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In an early-phase clinical trial, the PARP inhibitor olaparib was shown to be well- tolerated and safe. Furthermore, for patients who have mutations in BRCA, the majority had either an objective response, as confirmed by imaging studies, or suitable biochemical biomarkers or meaningful stabilization of disease.

PARP Inhibitors: Novel Chemotherapy Finding Its Niche

September 1, 2009

PARP Inhibitors: Novel Chemotherapy Finding Its Niche

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In an early-phase clinical trial, the PARP inhibitor olaparib was shown to be well- tolerated and safe. Furthermore, for patients who have mutations in BRCA, the majority had either an objective response, as confirmed by imaging studies, or suitable biochemical biomarkers or meaningful stabilization of disease.

Source: Fong PC, et al. Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.

Poly (adenosine diphosphate [adp]-ribose) polymerase (PARP) is a DNA-repair enzyme that may be critical for the survival of malignant cells that have deficiencies in other DNA repair pathways. Thus, PARP inhibition is a therapeutic strategy under active development. Cancer patients with tumors that have mutated BRCA1 or BRCA2 proteins may be particularly sensitive to PARP inhibition because it is known that these tumor-suppressor proteins are critical for error-free, homologous-recombination, double-stranded DNA repair.1,2 Olaparib is a novel, orally active PARP inhibitor manufactured by AstraZeneca and examined in the current clinical trial.

This was a phase I trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Although open to a wide range of patients with various tumor types, an effort was made to examine the safety and efficacy of this drug in those who carried BRCA1 or BRCA2 mutations. The trial was conducted in the United Kingdom and the Netherlands.

Sixty patients were enrolled and, of these, 22 were carriers of a BRCA1 or BRCA2. The olaparib dose and schedule were increased from 10 mg daily for two of every three weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). A separate cohort of patients consisting only of carriers of BRCA1 or BRCA2 mutation were enrolled and treated with olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens.

Commentary

Thus, olaparib was shown to be well-tolerated, with few of the adverse effects associated with conventional chemotherapy. The most common side effects were low-grade fatigue and indigestion. The drug was shown to inhibit the target (PARP) and to have pharmacokinetic properties that suggest a twice-daily schedule. Furthermore, among heavily pre-treated patients with cancer associated with the BRCA1 or BRCA2 mutation, the drug was shown to have impressive activity. Antitumor activity was observed only in confirmed carriers of these mutations. However, of these (n = 19), 12 (63%) had clinical benefit meeting radiological or tumor marker criteria for response or meaningful disease stabilization (four months or more). Nine BRCA carriers had a response that met RECIST criteria.

Olaparib is one of a class of PARP inhibitors representing a novel therapeutic approach specifically targeting DNA repair in malignant cells that already have faulty DNA repair capabilities on the basis of endogenous or acquired mutations in other key pathways. Another in this class is BSI-201, and this drug has been tested in "triple-negative" breast cancer with promising preliminary results. Homologous recombination DNA repair pathways are not uncommon in cancer cells, and it is quite possible that this agent will prove to be useful more broadly. However, even if this is not the case, an advance in the treatment of BRCA carriers alone would be a major breakthrough, and with the apparent safety and tolerability profile as described, its may prove a very useful treatment early in disease management, or even in cancer prevention for BRCA carriers. Quite clearly, oncologists will be learning more about these novel and very exciting agents.

References

1. McCabe N, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly (ADP-ribose) polymerase inhibition. Cancer Res. 2006;66:8109-8115.

2. Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006; 25:5864-5874.