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Delivering on the promise: poly ADP ribose polymerase inhibition as targeted anticancer therapy.

ABSTRACT: PURPOSE OF REVIEW:The article presents the rationale, clinical development, and current status of poly (ADP ribose) polymerase inhibitors (PARPis) as anticancer agents. RECENT FINDINGS:The recent approval of olaparib in heavily pretreated patients with advanced ovarian cancer carrying a BRCA1/2 mutation represents a significant therapeutic advance for patients with this difficult to treat disease. Though olaparib is the first agent in this class to be approved, multiple PARPis are in various stages of clinical development, including in combination with other treatment modalities such as radiation, antiangiogenic agents, and cytotoxic chemotherapies. SUMMARY:Clinical benefit has been observed with PARPis in patients with advanced BRCA1/2 mutant ovarian and breast cancers. Various PARPis, either as single agents or in combination, are being evaluated in the neoadjuvant, adjuvant, and metastatic settings.

SUBMITTER: O?Sullivan Coyne G

PROVIDER: S-EPMC4636335 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Delivering on the promise: poly ADP ribose polymerase inhibition as targeted anticancer therapy.

OʼSullivan Coyne Geraldine G Chen Alice A Kummar Shivaani S

Current opinion in oncology 20151101 6

<h4>Purpose of review</h4>The article presents the rationale, clinical development, and current status of poly (ADP ribose) polymerase inhibitors (PARPis) as anticancer agents.<h4>Recent findings</h4>The recent approval of olaparib in heavily pretreated patients with advanced ovarian cancer carrying a BRCA1/2 mutation represents a significant therapeutic advance for patients with this difficult to treat disease. Though olaparib is the first agent in this class to be approved, multiple PARPis are ...[more]

PMID: 26447876

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Project description:BackgroundDespite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors. Particularly, PARP inhibitors are active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated breast related cancer antigens (BRCA) function have HR deficiency, which is also present in a significant proportion of non-BRCA-mutated ovarian cancer ("BRCAness" ovarian cancer). The prevalence of germline BRCA mutations in EOC has historically been estimated to be around 10-15 %. However, recent reports suggest that this may be a gross underestimate, especially in women with high-grade serous ovarian cancer (HGSOC). The emergence of the DNA repair pathway as a rational target in various cancers led to the development of the PARP inhibitors. The concept of tumor-selective synthetic lethality heralded the beginning of an eventful decade, culminating in the approval by regulatory authorities both in Europe as a maintenance therapy and in the United States treatment for advanced recurrent disease of the first oral PARP inhibitor, olaparib, for the treatment of BRCA-mutated ovarian cancer patients. Other PARP inhibitors are clearly effective in this disease and, within the next years, the results of ongoing randomized trials will clarify their respective roles.ConclusionThis review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future. Moreover, combination strategies involving PARP inhibitors are likely to receive increasing attention. The utility of PARP inhibitors combined with cytotoxic chemotherapy is of doubtful value, because of enhanced toxicity of this combination; while, more promising strategies include the combination with antiangiogenic agents, or with inhibitors of the P13K/AKT pathway and new generation of immunotherapy.

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Delivering on the promise: poly ADP ribose polymerase inhibition as targeted anticancer therapy.

Publications

Delivering on the promise: poly ADP ribose polymerase inhibition as targeted anticancer therapy.

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