COMMENTARY

The Year in Gynecologic Cancer: Bevacizumab and Beyond

Maurie Markman, MD

Disclosures

December 19, 2014

Ovarian Cancer

Several studies published in 2014 have the potential to substantially influence the future management or prevention of ovarian cancer.

It had been well recognized that performing a prophylactic bilateral oophorectomy in women with a documented germline mutation in BRCA can substantially reduce the subsequent risk of developing ovarian cancer. However, until the publication of a landmark report this year including follow-up of more than 5500 women with such mutations in an international registry, the impact of this approach on overall survival due to all causes was uncertain.[2] This study confirmed both an 80% lifetime reduction in the risk for ovarian cancer associated following prophylactic bilateral oophorectomy in BRCA1 and BRCA2 carriers and a 77% reduction in all-cause mortality.[2]

Bevacizumab has been examined in randomized phase 3 trials in several clinical settings—front-line, recurrent, potentially platinum-sensitive, platinum-resistant—in the management of ovarian cancer. Perhaps the most impressive study result was reported in the peer-reviewed literature this year and involved women with platinum-resistant disease.[3]

The AURELIA trial included a quite innovative design permitting the investigators to select from one of three single chemotherapy agents known to produce a biologically and clinically meaningful objective response rate in the malignancy in this specific clinical setting (pegylated liposomal doxorubicin, weekly paclitaxel or topotecan).[4] In the experimental study arm, bevacizumab was added to one of these drugs.

The administration of the antiangiogenic drug with chemotherapy was associated with a statistically significant improvement in progression-free survival (median: 6.7 months vs 3.4 months; HR, 0.48; P < .001). Furthermore, adding bevacizumab more than doubled the objective response rate (27.3% vs 11.8%; P = .001). Although there was a numerical improvement in overall survival in the bevacizumab-containing study arm (median: 16.6 months vs 13.3 months; HR, 0.85; P < .174) this did not achieve statistical significance. Regarding overall survival, it is important to note that approximately 40% of patients in the study "control arm" ultimately received the antiangiogenic drug after progressing on their assigned trial regimen.

Of interest, there was a rather striking reduction in the incidence of abdominal pain in patients receiving the bevacizumab-containing regimen, a clear indication of the favorable impact of this strategy on a clinically relevant cancer-related symptom.[4]

Finally, it is noteworthy that the AURELIA study was the first phase 3 trial to reveal the superiority of any novel management strategy on a valid survival endpoint (eg, progression-free survival) in platinum-resistant ovarian cancer. Likely because of this important outcome, the FDA recently approved the marketing of bevacizumab in combination with chemotherapy in the management of patients in this very difficult clinical setting.

Another exciting new strategy employs the PARP inhibitor olaparib as maintenance treatment in ovarian cancer patients who had achieved a second response to platinum-based chemotherapy. Updated results of a phase 2 trial demonstrated an impressive favorable impact on the subsequent time to disease progression in patients with a documented BRCA mutation.[4] Compared with the placebo control arm patients, individuals receiving olaparib in this randomized study experienced a near tripling of the median time to disease progression (11.2 months vs 4.3 months; HR, 0.18; P < .0001). Patients with wild-type BRCA also experienced an improvement in time to disease progression associated with of olaparib treatment (median: 7.4 months vs 5.5 months; HR, 0.54; P = .0075), but this difference was not as great as that observed in the mutation-positive population. There was no difference in overall survival between patients randomly assigned to placebo or olaparib, but a substantial percentage of patients in the control arm ultimately received a PARP inhibitor.

Rather remarkably—and inappropriately, in my opinion—an advisory committee organized by the FDA voted against granting approval for this drug to be available for routine commercial use in the management of patients with ovarian cancer.[5] (Note: The final decision by the FDA on this matter was pending at the time of writing this review article.)

There were a number of additional studies of interest to oncologists caring for women with ovarian cancer, but their ultimate impact on disease management remains less certain than the results previously noted. These include the following:

Evidence that administration of the antiangiogenic agent pazopanib improves time to disease progression when employed as a maintenance strategy after primary platinum-based chemotherapy (but with a high level of clinically relevant adverse events)[6];

Evidence that the administration of weekly carboplatin plus weekly paclitaxel favorably affects serious adverse events but does not change survival outcome when delivered as primary therapy for ovarian cancer[7];

Evidence that the investigative antiangiopoietin agent trebananib improves progression-free survival when combined with weekly paclitaxel, compared with paclitaxel alone, in recurrent ovarian cancer[8]; and

Evidence that combining the investigative antiangiogenic agent cediranib with olaparib improves progression-free survival compared with olaparib alone in recurrent potentially platinum-sensitive ovarian cancer.[9]

Looking Back

This past year has seen the publication of an impressive number of highly clinically relevant papers whose results have the potential to substantially improve the outcome of patients with female pelvic malignancies.

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