Olaparib and adavosertib, work best when given sequentially in patients with advanced tumours: results from Phase Ib STAR clinical trial

Presenting results from the phase Ib STAR clinical trial to the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain Timothy A. Yap, said that sequential dosing with the two drugs was a strategy that was safe and well-tolerated, with promising signs of anti-tumour activity in patients with a range of different cancers.

"Based on these compelling pre-clinical data, we started the STAR study investigating sequential olparib and adavosertib to patients with BRCA1, BRCA2, PALB2, ATM, ARID1A and CCNE1 alterations," said Dr Yap.

Two men and eleven women, with an average age of 50 years, enrolled in the study between April 2020 and November 2021. Five had breast cancer, five had ovarian cancer, one patient had prostate cancer, one had gastric cancer and one had bowel cancer. Ten of the patients had received three or more previous lines of chemotherapy, and cancer had continued growing in seven patients who had been treated previously with a PARP inhibitor.

Three of the 13 patients received 300mg olaparib orally twice daily for the first five days and again from days 15-19, alternating with 250 mg adavosertib orally once a day from days 8 to 12 and days 22 to 26. This was dose level (DL) 1. The remaining ten patients received 300mg olaparib twice a day from days one to five and days 15 to 19, and 300mg adavosertib orally once a day on days eight to twelve and days 22 to 26. This was DL 2. Both DL 1 and 2 were given every 28 days in the absence of disease progression or unacceptable side effects.

Three of 12 patients available for evaluation had a partial response in which their tumours shrank by 30% or more, or levels in blood samples of a biological marker for cancer called CA125 fell by at least 50%. Of these, partial responses were seen in a patient with BRCA2 oestrogen receptor positive breast cancer for six months, and in a patient with PARP inhibitor-resistant BRCA2 mutation ovarian cancer for ten months. Five other patients had stable disease, in which their cancer neither grew nor shrank for four or more months.

Reference:

Timothy A. Yap, et al, NCI10329: Phase Ib Sequential Trial of Agents against DNA Repair (STAR) Study to investigate the sequential combination of the Poly(ADP-Ribose) Polymerase inhibitor (PARPi) olaparib (ola) and WEE1 inhibitor (WEE1i) adavosertib (ada) in patients (pts) with DNA Damage Response (DDR)-aberrant advanced tumors, enriched for BRCA1/2 mutated and CCNE1 amplified cancers