Pembrolizumab and Olaparib in Homologous-recombination Deficient (HRD) Advanced Colorectal Cancer (CRC).

This study is a phase 2, open-label, multicentric, single arm trial designed to evaluate the response to olaparib in combination with pembrolizumab in patients with metastatic colorectal cancer (mCRC) with homologous-recombination repair deficiency (HRD), defined as the presence of a BRCA deleterious mutation and/or a low RAD51 score (cut-off \<10% ) \[Castroviejo-Bermejo, 2018\]. Patients will be required to provide a sample of the most recent archival tumor tissue for HRD determination. A functional score evaluating HRD deficiency will be performed, the RAD51 score. This score will be determined in FFPE tumor samples. Oxaliplatin-sensitivity and a low RAD51 score (cut-off \<10%) will be required for patients to continue the screening process. Oxaliplatin-sensitivity is defined as a progression free survival ≥ 9 months in the first line setting, having received at least 8 cycles of FOLFOX (fluorouracil, folinic acid and oxaliplatin) or 6 cycles of XELOX (capecitabine and oxaliplatin) treatment as first line therapy. All patients will undergo screening assessments within 4 weeks prior to enrollment. Screening assessments will include demographics and medical history, prior anticancer treatments and sensibility to oxaliplatin therapy, prior and current medications, 12-lead ECG, ECOG performance status, hematology and serum/plasma chemistry, urinalysis, physical examination, vital signs measurements, and baseline radiologic assessment by whole body computed tomography (CT). All patients included in the study will undergo the Myriad MyChoice HRD test, but no specific cut-off value will be requested to participate in the trial. Treatment cycles will be 21 days in length. All participants will receive treatment as follows: Olaparib 300 mg, orally (po), twice a day (BID) continuously. Pembrolizumab 200 mg, intravenously (IV), every 21 days. Treatment will be continued in the absence of disease progression, unacceptable toxicity, withdrawal of consent or death. Pembrolizumab will be administered up to a maximum of 2 years (35 cycles). All patients will be monitored for efficacy as well as safety throughout this phase. Assessments will include physical examination, vital signs and weight assessment, hematology, serum chemistry, urinalysis, concomitant medications, ECOG performance status, disease status assessment, 12-lead ECG, AEs with any associated therapies and procedures, study drug administration and accountability. Disease response to study treatment will be evaluated by imaging methods, with tumor scans being done every 9 weeks of treatment (± 7 days). Disease progression will be determined by RECIST v1.1. Patients experiencing disease progression by RECIST v1.1, as assessed by the investigator, will be discontinued from study treatment and continue follow-up. However, if the patient has met criteria for radiologic progression by RECIST, but is still benefiting from the study drugs, according to the investigator, the decision to continue will be made jointly between the investigator and the sponsor. Upon treatment discontinuation (with the exception of withdrawal of consent or death), patients will have an End of Treatment Visit. All patients will be followed for at least 28 days after the last dose of study drug and will then be followed every 3 months for survival.