Looking Beyond PARP Inhibitors in Ovarian Cancer Treatment

Leslie M. Randall, MD, MAS

Leslie M. Randall, MD, MAS

Despite all the positive data associated with PARP inhibitors for the treatment of patients with epithelial ovarian cancer who have knownBRCAmutations, these agents are not curing patients, said Leslie M. Randall, MD, MAS, at the 2019 SGO Annual Winter Meeting.¹

She added that PARP inhibitors are not appropriate for all patients. A little over 50% of patients with high-grade serous biology have the high-risk homologous recombination deficient (HRD) phenotype.

“I did a presentation for survivors at MD Anderson and patients understand this disease almost as well as we do,” said Randall, associate professor in the Division of Gynecologic Oncology at the University of California in Irvine. “There was a woman who stood up in the audience and said, ‘ThisBRCAthing is great and these PARP inhibitors are great, but what about me? What do I do?’ For these patients, it's really important to tease out these pathways and alternate therapies.”

The treatment paradigm for this disease still includes antiangiogenic agents, antibody-drug conjugates (ADCs), DNA damage repair inhibitors, and epigenetic agents.

The most important and best studied antiangiogenic mechanisms of action in ovarian cancer are the VEGF pathway and VEGF pathway receptor. Treatments targeting these pathways have been evaluated in multiple phase III trials and have consistently demonstrated a progression-free survival (PFS) benefit. However, these agents have not been shown to improve overall survival.

The current antiangiogenic in the pipeline is cediranib, a potent small molecule pan-VEGF receptor tyrosine kinase inhibitor. It has been shown to improve PFS in women with measurable platinum-sensitive relapsed high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer when used in combination with olaparib (Lynparza).

Results from an analysis conducted after 67 PFS events presented at the 2017 ASCO Annual Meeting, Joyce F. Liu, MD, MPH, and colleagues found that the median PFS cohort was 8.2 months in the olaparib alone arm (n = 46) and 16.5 months in the cediranib/olaparib arm (n = 44; HR, 0.50;P= .007). In the patients who were known carriers of a germlineBRCAmutation, the median PFS was nearly identical between the 2 arms (16.5 vs 16.4 months; P = .42).²

There were 24 patients withBRCAmutations in the olaparib monotherapy arm and 23 in the cediranib/olaparib arm. In patients without a known germlineBRCAmutation, the median PFS was superior in the cediranib/olaparib arm compared with olaparib monotherapy, at 23.7 versus 5.7 months (HR, 0.32;P= .002).

In the primary analysis performed in March 2014 after 47 PFS events, the median PFS was 17.7 months for the women treated with the combination compared with 9.0 months for those treated with monotherapy (HR, 0.42;P= .005).

Ninety patients were enrolled in the phase II study and were randomized in a 1:1 ratio to olaparib, 400 mg twice daily, or the combination of cediranib, 30 mg/day, and olaparib, 200 mg twice daily. High-grade tumors of other histologies were allowed if patients carried a known deleterious germlineBRCA1/2mutation. Treatment continued with imaging every 8 weeks until disease progression by RECIST v1.1 criteria. PFS in the intent-to-treat population was the primary endpoint.

Based on these results, Liu and her team initiated the confirmatory randomized phase III NRG-GY004 (NCT02446600) trial. The expected primary completion date is December 2019.

Antibody—Drug Conjugates

Data from phase I pooled expansion cohorts showed that mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, induced a confirmed overall response rate (ORR) of 30% (95% CI, 22%-39%) in patients with platinum-resistant ovarian cancer who had received 1 to 3 prior lines of therapy.³

Patients were selected from 3 expansion cohorts of an ongoing phase I trial (n = 113), including 36 who met the eligibility criteria for FORWARD I, a pivotal phase III study comparing mirvetuximab soravtansine versus investigator’s choice of chemotherapy. Patients were eligible for FORWARD I if they have platinum-resistant disease, medium-to-high levels of folate receptor alpha (FRα) expression, and 1 to 3 prior lines of therapy.

In all pooled patients from the phase I analysis, the confirmed ORR was 47% (95% CI, 30%-65%) in the group eligible for FORWARD I.

The median PFS was 4.3 months (95% CI, 3.9-5.4) in the pooled group with a 19.3-week duration of response. Median PFS was 6.7 months (95% CI, 4.1-8.3) in the FORWARD I eligible group with a duration of response of 25.1 weeks.

In a phase I expansion study, mirvetuximab soravtansine demonstrated a confirmed ORR of 26% (95% CI, 14%-41%) among 46 patients with FRα-positive platinum-resistant ovarian cancer, including 1 complete and 11 partial responses.⁴

“If you look at administration of mirvetuximab alone in the platinum resistant population, it shows some impressive response rates that you would not necessarily expect for platinum-resistant disease,” Randall said. “Our chemotherapy response rates are generally in the 15% range, but if you look at mirvetuximab, it shows a 26% response rate in the unselected population.”

In results from the FORWARD II trial presented at the 2018 ASCO Annual Meeting, the combination of mirvetuximab soravtansine and bevacizumab (Avastin) induced an ORR of 43% with a median PFS of 7.8 months among 51 patients with platinum-resistant FR&alpha;-positive ovarian cancer. In a subset of 39 patients who received <3 prior lines of therapy and had medium to high FR&alpha; expression, the ORR was 39% and the median PFS was 9.5 months.5

Randall said cost remains a concern when discussing novel drugs and novel drug combinations. But the drugs in the pipeline appear to be effective. &ldquo;We have every reason to have hope,&rdquo; she said.

References:

1. Randall LM. Developmental therapeutics in ovarian cancer: Let's not talk about PARPi. Presented at: the 2019 SGO Annual Winter Meeting; January 17-19, 2019; Lake Tahoe, CA.
2. Liu J, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.J Clin Oncol. 2017;35(suppl; abstr 5535).
3. Moore KN, Matulonis UA, O&rsquo;Malley DM, et al. Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FR&alpha;)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts.J Clin Oncol. 2017;35(suppl; abstr 5547).
4. Moore KN, Martin LP, Matulonis UA, et al. IMGN853 (mirvetuximab soravtansine), a folate receptor alpha (FR&alpha;)-targeting antibody-drug conjugate (ADC): single-agent activity in platinum-resistant epithelial ovarian cancer (EOC) patients (pts). J Clin Oncol. 2016;34(suppl; abstr 5567).
5. O&rsquo;Malley D, Martin L, Gilbert L. Mirvetuximab soravtansine, a folate receptor alpha (FR&alpha;)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-resistant ovarian cancer: maturing safety and activity profile from the FORWARD II phase 1b study.J Clin Oncol. 2018;36(suppl; abstr 5549).