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Parp Inhibitor

Parp Inhibitor

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HOUSTON, June 24 -- 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.

Action Points��Explain to patients that an investigational drug showed activity in tumors that have certain types of genetic mutations.Emphasize that the drug is not yet available.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.

(See New Drug Class Promising in Breast Cancer) 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.



http://www.medpagetoday.com/HematologyOncology/BreastCancer/14851
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