Inhibition of Poly (ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
October, 2009
Commentary by Dr Gillian Mitchell
The article
Fong PC, Boss DS, Yap TA et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. N Engl J Med 2009;361(2):123-34 doi:10.1056/NEJMoa0900212 published online 24 June 2009
The Reviewer
Dr Gillian Mitchell is a clinical oncologist and the Director of the Familial Cancer Centre at the Peter MacCallum Cancer Centre, Melbourne.
Abbreviations
Homologous Recombination (HR); Poly(Adenosine Diphosphate [ADP]-Ribose) Polymerase (PARP)
Summary
Study design
This phase I trial included 60 patients with advanced solid tumours, of whom 22 were BRCA1 or BRCA2 mutation carriers. The aim of the study was to analyse the safety and pharmacokinentic and pharmacodynamic properties of olaparib, an orally active PARP inhibitor. PARP plays a key role in DNA repair of single-strand breaks. The adverse effect profile, maximum tolerated dose and dose at which PARP is maximally inhibited were examined.
Findings
Dose escalation studies led to the establishment of the maximum administered dose for olaparib as 600mg twice daily and the maximum tolerated dose as 400mg twice daily.
The most commonly reported adverse effects that were possibly related to olaparib included nausea (32%), fatigue (30%), vomiting (20%), taste alteration (13%), and anorexia (12%). There was no obvious increase in frequency or grade of adverse effects in BRCA mutation carriers compared with non-carriers.
Pharmacokinetic studies indicated rapid absorption and elimination, with a terminal half-life of approximately 5 to 7 hours. Pharmacodynamic studies indicated that PARP was inhibited by more than 90% in cells from patients treated with 60mg or more of olaparib twice daily. PARP inhibition was associated with induction of collapsed replication forks and DNA double-strand breaks.
Anti-tumour activity was observed in confirmed BRCA mutation carriers. Of 19 BRCA carriers (with either ovarian, breast or prostate cancer), 12 (63%) had a clinical benefit with radiologic or tumour-marker responses or disease stabilization. One patient with BRCA2 breast cancer had a complete remission.
Conclusion
The authors concluded that olaparib has an acceptable adverse effect profile, satisfactory pharmacokinetic and pharmacodynamic characteristics and was associated with anti-tumour activity in cancer associated with BRCA mutation.
Commentary
What does this article add to existing clinical evidence in this area?
There has been an intense focus in recent years on agents which target components of essential cellular processes that are differentially expressed in tumour cells compared to normal cells. This approach stands to maximise their therapeutic index but should also improve treatment response rates if tumours harbouring these altered processes can be reliably identified.
The poly(adenosine diphosphate [ADP]-ribose) polymerases (PARPs) are a large family of multifunctional enzymes which play a role in the repair of DNA single-strand breaks through the repair of base excisions. Inhibition of PARPs leads to the accumulation of DNA single-strand breaks which can lead to double-strand breaks at replication forks. Normally double-strand breaks are repaired by the homologous recombination (HR) pathway and key components of the HR pathway are the BRCA1 and BRCA2 proteins.1
Inheritance of a germline mutation in the BRCA1 or BRCA2 genes is associated with a significantly increased risk of male and female breast cancer, ovarian cancer and prostate cancer, often at early ages. BRCA1 and BRCA2 genes are tumour suppressor genes; during tumour initiation the function of the remaining normal allele is lost and the resulting tumour is therefore deficient in BRCA1 or BRCA2 function while BRCA function is maintained in other somatic cells. PARP inhibition in BRCA deficient tumours results in unrepaired double-strand breaks at the replication forks but has little effect on the other cells that retain a functioning copy of the BRCA gene therefore predicting a high therapeutic index for PARP inhibitors in BRCA mutation carriers – a concept termed “synthetic lethality”.1,2 Preclinical data supports this hypothesis,3 but concerns remain about the potential toxicity of PARP inhibitors in germline BRCA mutation carriers.
The phase I trial reported by Fong et al1 investigated a potent, oral PARP1 inhibitor, olaparib, in a cohort of patients with advanced malignancies, with a particular focus on its effects in a population of patients known to have germline BRCA mutations.
How adequate was the methodology used in addressing the aim of this study?
This study started as a conventional phase I trial with the objectives of determining safety, the side effect profile, the maximally tolerated dose and various pharmacokinetic and pharmacodynamic parameters. A standard phase I trial protocol of gradually increasing doses of olaparib was used in successive groups of patients with advanced cancer of any type for which no suitable standard treatments were available. What was more unusual about this trial was the planned enrichment of the cohort with known carriers of germline mutations in the BRCA1 or BRCA2 genes, which included an expansion phase of known BRCA mutation carriers at a fixed dose of olaparib.
The planned purpose for enrichment with known mutation carriers was not clearly stated but appears motivated by the concern for the potential of increased toxicity in germline BRCA mutation carriers but also gave an indication of olaparib activity in this group.
What are the implications of this study for clinical practice in Australia?
The results of this study were remarkable for the objective antitumour activity seen in known BRCA mutation carriers, some of whom remained on treatment with olaparib for over a year, whereas no responses were seen in non-mutation carriers. Toxicity was largely of grade 1 and 2 with a low incidence of myelosupression. Importantly there was no obvious increase in the frequency or grade of adverse effects in BRCA mutation carriers.
This is the first stage of investigating the role of PARP inhibitors in the treatment of BRCA-associated cancers. Olaparib does not appear to have excessive toxicity in BRCA mutation carriers and shows anti-tumour activity. Many questions remain, which will be the focus of future trials in this patient group and include defining the efficacy of these agents, toxicity profile and mechanisms of resistance. Another important area of investigation will be combining PARP inhibitors with conventional chemotherapy agents to maximise the lethality of PARP inhibition by accelerating the formation of DNA breaks. What agents to use, the doses of PARP inhibitors and chemotherapy agents and their scheduling will require careful consideration. The next phase of trials of PARP inhibitors in BRCA mutation carriers have completed recruitment and Australia has contributed an important proportion of the international recruitment to date.4,5 New trials are either in development or in progress.
While the early results of PARP inhibitors in BRCA mutation carriers are exciting, mutation carriers represent a small proportion of all women with breast and ovarian cancer or men with prostate cancer. What is of great interest to the wider oncology community is the potential to exploit the potential for synthetic lethality in other cancers that have acquired a defect of DNA-repair during tumourigenesis. The difficulty is identifying these tumours. One possible approach is to target breast cancers with the same phenotype as BRCA1-associated cancers, ie the “triple negative” breast cancers. O’Shaughnessy et al6 recently presented their results of a randomized phase II trial of a PARP inhibitor in combination with carboplatin/gemcitabine combination in metastatic “triple negative” breast cancer and demonstrated good activity with the PARP combination.
These early results are reminiscent of the first reports of activity with trastuzumab in HER2 positive breast cancer and the results of ongoing PARP inhibitor trials are eagerly awaited.
References
- Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123-34
- Iglehart JD, Silver DP. Synthetic lethality – a new direction in cancer-drug development. N Engl J Med 2009;361:189-91
- Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-21
- Tutt M, Robson JE, Garber S, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol 2009;27:18s (suppl; abstr CRA501)
- Audeh MW, Penson RT, Friedlander M, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 2009;27:15s (suppl; abstr 5500)
- O'Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol 2009;27:18s (suppl; abstr 3)
Editor: Dr Anne Nelson, Evidence Review and Research Leader, National Breast and Ovarian Cancer Centre
Clinical Update – Breast Cancer Editorial Committee: Mr John Collins - Surgeon, Ms Jo Keyser - Specialist Breast Nurse, Dr Warwick Lee - Radiologist, A/Prof Liz Lobb – Senior Research Fellow, Dr Sue-Anne McLachlan - Medical Oncologist, Dr Sally Meade - Breast Surgeon, Dr Sue Pendlebury - Radiation Oncologist, A/Prof Martin Stockler - Medical Oncologist.
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