Ovarian Cancer in the News

TON - December 2013 Vol 6 No 11 — December 20, 2013

The field of ovarian cancer is an active area of research, with a number of potential approaches showing promise in improving outcomes. Targeted therapies have made advances in this disease, and experts are learning how best to exploit these. A selection of news highlights on ovarian cancer, from the European Cancer Congress (ECCO/ESMO/ESTRO), the Chemotherapy Foundation Symposium, and the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, follows.

The Developing Role of PARP Inhibition

Poly (ADP ribose) polymerase (PARP) inhibitors show excellent activity in ovarian cancer. The optimal role of PARP inhibitors in ovarian cancer is not yet determined. Currently, 5 PARP inhibitors are in various stages of development, and the most widely studied is olaparib.

PARP inhibitors cause multiple double-strand breaks in DNA. In tumor cells that harbor BRCA1 and BRCA2 mutations, these breaks cannot be repaired, leading to cell death.

“The simple version is that PARP is important. PARP inhibitors lock the PARP enzyme on DNA and prevent normal DNA repair. These are DNA-damaging agents, and some subsets of patients may be more susceptible to PARP inhibition,” explained Elise C. Kohn, MD, National Institutes of Health, Bethesda, Maryland. She updated attendees on PARP inhibition in ovarian cancer at the 2013 Chemotherapy Foundation Symposium.1

The 5 PARP inhibitors under development include olaparib, rucaparib, niraparib, veliparib, and BMN-673. The first 3 are in registration studies, and the latter 2 are in phase 1/2 studies.

“I have confidence that this new class of agents is exciting in ovarian cancer. Encourage patient participation in clinical trials,” she told listeners.

Studies suggest that olaparib is more active in patients with germline BRCA mutations than in those without them, and platinum-sensitive patients seem to be the most responsive.

Olaparib improved progression-free survival (PFS) as maintenance therapy in patients with platinum-sensitive ovarian cancer in a randomized controlled trial. In an updated analysis, olaparib improved PFS by 65% overall; a more robust effect on PFS was observed in patients with germline BRCA1 and BRCA2 mutations, with an 82% improvement in PFS. However, olaparib maintenance was also effective in those with BRCA wild-type mutations, improving PFS by 47%.2

The phase 2 AZ Study 41 showed a PFS benefit for olaparib/carboplatin/paclitaxel followed by olaparib maintenance versus carboplatin/paclitaxel followed by no further treatment; median PFS was 12.2 months with olaparib versus 9.6 months without.3

“These results were provocative,” Kohn said. “PARP inhibitors are still being investigated in a wide variety of ovarian cancer patients with and without mutations and in combination with other drugs,” she continued.

A phase 1 trial of olaparib plus cediranib (VEGFR inhibitor) showed clinical benefit in ovarian cancer, and a randomized phase 2 study of this combination has been initiated.

Biomarkers are needed to determine which patients will respond to PARP inhibition. Germline BRCA1 and BRCA2 mutations are predictive of response and duration of response, but other biomarkers are needed for patients without these mutations. It may be that a homologous recombinant defect (HRD) is a biomarker, but more studies are needed.

“The HRD score is a provocative direction to study,” Kohn stated.

The optimal role of PARP inhibition remains to be determined; potential opportunities include prevention, after diagnosis, at first remission, concurrent with maintenance therapy, in platinum-sensitive recurrent ovarian cancer with chemotherapy, and in platinum-refractory patients.

“We don’t know the answer,” Kohn told listeners.

1. Kohn E. PARP inhibitors in ovarian cancer. Presented at: 2013 Chemotherapy Foundation Symposium; November 7, 2013; New York, NY.
2. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392.
3. Oza AM, Cibula D, Oaknin A, et al. Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): a randomized, open-label phase II study. J Clin Oncol. 2012;30(15 suppl):Abstract 5001.

Bevacizumab Appears to Benefit High-Risk Patients

Two phase 3 trials presented at the 2013 European Cancer Congress suggest that the optimal role of bevacizumab will be in high-risk patients.

AURELIA is the first phase 3 study to evaluate the addition of bevacizumab to chemotherapy in platinum-resistant ovarian cancer (defined as progression within 6 months of last platinum-containing therapy).1 The addition of bevacizumab to chemotherapy significantly improved progression-free survival (PFS) from 3.4 months to 6.7 months (P <.001), and median overall survival (OS) was improved from 13.3 months with chemotherapy alone to 16.6 months, but this did not reach statistical significance. Chemotherapy agents included paclitaxel, topotecan, and liposomal doxorubicin.

“No single agent has shown superiority to weekly paclitaxel, topotecan, or liposomal doxorubicin. Median survival in platinum-resistant ovarian cancer is typically around 12 months,” said lead author Petronella Witteveen, MD, DCOG, of University Medical Centre Utrecht, in the Netherlands.

AURELIA randomized 361 patients to receive bevacizumab plus investigator’s choice of chemotherapy versus chemotherapy alone. Treatment was continued until disease progression, unacceptable toxicity, or consent withdrawal.

At progression, patients in the chemotherapy arm were allowed to cross over to bevacizumab monotherapy; bevacizumab was discontinued after progression in the bevacizumab plus chemotherapy arm.

An exploratory subgroup analysis of OS suggested that weekly paclitaxel was the best partner for bevacizumab. In the weekly paclitaxel cohort, median OS was 22.4 months for bevacizumab versus 13.2 months in controls, representing a 35% relative improvement favoring bevaciz- umab. By contrast, in the cohort treated with liposomal doxorubicin, median OS was 13.7 months in those randomized to receive bevacizumab plus chemotherapy versus 14.1 months with chemotherapy only. For the topotecan-treated cohort, median PFS was 13.8 months for those treated with bevacizumab plus chemotherapy versus 13.3 months for chemotherapy only.

“The effect of weekly paclitaxel should be considered exploratory and requires prospective validation,” Witteveen said.

No new safety concerns were identified in an updated safety analysis. The main grade ≥3 toxicities in the bevacizumab arm were hypertension (7.8%) and proteinuria (2.2%).

The ICON7 trial evaluated bevacizu- mab in women with newly diagnosed ovarian cancer. The primary analysis (previously reported) showed a median PFS of 17.3 months for chemotherapy alone versus 19 months for bevacizumab added to chemotherapy (P = .004).2

In the final survival analysis presented at the European Cancer Congress, median OS was 58 months in the study for both arms; however, poor-prognosis patients experienced a 4.8-month prolongation of survival (from 34.5 months to 39.3 months) if they received bevacizumab.3

“The survival benefit in the overall trial of 0.9 months is not clinically meaningful. However in the high-risk subgroup, bevacizumab did show a clinically meaningful benefit of 4.8 months,” said Amit Oza, MD, Princess Margaret Cancer Centre, University of Toronto, Canada.

The international study randomized 1528 women to 6 cycles of every-3-week carboplatin/paclitaxel versus carboplatin/paclitaxel plus bevacizumab for 5 or 6 cycles followed by bevacizumab for 12 additional every-3-week cycles until disease progression. Patients were prestratified according to stage, extent of debulking, and time of therapy. A third of the women were considered high risk (stage III with >1 cm residual disease, stage IV, and nondebulked).

At a median follow-up of 49 months, PFS was not significantly different between the 2 arms, similar to the first interim analysis presented previously.

Over 4 years, the difference between the 2 curves was gradually eroded, Oza said. Because the curves are nonproportional, the final OS analysis was conducted using a restricted means analysis, and the difference between the 2 arms was 0.9 months, which was not statistically or clinically meaningful.

In a predefined high-risk subgroup of patients, the curves for the 2 arms separated and the bevacizumab arm was superior throughout the study, with a 4.8-month improvement over the control arm.

Oza said the difference in survival for high-risk patients given bevacizumab was clinically meaningful.

1. Witteveen P, Lortholary A, Fehm T, et al. Final overall survival (OS) results from AURELIA, an open-label randomized phase III trial of chemotherapy (CT) with or without bevacizumab (BEV) for platinum-resistant ovarian cancer. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA5.
2. Perren TJ, Swart AM, Pfisterer J, et al; the ICON7 investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496.
3. Oza AM, Perren TJ, Swart AM, et al. ICON7: final overall survival results in the GCIG phase III randomized trial bevacizumab in women with newly diagnosed ovarian cancer. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA6.

Trebananib in Platinum-Sensitive Ovarian Cancer

A new antiangiogenesis inhibitor with a different mechanism of action than bevacizumab shows promise in platinum-sensitive ovarian cancer, according to results of the phase 3 TRINOVA-1 trial presented at the 2013 meeting of the European Cancer Congress. Trebananib added to paclitaxel prolonged the time to disease progression or death by 52% compared with paclitaxel plus placebo (P <.001), said Bradley Monk, MD, Creighton University School of Medicine and University of Arizona Cancer Center, Phoenix.

Although angiogenesis is a proven target in ovarian cancer, anti–vascular endothelial growth factor (VEGF) therapy (with bevacizumab) causes adverse effects. Trebananib is a different approach, targeting a non-VEGF angiogenesis factor—angiopoietin 1 and angiopoietin 2. The hope is that this approach will be effective and have fewer adverse effects than a VEGF-targeted strategy, Monk said.

TRINOVA-1 enrolled 919 women with recurrent epithelial ovarian cancer and randomized them to receive treatment with weekly intravenous (IV) trebananib 15 mg/kg plus weekly IV paclitaxel (3 weeks on, 1 week off) or with placebo plus weekly paclitaxel (3 weeks on, 1 week off). Patients were treated until disease progression, toxicity, or withdrawal of consent.

Patients were stratified according to progression-free interval, measurable disease, and geographic region. At baseline, patients had received up to 3 prior cytotoxic regimens and had a progression-free interval of <12 months. One prior regimen failed in 40% of patients, 2 prior therapies in 40%, and 3 prior therapies in 20%.

Monk presented primary progression-free survival (PFS) and interim overall survival (OS) results of this international trial. At a median follow-up of 10 months, median PFS was 7.2 months in the trebananib group and 5.4 months for placebo (hazard ratio, 0.66; 95% confidence interval, 0.56-0.76; P <.001).

A prespecified subgroup analysis found that trebananib improved PFS in all subgroups. Overall response rate was 38% with trebananib versus 30% with placebo (most were partial responses).

Trebananib did not appear to increase toxicity when added to paclitaxel, according to the safety analysis. The rate of adverse events of any grade was similar between the 2 treatment arms: 96% for trebananib and 97% for placebo. The major toxicity of trebananib was edema: 57% versus 26% (any grade) for those in the placebo arm. Very few grade ≥3 adverse events were reported with trebananib. No increase in VEGF-associated adverse effects was seen with trebananib (ie, hypertension, proteinuria, wound healing complications, arterial thrombotic events).

Neutropenia and anemia were more common in the placebo arm, and neurotoxicity was more common in the trebananib arm, which may be attributable to increased exposure to paclitaxel in that arm.

An interim OS analysis showed a difference of approximately 2 months favoring trebananib (19 months vs 17.3 months for the placebo arm), but this is only a preliminary analysis, Monk reminded listeners.

TRINOVA-1 incorporated patient-reported outcomes using 3 different quality-of-life questionnaires: Functional Assessment of Cancer Therapy-Ovarian (FACT-O), Ovarian Cancer Screening (OCS), and EuroQol 5-dimension (EQ-5D). On these measures, no quality-of-life differences were reported between the 2 treatment arms.

Trebananib is continuing to be developed for ovarian cancer.

The formal discussant of this trial, Antonio Casado, MD, Hospital Universitario San Carlos, Madrid, Spain, said, “Weekly paclitaxel and trebananib could be an option in patients who progress within 12 months after 1 to 3 previous lines of therapy.”

Monk BJ, Poveda A, Vergote I, et al. A phase III, randomized, double-blind trial of weekly paclitaxel plus the angiopoietin 1 and 2 inhibitor, trebananib, or placebo in women with recurrent ovarian cancer: TRINOVA-1. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA41.

BMN-673: Investigational PARP Inhibitor

The investigational poly (ADP ribose) polymerase (PARP) inhibitor BMN-673 achieved an objective response rate (ORR) of >40% and delayed disease progression by >6 months in patients with heavily pretreated advanced BRCA-related breast and ovarian cancers in a phase 1 trial. The first-in-human study was reported at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics held in Boston, Massachusetts, in October 2013.

Lead author Zev A. Wainberg, MD, Jonsson Comprehensive Cancer Center at the University of California Los Angeles, called the novel agent “the most potent PARP inhibitor in clinical development.” He said the drug had optimized pharmaceutical properties and can be given orally with a long half-life that allows once-daily dosing.

“BMN-673 has high single-agent antitumor activity in ovarian and breast cancer patients with deleterious germline mutations of BRCA1 and BRCA2. The duration of response and progression-free survival appear to be promising in this early-phase trial,” Wainberg commented at a press conference.

The study enrolled 87 patients with a variety of cancers: breast, ovarian, small cell lung cancer, and Ewing sarcoma. All patients had received a mean of 3 prior regimens (range, 1-13).

Phase 1 response data were reported for 18 patients with germline BRCA-mutated breast cancer, 28 patients with germline BRCA-mutated ovarian cancer, 24 patients with Ewing sarcoma, and 12 patients with small cell lung cancer.

In 26 evaluable patients with BRCA-mutated ovarian cancer, ORR was 46% and clinical benefit rate (including response rate and stable disease) was 82%. Median duration of response was 26.9 weeks, and median progression-free survival was 33.4 weeks.

Among 18 patients with BRCA-mutated breast cancer, 44% responded including 1 complete response. The rate of clinical benefit was 72%, with stable disease for at least 24 weeks. When patients received the recommended clinical dose of 1 mg/day for phase 2, ORR went up to 50% and the clinical benefit went up to 86%.

Among patients with ovarian cancer, 70% had significant reductions in CA-125, several had no change, and 1 patient had an increase in CA-125.
Responses were also seen in the small cell lung cancer cohort, where no BRCA mutations were observed. No responses were seen in patients with Ewing sarcoma.

BMN-673 was tolerable in general. The most common drug-related adverse events occurring in <30% of patients were myelosuppression, fatigue, nausea, and alopecia.

BioMarin Pharmaceuticals has mounted a phase 3 study of BMN-673 versus physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine in metastatic breast cancer.

Wainberg ZA, de Bono JS, Mina L, et al. Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumor. Presented at: Molecular Targets and Cancer Therapeutics; October 22, 2013; Boston, MA. Abstract C295.

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