The pivotal cascade of molecular events that culminate in ovarian cancer has not been fully elucidated, and therefore, treatment of this tumor has lagged behind several others that now benefit significantly from targeted therapies. But as the underlying mechanisms for ovarian cancer slowly come to light, clinical research is paying off, and the poor prognosis for the average patient may be changing. The following are summaries of recent advances that are making news in ovarian cancer.

PARP Inhibition with Olaparib

BRCA1/2 mutations, causing loss of homologous recombination-mediated DNA repair, is one of the few recognized oncogenic genetic changes in ovarian cancer. The base excision repair pathway, activated with the loss of homologous recombination, requires poly(ADP-ribose) polymerase (PARP). The targeting of this enzyme with the new class of PARP inhibitors may render a blow to this backup system and thereby effectively fight the tumor.

The PARP inhibitor olaparib, active in some breast cancers, showed promise in ovarian cancer in a phase II Canadian study.¹ Patients with advanced ovarian cancer associated with BRCA mutations had a 41% response rate to single-agent olaparib 400 mg twice daily on a continuous basis in 4-week cycles. Those without the mutation had a 23% response rate. Median progression-free survival was 219 days, considered especially striking for heavily pretreated patients with advanced disease, according to principal investigator Karen Gelmon, MD, of the BC Cancer Agency, Vancouver.

Though small, this study was hailed as one of the most important at the 2010 ASCO Annual Meeting by James H. Doroshow, MD, of the National Cancer Institute. "This is the first clear demonstration of activity of PARP inhibition in non-BRCA-mutated ovarian cancer… Serous ovarian cancer may actually be a disease of inhibition of DNA repair…and this drug is likely to make an impact. I predict an exciting future for this interesting class of agents," he said.
The data appeared so encouraging that a listener at the session commented, "Patients are dying because of lack of access to good drugs. When can I get my hands on this as a physician in practice?"

Ongoing resequencing efforts from this study are of major importance in identifying somatic mutations for response.
Also showing promise in both sporadic and BRCA-deficient tumors is the oral PARP inhibitor MK-4827.² Among 19 patients treated, the clinical benefit rate (stable disease for 3 or more months) was 37%, and some patients had very prolonged responses (ie, 17, 22, and more than 44 weeks). One patient had received five prior lines of chemotherapy and had responded for almost 1 year. BSI-121 is a third PARP inhibitor being evaluated in ovarian cancer. Seven others are being studied in breast cancer and melanoma.

Monoclonal Antibody Therapy

Treatment with farletuzumab, a humanized monoclonal antibody targeting folate receptor-alpha-which is overexpressed in more than 90% of ovarian cancers-led to a 70% response rate when combined with standard therapy in a phase II clinical trial including 44 patients with ovarian cancer in first relapse. Total clinical benefit exceeded 90%, and more than 20% of women had a second platinum-free interval that was longer than the first, according to Allan J. White, MD, of South Texas Oncology and Hematology at the START Center in San Antonio, Texas.³

"Patients with a first platinum-free interval of less than 12 months responded as well as those with an interval of 12 months or greater," Dr. White noted.

The study included 54 women in first platinum-sensitive relapse after a first remission of 6 to 18 months. Patients with asymptomatic relapse received single-agent farletuzumab, those with symptomatic relapse received carboplatin/taxane chemotherapy plus farletuzumab, and those with disease progression on farletuzumab monotherapy could proceed onto the combination chemotherapy while continuing farletuzumab. Combination therapy was associated with a median progression-free survival of 10 months. Several patients had impressive platinum-free intervals-41 months, 37 months, and 17 months, which were all at least double their first platinum-free interval. Robust responses in CA-125 levels were also observed, he reported.

Antiangiogenesis Agents

Agents that block angiogenesis may also enter the armamentarium in ovarian cancer, based on encouraging results seen with bevacizumab in a study that earned a coveted plenary session spot at the 2010 ASCO Annual Meeting.⁴ Bevacizumab (Avastin) added to carboplatin/paclitaxel, followed by bevacizumab maintenance, extended progression-free survival by nearly 4 months (14.1 vs 10.3 months; P < .0001), in the Gynecologic Oncology Group 0218 study (see the July 2010 issue of The ASCO Post). AMG 386, a first-in-class peptibody that inhibits angiopoietin-1 and -2, has also shown early activity in combination with paclitaxel.5

Other Approaches

As a single agent, NKTR-102, a topoisomerase I inhibitor-polymer conjugate, showed strong activity in a phase II study of 68 patients with platinum-resistant disease.6 Response rates were 24% to 41% (depending on criteria), and median progression-free survival was 18 weeks. Based on these results, in patients whose median platinum-free interval was only 1 month, lead author Ignace Vergote, MD, of the Catholic University, Leuven, Belgium, maintained that NKTR-102 has "great therapeutic potential." ■

References

1. Gelmon KA, Hirte HW, Robidoux A, et al: C we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. 2010 ASCO Annual Meeting. Abstract 3002. Presented June 5, 2010.

2. Sandhu SK, Wenham RM, Wilding G, et al: First-in-human trial of a poly(ADP-ribose) polymerase inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient and sporadic ovarian cancers. 2010 ASCO Annual Meeting. Abstract 3001. Presented June 5, 2010.

3. White AJ, Coleman RL, Armstrong DK, et al: Efficacy and safety of farletuzumab, a humanized monoclonal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: Final data from a multicenter phase II study. 2010 ASCO Annual Meeting. Abstract 5001. Presented June 7, 2010.

4. Burger R, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer: A Gynecologic Oncology Group study. 2010 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2010.

5. Karlan BY, Oza AM, Hansen VL, et al: Randomized double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian carcinoma. 2010 ASCO Annual Meeting. Abstract 5000. Presented June 7, 2010.

6. Vergote IB, Micha JP, Pippitt CH Jr, et al: Phase II study of NKTR-102 in women with platinum-resistant/refractory ovarian cancer. 2010 ASCO Annual Meeting. Abstract 5013. Presented June 7, 2010.