Background

PARP inhibition with olaparib is a treatment with high efficacy in HR deficient cancers that arise in carriers of a germline mutation in the BRCA1/2 genes, particularly in ovarian cancer, a registered indication. Olaparib is also active in other BRCA1/2 mutation related cancers, including breast, prostate and pancreatic cancer. Olaparib acts through synthetic lethality in HR deficient cancers. Olaparib responses have however also been documented in cancers in which no BRCA1/2 mutations were found. It is possible that other HR deficiencies may play a role in such sensitivities. An array of other genes involved in HR deficiency, when mutated in the germline lead to an increased risk at least for breast and/or ovarian cancer and other cancers and may sensitize to olaparib. These genes include ATM, CHEK2, NBN, BRIP1, MRE11A, RAD50, NBS1, RAD51C, RAD51D, PALB2, and TP53 as well as BARD1.

Methods

The study recruits advanced cancer patients (pts) that harbor a somatic or a germline mutation in a HR gene. For each cohort a Simon minimax two-stage design is used. In the first stage, 13 patients will be accrued in each cohort. If there are no responses in these 13 patients, that cohort will be stopped.

Results

Currently, the BRCA and ATM cohort are the most advanced with regard to recruitment. Due to the low prevalence of other HR mutations, recruitment is slow in these cohorts. Currently, a total of 72 pts are included and 56 pts underwent a response assessment. Twenty-nine out of 56 pts experienced clinical benefit with olaparib. One complete response was observed in a stage IV breast cancer that harbours a PALB2 germline mutation. Six partial responses occurred: a RAD51D breast cancer, a BRCA1 gallbladder cancer, two BRCA1 and two BRCA2 pancreatic cancer pts. Recently we closed the ATM cohort due to the absence of a response in the first 13 pts.

In general, adverse events were mild to moderate (grade 1 and 2). Only 8 pts (11%) presented with a grade 3 adverse event (an allergic reaction, 5 pts anemia, anorexia and neutropenia).

Conclusions

Treatment with olaparib shows activity in cancer pts with a HR gene mutation and is well tolerated.

Clinical trial identification

NCT03967938, May 30 2019.

Legal entity responsible for the study

UZ Brussel.

Funding

De Stichting Tegen Kanker, Kom op Tegen Kanker, AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.