Olaparib (AZD2281, KU-0059436, LYNPARZA™)

Agent Description

Olaparib is a potent inhibitor of polyadenosine 5'diphosphoribose polymerase (PARP) developed as a monotherapy and in combination with chemotherapy, radiation and other anti-cancer agents including novel agents and immunotherapy.

Mechanism of Action

PARP inhibition. The mechanism of action for olaparib activity as a single agent has been proposed to involve the trapping of inactivated PARP onto DNA single-strand breaks, preventing their repair and generating a potential block for cellular DNA replication. An important consequence of this is that processing of trapped PARP-DNA complexes and/or the stalling of replication forks, or collapsing of replication forks, is predicted to lead to the generation of the more serious DNA double-strand breaks.

Classification

PARP inhibitor

Molecular Targets

PARP-1, PARP-2 and PARP-3

Monograph

The capsule formulation of olaparib was approved in December 2014 by the US Food and Drug Administration (FDA), as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

Most completed studies were performed with the capsule formulation of olaparib. Since 2012/2013 most new studies, including the Phase III registration studies, are being performed with the tablet formulation which was designed to deliver the therapeutic dose of olaparib in fewer dose units than the capsule. The recommended olaparib monotherapy capsule dose is 400 mg BID. The recommended olaparib monotherapy tablet dose is 300 mg BID. Olaparib monotherapy appears to be generally well tolerated across studies up to and including these doses.

Non-clinical studies looking at combinations of olaparib with chemotherapies such as alkylating agents, topoisomerase I inhibitors, platinum agents and taxanes, have demonstrated increased efficacy that ranges from additive to synergistic. For example, PARP inhibitors have been used to show that attenuating PARP activity leads to the chemo-potentiation of temozolomide, topotecan, irinotecan and cisplatin cytotoxicity in both in vitro and in vivo models. Olaparib has also been shown to potentiate ionizing radiation in preclinical lung cancer models.

Most high-grade serous ovarian cancers have abnormalities of BRCA1 or BRCA2 (germline or somatic mutations, or in the case of BRCA1, promoter methylation and loss of expression). A first-in-man Phase I dose escalation trial of single agent olaparib in patients enriched with hereditary BRCA mutations has indicated substantial PARP inhibition in surrogate tissues and anti-tumor activity in 9/15 (60%) ovarian cancer patients with hereditary BRCA mutations, based on combined Response Evaluation Criteria in Solid Tumors (RECIST) and Gynecological Cancer Intergroup CA-125 criteria, while additional trials in hereditary BRCA mutated breast and ovarian cancer patients extended these findings. Further clinical studies suggest single agent olaparib activity in BRCA mutated prostate and pancreas cancers. The clinical development program for olaparib continues to assess the effect of olaparib (as a single agent or in combination) in the treatment of patients with tumors enriched for HRD, including BRCA mutated cancers (germline and tumor).

Package Insert: https://www.azpicentral.com/Lynparza/pi_lynparza.pdf#page=1

Studies of Interest

Areas of interest:

Studies examining platform performance and/or approaches to diagnostic testing
Studies answering drug related questions within populations defined by biomarkers
Combinations of olaparib with other drugs (i.e., small molecule combinations, immunotherapy)
Combinations with other modalities of treatment (e.g., radiotherapy)
Studies identifying molecular profiles predictive for efficacy of olaparib + immunotherapy combinations
Studies assessing utility of liquid biopsies to detect emerging resistance biomarkers

Information collaborator would like included in investigator proposals

N/A