more new research: BRCA-Negative Ovarian Cancer Responds to Monotherapy With PARP Inhibitor

I don't know if many of you like to read new research, but I think it's good if we work to make this Discussion Board an important resource for anyone diagnosed with OVA. It is so great to have one place online that is nurturing and informative, with so much scary inaccurate stuff out there. So here's what I read on OncologyStat (brand-new research) today:

BRCA-Negative Ovarian Cancer Responds to Monotherapy With PARP Inhibitor

The PARP inhibitor olaparib, recently confirmed to achieve 46% response in BRCA-mutated ovarian cancers by Fong et al. using 200 mg bid (JCO May 20), was reported to produce response even in BRCA nonmutated cases by Gelmon et al. in a Canadian study. Although none of 28 nonmutated breast cancer patients responded, 23% of pretreated patients with BRCA-negative ovarian cancers responded to monotherapy at 400 mg bid, with a median PFS of 7 months. These results, and those of bevacizumab, increase the number of effective agents with unique mechanisms of action to attack this disease.

ABSTRACT
CHICAGO (EGMN) — A phase II translational study showed that monotherapy with the experimental PARP inhibitor olaparib can draw responses in women with advanced serous ovarian cancer regardless of whether the disease carried a BRCA mutation.

No women with triple-negative breast cancer responded to olaparib monotherapy in the non-randomized study presented at the annual meeting of the American Society of Clinical Oncology.
ABT-888 and MK-4827, two other experimental agents inhibiting poly (ADP-ribose) polymerase (PARP), also showed activity in two small phase I trials described in the same clinical science symposium.

"It is unequivocal that this is a critically important class of new drugs for the treatment of BRCA1 and BRCA2 mutant tumors," said discussant Dr. James H. Doroshow of the National Cancer Institute, Bethesda, Md. "As we saw today...there is exciting efficacy for single-agent PARP inhibitors in non-BRCA mutant serous ovarian cancer. Is this a disease of impaired DNA repair? I think this is a very important therapeutic focus for the future," he said.

PARP is an enzyme involved in DNA repair, particularly single strand break repair, said moderator Dr. Hilary Calvert of University College London. At least 17 PARP isoforms, and nine PARP inhibitors are currently in development. The inhibitors have several potential roles in cancer treatment, including to potentiate specific cytotoxic drugs and radiation therapy; to promote the death of cancer cells through a process being called "synthetic lethality," and for use in combination with drugs such as carboplatin, which are known to be active in tumors with hormone receptor defects, such as ovarian tumors.

Dr. Calvert also described some problems of PARP inhibitors, notably that specific potentiation of the drugs is not consistently seen in vivo. In addition, they carry the potential of enhanced toxicity when used in combination with other drugs. Patients may develop resistance to the inhibitors, and the inhibitors may promote genotoxicity, he said.

Dr. Karen Gelmon of the BC Cancer Agency in Vancouver presented the olaparib study of 26 patients with triple-negative breast cancer and 64 with high grade serous ovarian cancer. All patients were treated with olaparib 400 mg twice daily on a continuous basis in 4-week cycles. The objective response rate RECIST criteria was the primary end point.
Among ovarian cancer patients, it was 41.2% in 17 women found to be BRCA mutation carriers and 23% in 53 women determined to be BRCA negative. None of the breast cancer patients had an objective response by RECIST.

Median progression-free survival reached 219 days in the ovarian cohort and 54 days in the breast cohort. Olaparib was found to be effective and well tolerated in both ovarian and breast cancer populations, with side-effect profiles similar to previous trials.
The ovarian cancer cohort was older with a median age of 58 years vs. 47 years for the breast cancer cohort. The median number of prior chemotherapies in both groups was 3 (range 1-10). "Most patients had good performance status," said Dr. Gelmon.

In concluding remarks Dr. Gelmon said this was the first single-agent trial demonstrating encouraging activity of olaparib in high grade non-BRCA serous ovarian cancer.
"And this adds important translational science, for patients enriched for homologous recombination deficient tumors," she added. The investigators archived tissue samples from all patients before and after therapy and plan to do comprehensive analyses to detect BRCA mutations or promoter hypermethylation of BRCA1.

Dr. Antoinette Tan of the Cancer Institute of New Jersey in New Brunswick presented preliminary results of a phase I trial of ABT-888 in combination with cyclophosphamide. The 30-patient study was designed to determine the maximum tolerated dose of the drugs, evaluate pharmacokinetics, and assess PARP inhibition in peripheral blood mononuclear cells. Inclusion criteria was solid tumors or non-Hodgkin's lymphoma; ECOG performance status of 0-2; adequate hematologic, hepatic and renal function; and measurable or evaluable disease by RECIST analysis.

Dr. Tan concluded that ABT-888 at 200 mg PO every 12 hours given day 1 to day 4 could be safely combined with 750 mg/m2 IV cyclophosphamide given on day 3 every 21 days. The maximum tolerated dose of the drugs was not determined, but ABT-888 was not found to alter the pharmacokinetics of cyclophosphamide. In the patient population, 75% of patients had greater than 50% PARP inhibition in peripheral blood mononuclear cells at 4 hours post-dosing of ABT-888 on day 3.

Dr. Shahneen K. Sandhu of the Royal Marsden NHS Foundation Trust in Sutton, United Kingdom presented a first-in-human trial of the PARP inhibitor MK-4827 in 59 patients with advanced BRCA-deficient and sporadic ovarian cancers.

The drug was well tolerated, and continuous oral administration at 300 mg was found to be the maximum tolerated dose. Dosing was proportional to pharmacokinetic profile. Proof of mechanism confirmed PARP inhibition from doses greater than or equal to 80 mg.

Dr. Sandhu said that compelling anti-tumor activity was observed in heavily pre-treated BRCA1 and BRCA2 mutation carriers, and preliminary anti-tumor activity was seen in sporadic cancers.
In his concluding remarks, discussant Dr. Doroshow reiterated that PARP inhibitors have shown important activity as a class in BRCA 1 and 2 mutant tumors in the clinic, and are showing efficacy as single agents in non-BRCA mutant serous ovarian cancer. He said that an important focus for the future was whether ovarian cancer was perhaps a disease of impaired repair.
Interest in PARP inhibition was perhaps best reflected by the question an attendee at the packed session put to Dr. Gelmon.

"My problem is, as a practicing oncologist, I see these great, wonderful results, in a very difficult population of patients with ovarian cancer," he said. "I want to know when I can get my hands on some. There are patients dying today because of this lack of access."
"I think you'll have to ask the companies," she replied.

Dr. Doroshow, Dr. Tan, and Dr. Sandhu disclosed no relevant financial relationships. Dr. Calvert reported receiving inventor's rewards for AG-014699, research funding from Pfizer, and consultancy from Pfizer, BiPar, Inotek, and Biomarin. Dr. Gelmon disclosed consultant or advisory role to AstraZeneca, and research funding from AstraZeneca. The trial of ABT-888 was sponsored by the National Cancer Institute and the Cancer Institute of New Jersey.