The study reviewed here found that two-thirds of people with an abnormal BRCA1 or BRCA2 gene being treated for advanced-stage breast, ovarian, or prostate cancer got some benefit from olaparib, an experimental targeted therapy medicine. People who didn't have an abnormal BRCA1 or BRCA2 gene didn't get any benefit from olaparib. Olaparib is a type of targeted therapy medicine called a PARP inhibitor.
Most inherited cases of breast cancer are associated with two abnormal genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two). Women with an abnormal BRCA1 or BRCA2 gene have up to an 85% risk of developing breast cancer by age 70. Their risk of ovarian cancer also is higher than average. Men with an abnormal BRCA gene have a higher risk of both breast and prostate cancer.
DNA carries genetic information in both healthy cells and cancer cells. Cells can develop DNA damage spontaneously or from exposure to specific things in the environment (too much sun, for example) that make DNA damage more likely to happen. But cells can detect and repair damage to DNA. When DNA is damaged in a healthy cell and the damage isn't fixed, that cell can become cancerous. Abnormal BRCA1 and BRCA2 genes are thought to increase the risk of breast and other cancers because these abnormal genes interfere with cells' ability to repair damaged DNA.
The poly ADP-ribose polymerase (PARP) enzyme fixes DNA damage in both healthy and cancer cells. Researchers believe that a medicine like olaparib, which interferes with (inhibits) the PARP enzyme, might make it even harder for cancer cells with an abnormal BRCA1 or BRCA2 gene to fix DNA damage. This would make it harder for the cancer cells to survive. In other words, a PARP inhibitor might make some cancer cells less likely to survive their DNA damage.
Research in the lab on cancer cells with an abnormal BRCA1 or BRCA2 gene showed that the cells were 1,000 times more sensitive to PARP inhibition than cancer cells that didn't have an abnormal BRCA gene. Based on those results, the researchers felt that treating cancers in people with an abnormal BRCA1 or BRCA2 gene would likely be effective.
In this study, 60 people diagnosed with advanced-stage cancer that had stopped responding to other treatments received olaparib, a pill taken by mouth. About a third of the people in the study (21 people) were known to have an abnormal BRCA1 or BRCA2 gene. One other person was thought to have an abnormal BRCA gene based on a strong family history.
The results:
Because these results were so encouraging, the researchers suggested that medical groups and government agencies reconsider how targeted therapy medicines are tested and approved. For example, when testing olaparib, the researchers looked at how it worked on a number of different types of cancer that all had an abnormal BRCA1 or BRCA2 gene, rather than looking at how the medicine worked in just one type of cancer.
Based on these results, the researchers think that olaparib could be a successful treatment for cancers with an abnormal BRCA1 or BRCA2 gene.
In this study olaparib was used alone. Other research has shown that giving another PARP inhibitor, BSI-201, plus chemotherapy to women diagnosed with advanced-stage, triple-negative breast cancer caused the cancers to respond better to chemotherapy compared to cancers treated with chemotherapy alone. Cancers treated with BSI-201 plus chemotherapy also were less likely to become resistant to chemotherapy. Some chemotherapy medicines work by causing DNA damage in cancer cells. Using a PARP inhibitor with these chemotherapy medicines might make it harder for cancer cells to fix damaged DNA, which makes it harder for the cancer to become resistant to chemotherapy.
If you're being treated for an aggressive form of breast cancer such as triple-negative breast cancer or cancer associated with an abnormal BRCA1 or BRCA2 gene, you and your doctor may be considering a number of treatment options. If the cancer has stopped responding to standard treatments, other treatment options may include a PARP inhibitor such as olaparib if you're willing to participate in a clinical trial. Ask your doctor if there are any clinical trials that might be a good fit for you and your unique situation. Visit the Breastcancer.org Clinical Trials pages for more information.
HOUSTON, June 24 (MedPage Today) -- An investigational cancer therapy demonstrated significant antitumor activity in patients with BRCA1/2 mutations, according to the investigators in the most recent string of favorable studies.
Almost two-thirds of mutation carriers had a clinical benefit from treatment with olaparib, Johann S. de Bono, MD, PhD, of the Royal Marsden Hospital in London, and colleagues reported in the June 24 issue of the New England Journal of Medicine.
In fact, only mutation carriers had responses to the oral inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP). However, the agent demonstrated activity in patients with breast, ovarian, and prostate cancer.
The drug was well tolerated, and analysis of patient blood, hair, and tissue samples confirmed PARP inhibition.
The findings point to a need to rethink the drug approval process to accelerate development of anticancer therapies, the authors concluded.
"This study raises the possibility that for some anticancer drugs, the traditional processes of clinical development and registration need to be altered," they said.
"Due consideration must now be given to developing rationally designed molecularly targeted therapies for patients whose tumors have the same molecular defect but different origins, such as the ovary, breast, or prostate. Such a radical change in drug evaluation and registration may be key to accelerating the development of anticancer drugs."
PARPs have a major role in DNA repair mechanisms, including the repair pathway for the tumor-suppressor proteins BRCA1 and BRCA2. Mutations in the proteins disrupt normal repair processes and allow emergence of a tumor with aberrant DNA repair not found in normal tissues.
"This tumor-specific defect can be exploited by using PARP inhibitors to induce selective tumor cytotoxicity, sparing normal cells," the authors said. "PARP inhibition in these tumor cells with deficient homologous-recombination repair generates unrepaired DNA single-strand breaks that are likely to cause the accumulation of DNA double-strand breaks and collapsed replication forks."
In vitro studies showed that BRCA1/2-deficient cells were as much as 1,000-fold more sensitive to PARP inhibition compared with wild-type cells. Moreover, PARP inhibition prevented the growth of BRCA2-deficient tumor xenografts.
Success in the laboratory led to a phase I clinical trial reported by Dr. de Bono and colleagues. The trial involved 60 patients with solid tumors that had proved refractory to standard therapy or for which no suitable therapies existed. By design, the trial was enriched with 21 patients with BRCA-deficient tumors and one patient who had a strong BRCA-positive family history but refused testing.
Treatment with olaparib started at a dose of 10 mg a day for two of every three weeks. The dose subsequently was increased to 600 mg or more twice a day, given continuously for three weeks in four-week cycles.
Dose-limiting toxicity was defined as a grade 3 or 4 adverse effect occurring in the first cycle of treatment with a given dose of olaparib.
That occurred in patients who received 400 or 600 mg bid. The observations established 400 mg bid as the maximum tolerated dose.
Adverse effects possibly related to the study drug were primarily grade 1 or 2 in severity and included nausea (in 32% of patients), fatigue (30%), vomiting (20%), taste alteration (13%), and anorexia (12%). Three patients had anemia and two developed grade 4 thrombocytopenia.
Two patients died during the study: one with advanced non-small cell lung cancer and a history of lower respiratory tract infections and one with ovarian cancer, who died of septicemia. Neither death seemed related to treatment with olaparib.
Two patients had rapidly progressive disease. Both had tumors usually not associated with BRCA mutations: small-cell lung cancer and vaginal adenocarcinoma.
Of 19 BRCA carriers evaluable for tumor response, 12 (63%) had either radiologic or tumor-marker responses or disease stabilization for at least four months. Nine of the 12 met RECIST criteria for tumor response, one of which was sustained for 76 weeks. Two other patients had responses that persisted for a year or longer.
No tumor responses occurred in patients who did not have known BRCA mutations.
"These data indicate that using PARP inhibition to target a specific DNA-repair pathway has the necessary selectivity profile and a wide therapeutic window for BRCA-deficient cells, supporting the clinical relevance of the hypothesis that BRCA mutation-associated cancers are susceptible to a synthetic lethal therapeutic approach," the authors said.
The positive results follow those from two breast cancer studies reported in May at the American Society of Clinical Oncology meeting. One study involved only patients with triple-negative disease, and the other was limited to patients with BRCA mutations.
The study was supported by KuDOS Pharmaceuticals, a subsidiary of AstraZeneca. Additional support was provided by Cancer Research U.K., the Experimental Cancer Medicine Center, the National Institute for Health Research Biomedical Research Center, and Breakthrough Breast Cancer.
Co-authors Andrew Tutt, Mark J. O'Connor, Alan Ashworth, and Stan B. Kaye reported financial relationships with KuDOS or AstraZeneca. Co-authors included employees of KuDOS and AstraZeneca.
Primary source: New England Journal of Medicine Source reference: Fong PC, et al "Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers" N Engl J Med 2009; 361(2): DOI: 10.1056/NEJMoa0900212.
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