AstraZeneca’s PARP inhibitor olaparib looks promising in Phase II

AstraZeneca’s PARP inhibitor olaparaib, which targets cancer cells caused by mutations of the BRCA1 or BRCA2 genes, has shown significant potential to shrink tumours in inherited forms of breast and ovarian cancer.

Results from two Phase II proof-of-concept trials with olaparib, both sponsored by AstraZeneca, have been published in The Lancet. They demonstrated objective response rates of up to 41% and up to 33% in breast and ovarian cancer respectively.

Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in BRCA-deficient cells. According to King’s College London, around 1,500 of the nearly 46,000 women diagnosed with breast cancer in the UK each year have faulty BRCA1 or BRCA2 genes.

Dr Andrew Tutt, director of the Breakthrough Breast Cancer Research Unit at King’s College London, was the study leader for the breast cancer trial with olaparib and was one of the study authors for the ovarian cancer trial.

Conducted at 16 centres in Australia, Germany, Spain, Sweden, the UK and the US, the breast cancer trial involved 54 women with confirmed BRAC1 or BRAC2 mutations and recurrent, advanced breast cancer who had received a median of three previous chemotherapy regimens.

The objective response rate (ORR) was 11 (41%) of 27 patients assigned to olaparib 400mg twice daily and six (22%) of 27 patients given olaparib 100mg twice daily. In the higher-dose group, tumours were prevented from progressing for an average of six months, Kings College London noted.

The other trial enrolled two sequential cohorts of women with confirmed BRAC1 or BRAC2 mutations and recurrent, measurable ovarian cancers at 12 centres in Australia, Germany, Spain, Sweden and the US. Once again, the women had been through a median of three previous chemotherapy regimens.

In this case, the ORR was 11 (33%) of 33 patients in the cohort assigned to otaparib 400mg twice daily and three (13%) of 24 patients in the cohort given olaparib twice daily. Tumours in the higher-dose group were again prevented from progressing for an average of six months. Side-effects in both trials were relatively minor, including fatigue and nausea, King’s College London said.