The first-in-class drug olaparib

Lynparza, trade name has been approved for the treatment of advanced ovarian cancer with BRCA mutations.

To be used in patients with BRCA-mutated ovarian cancer who have already received three or more chemotherapy treatments.

An inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.

A potent oral inhibitor of PARP 1and 2, functions by trapping PARP 1 at sites of DNA damage, which leads to the collapse of DNA replication forks, the accumulation of DNA double – strand breaks, and the eventual death of the cell.

An Inhibitor their blocks DNA base-excision repair and causes synthetic lethality in tumors with homologous recombination repair deficiencies.

Acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast, and prostate cancers.

Approved as monotherapy at 400 mg taken twice per day, for patients with germline BRCA mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

Olaparib is the first in a class of drugs that inhibit poly(ADP)-ribose polymerase (PARP), and it is indicated for use in heavily pretreated women with advanced ovarian cancer with BRCA mutations.

Has a 30-50% response rate when employed as a second line, or later, strategy in the presence of BRCA mutations and ovarian cancer.

Can be used as maintenance therapy in patients with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy, regardless of BRCA mutation status and for HER2 negative breast cancer with deleterious OR suspected deleterious germline BRCA mutations who have previously been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.

Clinical activity is most common in platinum sensitive patients, although platinum resistant can respond.

Clinical activity has been observed in high grade serous ovarian cancers. in the absence of BRCA mutation, although response rates are lower.

Patients with high grade ovarian cancer in a second remission following platinum based chemotherapy, after obtaining an objective response or achieving a status stable disease, utilizing this drug has statistically significant improved progression free survival of 8.4 months versus 4.8 months with placebo, and, in patients with BRCA it was a median of 11.2 months versus 4.3 months for placebo.

In a randomized phase III study of olararib compared to placebo in patients with platinum sensitive recurrent ovarian Ca in partial or complete remission the median time to progression free survival for active maintenance was 19.1 months vs 5.5 months for placebo(Pujade-Lauraine).

The use of maintenance therapy olaparib in regards to progression free survival among women with newly diagnosed advanced ovarian cancer and a BRCA 1/2 mutation had a 70% lower risk of disease progression or death than with placebo (Moore K).

The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth.

Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and it is estimated that 10% to 15% of all ovarian cancer is associated with these hereditary BRCA mutations.

Generally well tolerated, the side effects consist mainly of fatigue, somnolence, nausea, loss of appetite and thrombocytopenia.

Response rate in metastatic hormonal resistant prostate cancer 32%.

Responses in metastatic hormonal resistant prostate cancer with BRCA2 gene very high.

In men with metastatic castrate resistant prostate cancer who have BRCA 1, BRCA 2, or ATM mutations and who had  disease progression while receiving a new hormonal agent, olaparib lead to significantly longer progression free survival then enzalutamide or abiraterone.

Recommended dose is two 150 mg tablets BID.

Efficacious for patients with BRCA mutation breast cancer-improves median progression free survival in patients with such mutations compared to chemotherapy.

The SOLO-1 trail of women who had advanced BRCA mutated ovarian cancers and who had undergone cytoreduction Surgery and who were in complete or partial response to platinum based chemotherapy randomize to Olaparib or placebo: follow up for 40.7 months the olaparib reduced risk of progression free survival by 70%.



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