Targeting DNA Repair in BRCA Mutation Carriers (2007)

CHICAGO—A new targeted drug that blocks DNA repair appears safe and shows preliminary evidence of activity in familial ovarian cancer patients, researchers reported here at the ASCO Annual Meeting. Already several drugs in this same class are being tested in early clinical trials. Researchers say that they expect that the agents will work in BRCA-associated ovarian and breast cancers and that they may increase the potency of DNA-damaging agents in other cancers. The new drugs inhibit an enzyme called poly(ADP-ribose) polymerase (PARP), which is critical for repairing single-strand DNA breaks. Preclinical studies have shown that the agents are particularly toxic to cells that lack either BRCA1 or BRCA2 genes, which disrupt another type of DNA repair called homologous recombination. “BRCA1- or −2-deficient cells are approximately 400 to more than 1,000-fold more sensitive to PARP inhibition than wild type and, importantly, heterozygous BRCA cells, which showed no increase in sensitivity,” said the researcher who presented the early clinical trial data, Timothy A. Yap, MD, of the Drug Development Unit at the Royal Marsden NHS Foundation Trust. “It was hypothesized that targeted inhibition of BRCA-deficient cells with a PARP inhibitor would result in a selective and less toxic therapy.” To test that hypothesis, Dr. Yap and colleagues enrolled 56 patients in a Phase I study of AZD2281 (formerly called KU-005943) at Royal Marsden Hospital and the Netherlands Cancer Institute. In the initial dose-escalation phase, patients with any solid tumor type were eligible for entry; however during an expansion phase of the trial, only patients with BRCA1 or 2 associated breast and ovarian cancers were eligible. Thirteen of the patients in the study had confirmed BRCA1 mutations, including nine patients with ovarian cancer, one each with breast cancer, fallopian tube cancer, primary peritoneal, and small cell lung cancer. Four patients carried BRCA2 mutations, including one with ovarian cancer, two with breast cancer, and one with prostate cancer. Additionally, one ovarian cancer patient has a family history that is consistent with a BRCA mutation, but she declined to be tested. The drug appeared to be well tolerated, Dr. Yap said, with most toxicities limited to Grade 1 or 2. Nineteen patients (35%) had some nausea, which was the most common side effect. Fifteen patients (28%) had fatigue of any grade, seven (12%) had vomiting, five (9%) reported taste alteration, and five had (9%) anorexia. In terms of Grade 3 or higher non-dose limiting toxicities, two patients (4%) had Grade 3 fatigue, one (2%) had nausea, one (2%) had vomiting, one (2%) had dizziness, and another had Grade 3 thrombocytopenia. Additionally one patient with small-cell lung cancer died of a respiratory infection while on therapy, although clinicians concluded that it was not related to the drug. Three dose-limiting toxicities were reported at 400 and 600 mg twice daily dosing, including one patient with neurocognitive impairment, which was characterized by low mood and occurred with Grade 3 fatigue, and one patient with Grade 3 sleepiness. All of these problems resolved within 24 hours of stopping the drug. One patient had Grade 4 thrombocytopenia, which resolved within two weeks of stopping therapy. Based on these data, the dose for subsequent enrollment and trials was set at 200 mg twice-daily continuous dosing. There was evidence of anti-tumor activity, particularly in patients with BRCA 1 or 2 mutations. Five patients with hereditary ovarian cancer had partial responses by Response Evaluation Criteria in Solid Tumors, as did one patient with BRCA-associated fallopian cancer. Three of these individuals are still on therapy, at 17, 20, and 31 weeks. Additionally, five patients have stable disease, with one ovarian and one breast cancer patient continuing on therapy at 15 and 10 weeks, respectively. One BRCA-mutation carrier with ovarian cancer has had a CA-125 response and continues on therapy at 28 weeks. Dr. Yap said that the research team fully expects that the drug will also show efficacy in BRCA-related breast cancer, but the three patients with that malignancy in the study started on the trial only recently and so are not yet evaluable. Dr. Yap showed CT scans of several tumors before and after treatment, including a brain scan of a patient with a BRCA-related breast cancer. After six weeks on treatment, a brain metastasis shrank from 6.5 mm to 3 mm, indicating that the drug can cross the blood-brain barrier, he said. To find out whether the drug was inhibiting the target enzyme, Dr. Yap and colleagues tested peripheral blood mononuclear cells (PBMCs) and tumor biopsies with an antibody that binds to a modified form of the PARP enzyme, called PAR, which is formed during the first step in PARP-mediated DNA repair. In five of six tumor samples analyzed, they found more than 55% inhibition of PARP. There was as much as 85% enzyme inhibition in PBMCs. Interestingly, Dr. Yap said, the team assayed for a downstream product of PARP inhibition, called gH2AX, in the follicle of plucked eyebrow hairs. “Our results are still preliminary, but we are cautiously optimistic that this may provide a non-invasive way of detecting target inhibition with this drug,” he said. “We have observed substantial inhibition of the target in both tumor and surrogate tissue. And encouragingly we have also observed compelling efficacy data in hereditary ovarian cancer patients,” he concluded. In June, AstraZeneca launched two international Phase II trials to test the agent in BRCA mutation carriers with ovarian and breast cancers. The study's Discussant, Janet E. Dancey, MD, Senior Investigator at the Cancer Therapy Evaluation Program at the National Cancer Institute, called the abstract exciting, based on activity and proof of concept. She noted that AZD2281 is just one of six PARP inhibitors currently in clinical development. The one that is farthest along is a Pfizer drug, AG014699, which is in Phase 2 trials in combination with temozolomide in patients with melanoma. “PARP inhibition proof-of-concept has been shown, with responses in the BRCA-mutation patients, and the target patient population has clearly been identified,” Dr. Dancey said. “I would say that wild type and BRCA patients will have to be evaluated separately for the efficacy of combinations.” Additionally, other patient groups may benefit from the drug, particularly those whose tumors have mutations in other DNA repair genes. She urged the drug developers not to ignore this possibility, even while focusing on developing the drug in BRCA patients. Phase 0 trial of ABT-888 Meanwhile, Shivaani Kummar, MD, a staff clinician in the NCI's Developmental Therapeutics Section, reported the results of a Phase 0 trial testing another PARP inhibitor, ABT-888, during a session devoted to novel agents. The primary goal was to determine a dose that inhibited PARP in PBMCs and tumor biopsies. “Inhibition of PARP is associated with persistent DNA damage, eventually leading to apoptosis and cell death. In preclinical models, ABT-888 from Abbott Laboratories potentiates the activity of DNA-damaging agents, such as platinum, temozolomide, topo[isomerase] I inhibitors, and radiation,” Dr. Kummar said. A single dose of 50 mg of ABT-888 was found to be adequate to achieve 95% inhibition of PARP activity in PBMCs, which extended to 24 hours. Additionally, the drug inhibited more than 90% of PARP activity in five tumors biopsied. The Phase 0 dosing data will be used in Phase I combination trials due to begin shortly, Dr. Kummar said. “The question we can ask is ‘Are we there yet?’ Is this dose adequate for all comers?” commented Edward Sausville, MD, PhD, Associate Director for Clinical Research at the University of Maryland Greenebaum Cancer Center, the Discussant for this abstract. “Although experience in the clinic will have to build on this, I think it is fair to say this trial allows for the expeditious development of more definitive trials to establish this and to get the agent out for general use. Is there a value to pursuing higher doses? I don't think so. There is clear evidence of inhibition in peripheral blood mononuclear cells, and more importantly, in the majority of tumors assayed after dosing. So I do believe we are there.”