Emerging Therapies for Advanced Ovarian Cancer

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 17th International Meeting of the European Society of Gynecological Oncology

Milan, Italy / September 11-14, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Generally, platinum sensitivity refers to a platinum-free interval (PFI) >12 months. However, that definition does not address a substantial proportion of patients with partial platinum sensitivity (PPS), defined as a PFI of 6 to 12 months. The optimal approach to management of recurrent PPS ovarian cancer has yet to be determined. However, strategies to extend the PFI offer an attractive therapeutic approach for the subgroup of patients with PPS tumours.

“It has been proposed that the ‘PFI extension strategy’ treatment algorithm by intercalation of a non-platinum therapy increases the likelihood of response to a later platinum rechallenge,” Dr. Nicoletta Colombo, European Institute of Oncology, Milan, and colleagues noted in their ESGO presentation.

In the multinational phase III OVA-301 trial, the antineoplastic agent trabectedin, synthesized from the marine tunicate Ecteinascidia turbinata, was combined with pegylated liposomal doxorubicin (PLD). The combination significantly improved survival in patients with relapsed platinum-sensitive (PS) ovarian cancer, as compared with PLD plus placebo (Monk et al. J Clin Oncol 2010;28:3107-14). Here at ESGO, 2 analyses of OVA-301 data reaffirmed the survival advantage conferred by trabectedin/PLD in patients with relapsed PS and PPS ovarian cancer.

The overall survival (OS) data from OVA-301 showed that outcomes in relapsed ovarian cancer correlate with the PFI, and are influenced by subsequent treatment, noted Dr. Colombo. “Thus, a longer PFI is an important predictor of a better response and longer OS to further treatments,” she told delegates. “Extending the PFI by the non-platinum/non-taxane combination of PLD/trabectedin may also have positive effects in treatment tolerability and allow further treatments with platinum-based chemotherapy in recurrent ovarian cancer patients.”

Extending the Platinum-free Interval

To examine the “PFI extension strategy” among patients in OVA-301, Dr. Colombo and colleagues performed a post hoc analysis of OVA-301, exploring OS in the subset of patients with PPS recurrent ovarian cancer. A total of 672 patients were randomized to treatment with PLD/trabectedin or PLD alone. The study population included 214 patients who had a PFI of 6 to 12 months. Of those, 94 subsequently received a platinum-containing regimen as third-line systemic treatment upon completion of protocol therapy.

In the overall analysis, the addition of trabectedin to PLD was associated with a statistically significant improvement in median progression-free survival to 7.3 months vs. 5.8 months with PLD alone (HR 0.79, P=0.019). The subgroup of patients with PPS tumours derived a greater benefit from the combination with a median PFS of 7.4 months vs 5.5 months with PLD alone, representing a 35% reduction in the odds of progression or death (HR 0.65, P=0.0152). This combination also led to a median OS of 22.4 months compared with 16.4 months (HR 0.64, P=0.0027).

The 94 patients who subsequently received third-line platinum-based chemotherapy had an even greater increase in survival. According to the Kaplan-Meier estimates, there was an outstanding reduction of 42% in the risk of death in this patient subset (HR 0.58, P=0.0153), with a median OS of 27.7 months for the combination vs. 18.7 months for PLD alone (Figure 1).

Figure 1.

“At 24 months, 61% of patients treated with the trabectedin/PLD combination were still alive compared with 36.7% of patients who received PLD monotherapy,” Dr. Colombo reported.

In patients with PPS tumours, the analysis also showed that addition of trabectedin significantly prolonged PFI vs. PLD monotherapy (11.5 vs. 7.5 months; HR 0.61, P=0.0203). The delay in initiation of third-line platinum-based therapy translated into a “remarkable” 8.9-month increase in median OS (18.8 vs. 9.9 months; HR 0.64, P=0.0513). Moreover, 12-month survival after initiation of platinum chemotherapy in third line was 69.4% with the combination compared with 41.1% with PLD monotherapy.

Safety data from OVA-301 have been reported previously (Poveda et al. J Clin Oncol 2010;15(suppl):5046). The subset analysis revealed no new or unexpected adverse events. No patient treated with trabectedin/PLD developed grade 3-4 toxicity and no treatment-related deaths occurred.

“Results of the trabectedin plus PLD treatment, a new non-platinum/non-taxane therapeutic alternative, suggest that the prolongation of PFI may improve the outcome with subsequent platinum and ultimately lead to longer survival of patients with PPS relapsed ovarian cancer,” Dr. Colombo concluded.

Platinum-sensitive Cancer

A second study reported here at ESGO broadened the analytical focus to include all 430 OVA-301 patients whose tumours exhibited some degree of platinum sensitivity (PFI >6 months). Specifically, investigators sought to examine and compare outcomes in patients with PS (PFI >12 months) and PPS (PFI 6 to 12 months) relapsed ovarian cancer.

The analysis showed a significant survival advantage for PS and PPS ovarian cancer, reported Dr. Ignace Vergote, Catholic University, Leuven, Belgium. PS patients had a 3-month survival advantage when treated with trabectedin and PLD (27.0 vs. 24.1 months; HR 0.78, P=0.0319). As reported also by Dr. Colombo, the subgroup of patients with PPS cancer had a 6-month improvement in survival with the trabectedin/PLD combination (22.4 vs. 16.4 months; HR 0.65, P=0.0056).

“PFI is a key factor for the treatment selection in relapsed ovarian cancer and trabectedin plus PLD has shown significantly superior OS for PS patients,” Dr. Vergote concluded. “In particular, results of the analysis in PPS relapsed ovarian cancer patients strongly suggest the combination of trabectedin and PLD as a relevant therapeutic approach in this subpopulation.”

Ongoing Clinical Development

The historically poor outcomes in advanced ovarian cancer have sparked persistent interest in the development of new, more effective therapies. Other presentations at ESGO reflected the ongoing activity to find optimal treatment strategies with novel compounds with an acceptable benefit:risk.

Of interest was a phase II trial with the investigational PARP inhibitor olaparib in patients with PS relapsed serous ovarian cancer who had received =2 previous platinum regimens and maintained partial or complete response following their last platinum-containing regimen (Abstract 1370). Patients were randomized to receive oral olaparib 400 mg b.i.d. or placebo. The PARP inhibitor was associated with significant improvement in PFS from 4.8 months with placebo to 8.4 months (P<0.00001) when given as maintenance therapy after second- or third-line platinum chemotherapy.

In patients with relapsed low-grade serous ovarian cancer, treatment with the MAP-K inhibitor AZD6244 (selumetinib) was associated with clinical benefit (Abstract 1719). Response and stable disease were reported in 42 of 52 (81%) patients. Eight patients had objective responses, which included one complete response, reported Dr. John Farley, Uniformed University of the Health Sciences, Bethesda, Maryland.

Dr. Jacobus Pfisterer, Hospital Solingen, Germany, reported on a phase III trial on the murine monoclonal anti-idiotypic antibody directed against CA125 abagovomab involving 870 patients with advanced ovarian cancer (Abstract 555). Maintenance abagovomab therapy after platinum/taxane chemotherapy “was able to induce a specific immunologic response soon after the induction period and was able to induce a nonspecific human antimouse antibody response,” stated Dr. Pfisterer. However, findings showed no improvement in PFS vs. placebo with an identical 13.2-month median PFS.

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