explained that women now often get ≥8 lines of therapy, and despite studies struggling to show an OS advantage with frontline treatments, patients are living longer.

“These incremental—or sometimes not incremental but meaningful—improvements in progression-free survival in 1 particular study do matter over time [as] to how long our patients are living,” Kathleen N. Moore, MD, said, noting that studies have shown markedly increased OS overall. Monk noted that the National Cancer Institute’s latest Surveillance, Epidemiology, and End Results (SEER) Program provides evidence of this. According to the latest SEER data, almost 50% of women are surviving at least 5 years, with death rates decreasing by approximately 2.3% each year since 2007.³

Frontline Use

The panelists proceeded to discuss which of their patients receive bevacizumab in the frontline setting. “All my patients with newly diagnosed ovarian cancer, if they’re not a BRCA patient, are going to get maintenance therapy with bevacizumab,” Brian M. Slomovitz, MD, said.

The panelists also said they use bevacizumab in patients with malignant ascites, which was supported by an analysis of data from the GOG-0218 trial.⁴ In the trial, 886 women (80%) had ascites (>50 cm³ of peritoneal fluid), which was associated with poorer performance status, high-grade serous histology, higher baseline cancer antigen (CA) 125 levels, and suboptimal cytoreduction compared with no ascites.

Nevertheless, the women with ascites who received bevacizumab had significantly improved PFS (HR, 0.71; 95% CI, 0.62-0.81; P <.001) and OS (HR, 0.82; 95% CI, 0.70-0.96; P = .014), whereas bevacizumab-treated women without ascites had no benefit in PFS (HR, 0.81; 95% CI, 0.59-1.10; P =.18) or OS (HR, 0.94; 95% CI, 0.65-1.36; P =.76).⁴

Platinum-Resistant and Recurrent Platinum-Sensitive Disease

Bevacizumab was approved for platinum-resistant disease based on results of the AURELIA study and for recurrent platinum-sensitive disease based on results of the OCEANS and GOG-0213 studies, where it was combined with carboplatin/gemcitabine and carboplatin/paclitaxel, respectively.^5,6 “We’re still struggling, though, with what the right chemotherapy backbone is in recurrent disease. I think in the AURELIA study, we’ve agreed that it is weekly paclitaxel,” Monk said.

The panelists discussed findings presented at the European Society for Medical Oncology 2018 Congress, which suggested that carboplatin/pegylated liposomal doxorubicin/bevacizumab (CD-BEV) might be another important addition to the therapeutic options for platinum-sensitive patients with recurrent disease who are candidates for platinum-based retreatment.⁷ The investigators compared CD-BEV with the standard of carboplatin/ gemcitabine/bevacizumab (CG-BEV) and found significant improvement in PFS with CD-BEV versus CG-BEV (13.3 months vs 11.7 months, respectively; HR, 0.80; 95% CI, 0.680.96; P = .0128). A small improvement in PFS was also observed in the subgroup of patients who received previous antiangiogenic therapy (11.3 months with CD-BEV vs 10.1 months with CG-BEV; HR, 0.73; 95% CI, 0.57-0.94; P =.0126).⁷

The adverse effect (AE) profile was also improved with CD-BEV, suggesting that this regimen may be preferable to CG-BEV. Slomovitz said. However, the study did not assess carboplatin/paclitaxel/bevacizumab, so it remains unclear how this regimen compares with the other standard regimen of CG-BEV or the experimental regimen of CD-BEV.

Slomovitz discussed his selection process for determining the chemotherapy backbone. “In my practice, in those patients who [have received] taxanes within a year, I’ll probably go to 1 of the other doublets that doesn’t contain a platinum. But if they’re a year and a half or 2 years out without disease, I’ll go back to carboplatin and paclitaxel,” he said.

PARP Inhibitors: Practice-Changing Advances

Proteins encoded by BRCA1/2 play a role in repairing double-strand DNA breaks; thus, tumors with these mutations have lost this function and rely on alternative DNA repair mechanisms, including single-strand DNA repair.⁸ Because PARP inhibitors inhibit single-strand DNA repair in BRCA-mutated ovarian cancer, they increase the vulnerability of these tumors to cytotoxic agents.⁸

Currently, the 3 FDA-approved PARP inhibitors—olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca)—have 6 indications in ovarian cancer (Table).^9-11 The panelists expressed particular excitement over the FDA approval of olaparib in the first-line setting, which occurred in December 2018, based on data from the SOLO-1 study.¹²

Table. FDA-Approved PARP Inhibitors for Ovarian Cancer and Their Indications^9-11

“PARP inhibitors in general completely changed my practice,” Elena S. Ratner, MD, said. “I was excited about them in the recurrent setting, but [SOLO-1] changed my entire disease management.” The group concurred that, based on this study, they now use olaparib in the frontline setting for their BRCA-positive patients.

Olaparib in the Frontline: SOLO-1 Trial

SOLO-1, an international, randomized, double-blind, phase III study, assessed the efficacy of olaparib as maintenance therapy in women with newly diagnosed BRCA-mutated advanced ovarian cancer who had excellent performance status, underwent at least 1 attempt at cytoreduction, and achieved a complete or partial response to frontline platinum-based chemotherapy (N = 391).¹³

After completing chemotherapy, patients were randomly assigned 2:1 to receive oral olaparib (n = 260) or placebo (n = 131) twice daily. They continued their assigned therapy for 2 years or until disease progression. Patients could continue olaparib if there was evidence of disease at 2 years (eg, CA 125 elevation) or the oncologist requested treatment continuation.

The study’s primary endpoint was PFS. After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo. The KaplanMeier estimate of the rate of freedom from disease progression and death at 3 years was 60% with olaparib versus 27% with placebo. (HR for disease progression or death, 0.30; 95% CI, 0.23-0.41; P <.001). No unusual AEs were observed with olaparib.¹³

“If you look at our sensitivity analyses, the estimate for the median [PFS] for olaparib was somewhere between 47 and 50 months…a 3-year difference [over placebo],” Moore, a lead investigator on the study, said. “The shape of the curve on the olaparib group is unlike any curve we’ve shown in ovarian cancer to date in that it flattens, and that shape is maintained beyond the 2-year stop point. Unlike bevacizumab, where you stop at 15 months and then start to tail off, here you stop and just keep right on not progressing.”

Moore said that the study arms were very well balanced and representative of ovarian cancer in general. “About 30% of patients had neoadjuvant chemotherapy, but 70% had primary cytoreduction. And of those, over 70% were debulked per the surgeon’s report to no gross residual, and 80% were stage III versus stage IV. This is a really good prognostic group of patients,” she said, noting that such patients have historically been considered to be at such low risk of subsequent disease that they have been excluded from clinical trials, but olaparib appears to significantly increase these patients’ chance at cure.

Based on SOLO-1’s practice-changing findings, the panelists emphasized the importance of testing all patients for germline and/or somatic BRCA mutations up front to ensure that all patients who qualify for this treatment are identified. “I think anybody who does not test their patients in the primary setting is practicing mismanagement,” Ratner said, noting the patients at her practice receive germline and somatic testing.

However, the panelists made clear that there is no consensus yet on which testing methods to use, including whether concomitant or sequential testing should be undertaken. “Any CLIA [Clinical Laboratory Improvement Amendments]—approved test qualifies [as a companion diagnostic],” Moore said, indicating that next-generation versions of these tests can identify most somatic and germline mutations. Slomovitz also suggested that testing may depend on payers and recommended that oncologists work with payers to enable their patients to get tested in the most cost-effective manner.

Platinum-Sensitive Recurrent Ovarian Cancer

Monk asked the panelists if it is unethical to observe patients after a response to second-line platinum therapy. Ratner responded that it would be unethical not to offer PARP to women with deleterious germline, somatic, or homologous ELENA S. RATNER, MD recombination deficiency (HRD) mutations.

Although little is yet known about HRD mutations, data suggest that approximately 50% of high-grade serous ovarian cancers are characterized by HRD mutations and that the homologous recombination pathway for DNA repair can be disrupted by mutations in other genes, not just by germline and somatic BRCA mutations.⁹ “We know so little about [HRD], but there are going to be subsets of women within that group who are going to respond beautifully. We all have seen them,” Ratner said.

The panel also acknowledged that some patients may prefer observation to PARP maintenance. Although this is a valid option, Moore said, it is important for oncologists to inform their patients that it is not an equivalent option. “You set patients up to become resistant to platinum by just leaving them on nothing. And I think we’ve learned that now, so maintenance has a much more important role than [previously thought],” she said, indicating that once patients understand the ramifications, their decision should be supported.

Another important decision in the setting of second-line platinum-sensitive relapse is whether to use bevacizumab or a PARP inhibitor. “When I look at all my patients with ovarian cancer, I don’t look at them specifically in a vacuum at that line of therapy. I feel strongly that all women with advanced ovarian cancer, in their treatment course, deserve, at some point, bevacizumab. And at some point, they deserve a PARP inhibitor,” Slomovitz said, noting that he would probably lean toward giving a PARP inhibitor first.

Ratner agreed. “I save my bevacizumab for the women who become platinum resistant, for whom you know that’s actually going to make a difference,” she said. Additionally, when considering between bevacizumab and PARP, the panel noted that 3 predictors of PARP sensitivity should be considered: BRCA-positive status; platinum sensitivity; and number of lines of therapy, with increasing lines rendering PARP less effective.

Selecting Between Available PARP

With 3 PARP inhibitors to choose from, it may be challenging to decide which one to use. Moore said that efficacy and AE data show all 3 to be “very good drugs” and that there is no best or least-best PARP.

“When you look at the BRCA hazard ratios for maintenance, [they] are almost identical. If you look at HRD-positive [hazard ratios for maintenance], they are almost identical,” she said. She also noted that the AE profile does not help much in differentiating between them. “Niraparib has some hypertension and thrombocytopenia. Rucaparib has transaminase elevation. There’s some anemia with olaparib. But none of them make you pick one over the other. It honestly comes down to what you’re comfortable with,” she said.

In contrast, dosing may play a role in treatment selection. Olaparib and rucaparib are taken twice daily, whereas niraparib is taken once daily. Ratner suggested that this might make a difference to some women, depending on where they are in their treatment course. “I think women in the maintenance setting do not accept as much in terms of [AEs] or inconvenience as they will in treatment. Even though we all know it is truly treatment…in the maintenance setting, it must be something that has a low [AE] profile and is convenient,” she said.

Ratner emphasized the importance of personalizing therapy. “In someone with metastatic disease, I will use niraparib because I see data about it crossing the blood—brain barrier. In other women who have lower platelets, and I know they have had trouble before with thrombocytopenia, I won’t use niraparib. But, just like [Slomovitz], I believe in PARP after PARP after PARP. So, all my women have been on all 3 PARPs, maybe even 6 times,” she said.

References

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