Results from a federally funded, NCI-sponsored phase II clinical trial shows that the combination of two investigational oral drugs, olaparib (AZD-2281; AstraZeneca), a potential first-in-classpoly ADP ribose polymerase or PARP inhibitor and cediranib (AZD-2171; AstraZeneca), an anti-angiogenesis drug, is significantly more active against recurrent, platinum chemotherapy-sensitive disease or ovarian cancer related to mutations in BRCA genes than olaparib alone. [1][2] The progression-free survival was 17.7 months with the combination treatment vs. nine months with olaparib alone. The study findings were presented at the 50th Annual Meeting of the American Society of Clinical Oncology, being held May 30 – June 3, 2014 in Chicago, Il.

Commenting on the findings, lead study author Joyce Liu, MD, MPH, an instructor in medical oncology at Dana-Farber Cancer Institutein Boston, MA, said: ?The significant activity that we saw with the combination suggests that this could potentially be an effective alternative to standard chemotherapy. At the same time, this approach is not yet ready for clinical practice as neither of these drugs is currently FDA approved for ovarian or any other cancer. We also need additional clinical trials to confirm the findings of this study to see how this combination compares to standard treatment.? Liu was the recipient of a 2008 Conquer Cancer Foundation of ASCO Young Investigator Award.

The combination of cediranib plus olaparib resulted in a significantly higher response rate… and represents an oral, non-chemotherapy-based combination treatment option for women with high-grade serous or BRCA-mutation related ovarian cancers which definitely warrants further study…

Combination: PARP Inhibitor and anti-angiogenic drug
This study is the first time a combination of a PARP inhibitor and an anti-angiogenic drug has ever been explored in a clinical trial for ovarian cancer.

Poly ADP ribose polymerase orPARP is an enzyme involved in many functions in a cell, including repair of DNA damage. Inhibition of PARP may cause cancer cells to die. Anti-angiogenic drugs block the growth of blood vessels in the tumor.

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BRCA1 and BRCA2 belong to a type of genes known as tumour suppressors. Researchers have shown that mutation of these genes has been linked to hereditary breast and ovarian cancer and a woman’s risk of developing breast and/or ovarian cancer is greatly increased if she inherits a BRCA1 or BRCA2 mutation. Only 15% of ovarian cancers are found before the cancer has spread outside the ovary. Despite advances in treatment and diagnosis, for patients with ovarian cancer that has spread beyond the ovary the five-year survival rate is well below 50%

The findings of the study confirms preclinical research which suggested that olaparib and cediranib synergize, meaning they work together to make each other more active. Liu and her colleagues designed this trial to confirm, in a clinical setting, that the combination of these two drugs was more active than the single drug olaparib alone.

As many as 80% of women with high-grade serous ovarian cancer experience a relapse after initially responding to chemotherapy. When the cancer comes back, it is more difficult to treat, because it will have spread to the pelvis and abdomen, or even the lungs.

Standard treatment
The current standard treatment for recurrent ovarian cancer is chemotherapy, which often causes significant side effects. Even in the setting of initial response, resistance to chemotherapy eventually develops. Hence, researchers have been exploring alternate regimens using targeted drugs, with the goal of overcoming such treatment resistance.

Trial design
Ninety women with recurrent, platinum-sensitive, a disease that responds to treatment with platinum-based chemotherapy, high-grade serous or BRCA mutation-related ovarian cancer, were randomly assigned to treatment with olaparib alone or olaparib plus cediranib. The women had no prior treatment with anti-angiogenic drugs in the setting of recurrent ovarian cancer or PARP inhibitors.

Study results
Tumor shrinkage rates were markedly higher in the combination arm than in the olaparib arm (80 vs. 48%). Five patients in the combination arm and two patients in the olaparib alone arm had a complete remission. The combination treatment substantially delayed disease progression, with a progression-free survival of 17.7 months compared to nine months for olaparib alone. Past trials of standard chemotherapy in the platinum-sensitive setting have demonstrated progression-free survival times between eight and 13 months.

Adverse events
Although certain side effects ? high blood pressure, fatigue, and diarrhea ? occurred more frequently in the combination arm, they were usually controllable by symptom management and dose reductions as needed.

Previous studies
Prior trials have suggested that PARP inhibitors tend to have the most activity in women who have either platinum-sensitive ovarian cancer or BRCA mutations in their tumors. An exploratory analysis from this study suggests that the combination treatment appears to also be active in patients without a known BRCA-mutation. Liu observed that it is reasonable to explore whether the combination treatment would be effective in women with platinum-resistant disease as well.

Further study
Don S. Dizon MD, FACP, ASCO Expert and the Director, Oncology Sexual Health Clinic at the Massachusetts General Hospital, Boston, MA, noted: ?The combination of cediranib plus olaparib resulted in a significantly higher response rate, though at the expense of higher toxicity. Whether this response translates into gains in survival needs further follow-up,? said. ?However, this combination represents an oral, non-chemotherapy-based combination treatment option for women with high-grade serous or BRCA-mutation related ovarian cancers and definitely warrants further study.?

Importance of Federally Funded Research
Forty years after President Richard Nixon signed the National Cancer Act into law, which created a robust federal investment in cancer research and resulted in rapid advancement in the understanding of cancer, a number of medical organizations are concerned about the future of federal research funding. Data real released in 2013 shows that federal funding for cancer research has remained flat for more than a decade, and when adjusted for inflation, has actually decreased. Recently, the National Institutes of Health (NIH) Director Francis Collins, MD, called 2013 the ?darkest ever? year for his agency’s funding.

The NCI’s National Clinical Trials Network, involve approximately 3,100 inst
itutions in the United States and Canada and each year more than 20,000 patients who, as a result, have access to promising new treatments. In addition, at any given time, there are hundreds of research studies taking place at the 68 NCI-designated cancer centers around the country. A reduction in research funding directly impact the ability to develop new medicines. ?Only clinical trials determine what works and what does not work in medicine and health care. They are the best way to determine the efficacy of specific interventions designed to treat diseases like cancer,? said Denis Brin Hammond, MD, chair of ASCO?s Government Relations Committee.

?After forty years of unprecedented progress, cancer science is in a period of revolutionary change,? noted Clifford A. Hudis, MD, FACP, 2013 – 2014 ASCO President and chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York, NY. ?This makes research much more challenging but offers the real possibility of benefit for millions of patients and survivors worldwide. Now is the time to renew our nation?s commitment to conquering cancer and we call on all ASCO members to join us in this effort.?

For more information:
[1] Liu J, Barry WT, Birrer MJ, Lee J, Buckanovich RJ, Fleming GF, Rimel BJ, Buss MK, et al A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. 2014 ASCO Annual Meeting. Oral Abstract Session. Saturday May 31, 1:15 PM to 4:15 PM. Abstract No: LBA5500. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA5500).[Abstract]
[2] NCT01116648 – Cediranib Maleate and Olaparib in Treating Patients With Recurrent Ovarian, Fallopian Tube, Peritoneal Cancer, or Triple-Negative Breast Cancer. [Study Record Detail]

Photo: Joyce Liu, MD, MPH speaks at the American Society of Clinical Oncology (ASCO) Annual Meeting. Photo Courtesy: ?ASCO/Zach Boyden-Holmes.

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