Novel Frontline Regimens Are Emerging for Advanced Ovarian Cancer

Bradley J. Monk, MD, FACOG, FACS

Over the past few years, the FDA has approved various medicines from several new drug classes to treat patients with ovarian, fallopian tube, and peritoneal cancers. Although most approvals occurred in the recurrent ovarian cancer setting, numerous studies are expected to present data in the coming year that may transform how clinicians manage newly diagnosed disease.

Ongoing clinical trials are investigating the frontline use of PARP inhibitors, immunotherapies, and targeted agents and how to combine these drugs with each other and with standard chemotherapy. During an OncLive Peer Exchange^® panel discussion, moderator Bradley J. Monk, MD, and other gynecologic oncology experts from across the United States talked about how new evidence has affected their approach to treating advanced ovarian cancer.

They also debated the potential benefits and obstacles to incorporating bevacizumab (Avastin) into frontline regimens. Shortly after the panel session, the FDA approved bevacizumab as an add-on to adjuvant carboplatin and paclitaxel (Abraxane) for patients with advanced ovarian, fallopian tube, or peritoneal cancer.

Neoadjuvant Choices

Because advanced ovarian cancer has a high risk of recurrence and mortality, Monk said, “It is paramount to understand optimal management of this disease and how to achieve the best outcomes for each individual patient in a first-line fashion.”Before any treatment decisions are made, it is paramount to fully stage the patient, including omentectomy and lymph node dissection, stressed panelist Matthew Powell, MD. He said despite the importance of full staging to identify patients more likely to benefit from aggressive therapies, “it’s not widely done across communities.” If staging confirms a patient has advanced disease, the next decision is whether to proceed with neoadjuvant chemotherapy (NADT) or primary debulking surgery (PDS). Because patients who begin with NADT ultimately have surgery, David M. O’Malley, MD, said all patients with advanced disease should be referred to a gynecologic oncologist before treatment, a position consistent with joint treatment guidelines from the American Society of Clinical Oncology (ASCO) and the Society of Gynecologic Oncology.¹ The guidelines recommend NADT for women unfit for PDS or for whom complete cytoreduction is unlikely.¹

Ursula A. Matulonis, MD, said several trials have shown NADT offers similar progression- free survival (PFS) and overall survival (OS) outcomes to PDS. For example, at this year’s ASCO Annual Meeting (ASCO 2018), findings from 2 randomized phase III trials showed no significant difference in survival outcomes between NADT and PDS in women with advanced ovarian cancer.^2,3 However, NADT was beneficial for women with poor performance status. “It’s really been one of the breakthroughs, that chemotherapy can convert an inoperable patient to an operable patient, and it certainly changed my practice in almost half the cases,” Monk said.

Bevacizumab in the Frontline

A recent study investigated whether adding hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes in women with unresectable advanced ovarian cancer who received NADT.⁴ Shannon N. Westin, MD, MPH, said that in the group of patients who received HIPEC at the time of debulking surgery, PFS was about 4 months longer and OS was about 11 months longer than in the group of patients who did not receive HIPEC. Westin said although the investigators said the safety profile was about the same between the 2 groups, a closer look at surgical outcomes showed a much higher rate of colostomy or ileostomy in patients who received HIPEC. “[Colostomy] wasn’t something that was mandated, and they don’t really have a good explanation for it,” she said. The panelists largely agreed they wanted more evidence of HIPEC’s efficacy before recommending it to patients.In March 2018, the National Comprehensive Cancer Network (NCCN) updated its guidelines for ovarian cancer.⁵ Powell, an NCCN panelist, explained that the NCCN downgraded several treatment recommendations because when cost and toxicity were factored in, there was insufficient evidence to support one approach over another. Thus, intraperitoneal and dose-dense weekly chemotherapy were downgraded from category 1 to 2a, whereas bevacizumab was upgraded from 2b to 2a.⁵

In 2011, findings from the ICON7 and GOG-0218 phase III trials established that adding bevacizumab to chemotherapy and continuing bevacizumab for several cycles after chemotherapy improved PFS in patients who underwent initial resection of advanced ovarian cancer.^6,7

Although the GOG-0218 results led to approval of bevacizumab as frontline therapy for advanced ovarian cancer in several countries, where its use is widespread, bevacizumab was not approved in the United States in this setting until June 2018. Approval was based on the improvement in PFS observed in updated GOG-0218 results. The findings showed that the use of bevacizumab with carboplatin and paclitaxel, followed by single-agent bevacizumab, was associated with a 6.2-month improvement in PFS compared with chemotherapy alone (18.2 months vs 12.8 months), with an HR for progression or death of 0.62 (95% CI, 0.52-0.75; P <.0001).⁸ For those who received bevacizumab plus chemotherapy without follow-up bevacizumab, the median PFS was 12.8 months (HR, 0.83; 95% CI, 0.70-0.98), a finding that was not statistically significant.

Final data from GOG-0218 were presented at ASCO 2018 in June and showed no significant difference in OS between patients who received bevacizumab with chemotherapy and those who did not. In the intention-to-treat population, the HRs for participants who received bevacizumab versus the chemotherapy-alone cohort were 0.95 (95% CI, 0.84-1.09; P = .49) for those who also took the drug as follow-up therapy and 1.05 (95% CI, 0.91-1.19; P = .41) for those who took it only at initiation. Investigators noted that patients with stage IV disease who took the bevacizumabcontaining regimen followed by single-agent therapy with the drug had a greater median OS benefit than those who received the regimen without followup bevacizumab or who had chemotherapy alone (42.8, 34.5, and 32.6 months, respectively).⁹

PARP Maintenance Therapy

Monk said the ICON7 and GOG-0218 trials used different dosing regimens for bevacizumab. The FDA approved the dose used in GOG-0218, which was bevacizumab 15 mg/kg every 3 weeks plus carboplatin/paclitaxel for up to 6 cycles followed by single-agent bevacizumab 15 mg/kg every 3 weeks for up to 22 cycles.⁶ O’Malley said he expects that the FDA approval of bevacizumab in the frontline setting combined with the NCCN guideline change will make insurers more likely to approve its use. All of the panelists agreed that approval of bevacizumab would make them more likely to offer it to select patients, but they debated when to use it. O’ Malley said he would likely use it for high-risk patients, who he considers to be those with “large ascites, largevolume disease, and extra-abdominal disease.”“We live in a PARP world,” Monk said, referring to the growing use of PARP inhibitors for recurrent ovarian cancer. He questioned whether the evidence supports moving PARP inhibitors into the frontline as maintenance therapy.

“Numerous ongoing trials are examining this question,” Matulonis said. She mentioned SOLO-1 (NCT01844986), a phase III trial in which women with a germline or somatic BRCA mutation who achieved remission after chemotherapy were randomly assigned to olaparib (Lynparza) maintenance therapy (300 mg twice daily) or to placebo. AstraZeneca, the manufacturer of olaparib, recently announced that preliminary data from SOLO-1 showed frontline maintenance with olaparib improved PFS compared with placebo.¹⁰

Niraparib (Zejula) is another PARP inhibitor being evaluated as maintenance therapy in the frontline setting. O’Malley said the phase III PRIMA trial (NCT02655016) randomly assigned women with advanced ovarian cancer who responded to platinum-based chemotherapy to maintenance treatment with niraparib or to placebo. He said PRIMA was “originally designed to have homologous recombination deficiency [HRD]-positive [women] and then was amended to have all-comers.” The PRIMA trial is in the early stages, and Monk said he does not expect any data to be released this year.

Westin explained that most PARP inhibitors cannot be administered concurrently with cytotoxic chemotherapy due to overlapping toxicities. When using them together, the PARP inhibitor and/or chemotherapy agents have to be administered at reduced doses to prevent myelosuppression, which compromises their effectiveness. “However, veliparib is a PARP inhibitor that has been able to sort of play nicely with chemotherapy,” she said. GOG-3005 (NCT02470585), a phase III randomized trial of veliparib in women with untreated ovarian cancer, recently completed accrual. Westin said patients in GOG-3005 are receiving chemotherapy with or without veliparib followed by veliparib maintenance therapy or placebo.

Potential for New Combinations

PAOLA-1 (NCT02477644) is another phase III trial evaluating maintenance therapy with olaparib in women with advanced ovarian cancer who received treatment with chemotherapy plus bevacizumab. “The patients get bevacizumab maintenance plus/minus olaparib,” Powell explained.With new options in play, "combinations make sense, at least theoretically,” Monk said.

Matulonis added, “There are some preclinical data as well as some data in the recurrent setting that suggest placing together a PARP inhibitor plus an immuno-oncology agent—[targeting] PD-1 or PD-L1—is going to give you enhanced benefit.” She said a phase I/II trial of niraparib plus pembrolizumab (Keytruda) in patients with platinum- resistant/-refractory ovarian cancer showed enhanced response rates and established the safety of the combination. Matulonis said several trials combining a PARP inhibitor with a checkpoint inhibitor were being planned. “A lot of these studies are saying plus or minus bevacizumab [and] some are mandating bevacizumab,” she said.

The phase III IMagyn050 trial (NCT03038100) is evaluating the efficacy of an initial frontline regimen that combines the immunotherapy agent atezolizumab (Tecentriq) with platinum-based chemotherapy and bevacizumab and follows it with atezolizumab maintenance therapy. Monk said the results of studies that have evaluated the combination of atezolizumab and bevacizumab in renal cell carcinoma and lung cancer suggest bevacizumab and checkpoint inhibitors may be synergistic. “The science, I think, is farther along than PARP inhibitors and immunotherapies,” he said.

O'Malley noted the "unbelievably exciting combinations" being tested in clinical trials. He questioned whether clinicians should be using HIPEC, which he said was “not ready for the big time,” or enrolling patients in clinical trials that may have a greater chance of curing them. He suggested the choice may depend on associating biomarkers such as HRD and BRCA with response and “identifying those patients who are going to benefit the most.”

References

1. Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(28):3460-3473. doi: 10.1016/j.ygyno.2016.05.022.
2. Onda T, Satoh T, Saito T, et al. Comparison of survival between upfront primary debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomized trial: JCOG0602. J Clin Oncol. 2018;36(suppl 15; abstr 5500). meetinglibrary.asco.org/record/160510/abstract.
3. Fagotti A, Vizzielli G, Ferrandina G, et al. Survival analyses from a randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer with high tumor load (SCORPION trial). J Clin Oncol. 2018;36(suppl 15; abstr 5516). meetinglibrary.asco.org/record/160515/abstract.
4. van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378(3):230-240. doi: 10.1056/NEJMoa1708618.
5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): ovarian cancer, including fallopian tube cancer and primary peritoneal cancer, v. 2.2018. 2018. NCCN website. nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed July 11, 2018.
6. Burger RA, Brady MF, Bookman MA, et al; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483. doi: 10.1056/NEJMoa1104390.
7. Perren TJ, Swart AM, Pfisterer J, et al; ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496. doi: 10.1056/NEJMoa1103799.
8. Avastin [prescribing information]. South San Francisco, CA: Genentech, Inc; 2018. accessdata.fda.gov/drugsatfda_docs/label/2018/125085s323lbl.pdf. Updated June 13, 2018. Accessed July 18, 2019.
9. Burger RA, Enserro D, Tewari KS, et al. Final overall survival (OS) analysis of an international randomized trial evaluating bevacizumab (BEV) in the primary treatment of advanced ovarian cancer: a NRG oncology/Gynecologic Oncology Group (GOG) study. J Clin Oncol. 2018;36(suppl 15; abstr 5517). meetinglibrary.asco.org/record/160513/abstract.
10. Lynparza (olaparib) significantly delays disease progression in phase 3 first-line SOLO-1 trial for ovarian cancer [press release]. Kenilworth, NJ: Merck; June 27, 2018. investors.merck.com/news/press-release-details/2018/LYNPARZA-olaparib-Significantly-Delays-Disease-Progression-in-Phase-3-First-Line-SOLO-1-Trial-for-Ovarian-Cancer/default.aspx. Accessed July 17, 2018.