Episode 18: Olaparib increases ORR in advanced cancers with BRCA1/2 but not CHEK2 and ATM mutations, the PRECISION 2 trial

In this episode of WND Breast, Dr. Kevin Punie from GZA Hospitals and Prof. Evandro de Azambuja from Institut Jules Bordet will discuss the updated findings of the PRECISION 2 trial.

This tumour-agnostic open-label, single-arm phase 2 study was sponsored by the Belgian Society of Medical Oncology in collaboration with Kom op tegen kanker, Stichting tegen kanker, and received funding from AstraZeneca and MSD.

The study investigated olaparib as a treatment option for advanced solid cancer in patients with either a germline or somatic mutation in a gene involved in homologous recombination. It established gene-specific cohorts, with each cohort following a two-stage design for assignment. Initially, 13 patients were recruited, and upon observing an objective response in one patient, the cohort expanded to 27 patients, with the ORR within each gene-specific cohort measured as the primary outcome. Breast and ovarian cancer patients were excluded from participation. The data presented encompass the results of four completed cohorts: BRCA1, BRCA2, ATM, and CHEK2.

In the BRCA1 and BRCA2 cohorts, where most patients had somatic mutations, the overall ORR was 11% and 22% respectively. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas, and parathyroid cancer. Notably, a patient with gallbladder carcinoma achieved over 2 years of disease stabilization, indicating significant clinical benefit even without partial response. The data is encouraging, especially considering that these patients were heavily pretreated before participating in this clinical trial. No response was observed in the initial patients of the ATM and CHEK2 cohorts, suggesting olaparib did not provide clinical benefit in targeting the DNA damage response.

For rare tumours with uncommon mutational profiles, treatment decisions will not be based on evidence from large randomized trials. Agnostic study designs aid in developing robust biological concepts targeted by specific drugs like olaparib. Patients with rare diseases, yet common alterations across cancer types, can benefit from existing drugs within the setting of a clinical trial. Another significant finding from this trial design is that the benefit of a PARP inhibitor to target homologous recombination deficiency expands beyond traditional indications.