Optimal Sequencing Remains a Hurdle in Ovarian Cancer Treatment

Maurie Markman, MD

The surge of treatment options for patients with ovarian cancer poses a daunting challenge as answers for optimal sequencing continue to elude clinicians. Bevacizumab (Avastin) continues to hold the most utility in this disease setting, but the addition of PARP inhibitors, and immunotherapy raises the question of how to best deliver efficient regimens to patients. The future looks to be defined by essential clinical trials.¹

“The problem relates to chaos in ovarian cancer management,” said Maurie Markman, MD during the virtual live webcast of the 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ hosted by Physicians’ Education Resource®, LLC (PER®). “The questions that confront the clinicians the individuals designing clinical trials are profound and overwhelming.”

Markman, who is the president of Medicine & Science at Cancer Treatment Centers of America and clinical professor of medicine, Drexel University College of Medicine in Philadelphia, PA, discussed the how currently available treatments may hold untapped potential and how the design of clinical trials can help unlock the best outcomes for patients.

Navigating the Ovarian Cancer Treatment Landscape

Bevacizumab

Bevacizumab’s approval in 2014 kicked off the wave of new agents and indications in a stagnant treatment landscape. The initial approval was based on results from the phase 3 AURELIA study (NCT00976911) in 361 women with epithelial ovarian, primary peritoneal, or fallopian tube cancer in which bevacizumab plus chemotherapy decreased the risk of progression or death by 62% compared with chemotherapy alone. The median progression-free survival (PFS) was 6.8 months with bevacizumab versus 3.4 months with chemotherapy alone (HR, 0.38; P <.0001).²

“There had never been a phase 3 randomized trial in 50 years since cisplatin was developed showing an impact on an end point like PFS in platinum-resistant disease, the AURELIA trial was the first and remains the only positive trial with bevacizumab,” Markman said.

Next, 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 (NCT00434642), and GOG-0213 (NCT00262847) studies, where it was combined with carboplatin/gemcitabine and carboplatin/paclitaxel, respectively.

In the OCEANS study, bevacizumab in combination with platinum-based chemotherapy increased the median PFS to 12.4 months versus 8.4 months with chemotherapy alone (HR, 0.46; 95% CI; 0.37-0.58; P <.0001) in patients with recurrent, platinum-sensitive disease.³

In June 2018, bevacizumab was approved in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent, for patients with stage III or IV disease following initial surgical resection. Efficacy was determined in the GOG-0218 study in which the use of initial and maintenance bevacizumab demonstrated a median PFS of 18.2 months compared with 12.0 months for chemotherapy alone (HR, 0.62; 95% CI, 0.52-0.75; P <.0001). In a third arm of the study, patients who received bevacizumab plus carboplatin and paclitaxel without the maintenance phase reached a median PFS of 12.8 months compared with 12.0 months chemotherapy alone, a difference that was not statistically significant.³

In final analysis none of the 3 treatment arms resulted in a statistically significant gain in OS after a median follow-up of 102.9 months. However, in patients who started with stage IV disease, the use of concurrent-plus-maintenance bevacizumab with chemotherapy was associated with a longer median OS of 42.8 months versus 32.6 months with chemotherapy alone (HR, 0.75; 95% CI, 0.59-0.95).⁴

“Data that demonstrates not only in ovarian cancer but other cancer types, the ability to give bevacizumab after bevacizumab continues to improve outcomes if you have a different backbone,” he added.

PARP Inhibitors

Three FDA-approved PARP inhibitors include olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca), which currently have 7 indications in ovarian cancer.^5-7 Most recently on April 29, 2020, niraparib gained another indication with the approval of the agent for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response (PR) to first-line platinum-based chemotherapy, regardless of biomarker status.

While these approvals all mark progress, Markman noted that one of the controversies surrounding these 3 agents are their utility across real-world patient populations. “Is there a superior anti-PARP agent and does this differ based on specific clinical settings?” asked Markman.

Combinations for PARP inhibitors also extends beyond their utility and sequencing of one another, it also should be thought of for treatments such as bevacizumab, said Markman. “What is the role of adding an anti-PARP agent to bevacizumab in primary or second-line therapy, in specific molecular subtypes, like BRCA mutations or patients who are HRD positive, and is there greater clinical benefit associated with either combination versus sequential therapy?”

PARP inhibitors in combination with bevacizumab are in fact on the horizon as the FDA considers olaparib plus bevacizumab as frontline maintenance therapy for the treatment of patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy with bevacizumab. Of note, none of the other FDA-approved PARP inhibitors have received regulatory approval as frontline maintenance.

Data from the phase 3 PAOLA-1 trial (NCT02477644) showed a benefit with maintenance PARP inhibition in this setting. Patients were randomly assigned maintenance therapy with olaparib plus bevacizumab (n = 537) or placebo plus bevacizumab (n = 269). Olaparib or placebo were administered for up to 24 months and bevacizumab was administered for up to 15 months.^8,9

The trial met its primary end point, showing that for the overall population, patients who received olaparib plus bevacizumab as maintenance therapy had a 5.5 longer median PFS and a 41% lower likelihood of relapse or death compared with patients who received placebo plus bevacizumab (22.1 vs 16.6 months; HR, 0.59; 95% CI, 0.49-0.72; P <.0001).

Further, patients harboring a BRCA1/2 mutation had an even greater PFS benefit of 37.2 months versus 21.7 months (HR, 0.31; 95% CI, 0.20-0.47), and patients who were HRD-positive also had a greater PFS benefit of 37.2 months versus 17.7 months (HR, 0.33; 95% CI, 0.25-0.45).

Markman also posed whether there is untapped potential of these agents that would come with optimal sequencing. “Is there a clinical utility associated with employing a PARP after PARP strategy and if there is, what difference does that specific combination or sequence make?” asked Markman.

In addition to testing for BRCA and HRD in patients, Markman transitioned to discussing the presence of mismatch repair deficiency (MMR) or microsatellite instability (MSI).

In a recent study, 582 patients with ovarian cancer were screened for MMR deficiency by immunohistochemistry. MMR deficiency/MSI was predominantly seen in endmetrioid cancers (8 of 35, 23%) signaling a higher prevalence of patients in this tumor subtype who may benefit from tailored treatments.¹⁰ “The question is should it be standard of care in that setting to do such testing and what line of therapy [should be used?” asked Markman.

Where Does the Treatment Go From Here?

The future of ovarian cancer management is in clinical trials. However, he stressed the need for pragmatic clinical trials designed to address simply address questions that are relevant to patients and their oncologists. “By quickly addressing multiple current clinical issues and controversies we can help oncologists optimally plan treatment for future patients,” he said.

Included in suggestions for how to best assess these patient populations were selecting end points that are meaningful to patients including efficacy, toxicity, and quality of life. Markman also added that trial design should strive to reflect real world populations by avoiding objectively unnecessary inclusion and exclusion criteria. Additionally, designs should address multiple current clinical issues and optimally plan treatments for future patients, while also allowing for and encouraging crossover.

“Hopefully these trials can be strongly supported by the FDA and receive the appropriate funding from agencies, payers, academic centers, patient advocacy groups, and pharmaceutical or biotech companies,” Markman concluded.

References

1. Markman M. Future directions: where are we headed. Presented at: 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ hosted by Physicians’ Education Resource®, LLC (PER®). May 2, 2020.
2. Bevacizumab solution in combination with paclitaxel. FDA website. Accessed May 2, 2020. bit.ly/33ZCsS9
3. Avastin. Prescribing information.
4. Tewari KS, Burger RA, Enserro D, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol. 2019;37(26):2317-2328. doi:10.1200/JCO.19.01009
5. Lynparza. Prescribing information. AstraZeneca Pharmaceuticals LP; 2018. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s006lbl.pdf
6. Zejula. Prescribing information. Tesaro, Inc; 2017. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf
7. Rubraca. Prescribing information. Clovis Oncology, Inc; 2018. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf
8. Lynparza (olaparib) regulatory submission granted priority review in US for 1st-line maintenance treatment with bevacizumab in advanced ovarian cancer. News release. Kenilworth, NJ. AstraZeneca and Merck & Co, Inc. Published January 13, 2020. bit.ly/2Tl5GYS
9. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Eng J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361
10. Fraune C, Rosebrock J, Simon R, et al. High homogeneity of MMR deficiency in ovarian cancer. Gynecol Oncol. 2020;156(3):669-675. doi:10.1016/j.ygyno.2019.12.031

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