A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer

Abstract

In this heavily pretreated mCRC population, a combination of veliparib and temozolomide was well tolerated with temozolomide doses up to 200 mg/m /d, and it was clinically active. PARP inhibitor-based therapy merits further exploration in patients with mCRC. Cancer 2018;124:2337-46. © 2018 American Cancer Society.

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

“…In the BRCA wild‐type HRD subgroup, HRD status was determined based on the dichotomized HRD score (n = 106) or HRD‐LOH (genomic loss of heterozygosity) score (n = 188) using a predefined threshold. Mutations in HRD genes rather than BRCA1/2 included ATM low or negative (n = 125), high‐level microsatellite instability (n = 13), PTEN loss (n = 30), and other aberrations in DNA repair genes (n = 16) . Patients with BRCA wild‐type, low HRD or HRD‐LOH score, ATM high or positive, or microsatellite‐stable or without defects in DNA repair gene were collectively classified as the non‐HRD subgroup (n = 1,417).…”

“…It is noteworthy that both analyses on ovarian carcinoma and nonovarian carcinomas showed similarly favorable PFS6 and PFS12 in the HRD group only in the context of monotherapy but not in combination therapy. The strategy of combination therapy is developed based on the definition of “contextual synthetic lethality” by inducing HRD or downregulating HR DNA repair through the addition of other agents, such as cytotoxic chemotherapy, radiotherapy or targeted inhibitors . This strategy offers a new insight that may help increase the benefit of PARPis even in the absence of HRD.…”

“…The vulnerability caused by HRD mutation genes could also be largely different depending on the cancer types. For example, BRCA mutations are predictive of response to PARPis for ovarian cancer, while in gastric or colorectal cancer the biomarker could be ATM or PTEN . Therefore, taking into account cancer heterogeneity, systematic genetic and pharmacological studies on HR DNA repair pathway genes in diverse cancer types are necessary to reveal novel biomarkers predicting PARP inhibition sensitivity, in addition to BRCA mutations.…”

“…However, they support the hypothesis that patient stratification based on underlying genetic defects in DNA repair pathways could be a meaningful approach for identifying patient populations that are likely responding to PARPis. To date, the clinical results of tumor response and prognosis in different HRD cancer populations appear to be inconsistent . In terms of long‐term clinical benefit, such as progression‐free survival (PFS) and overall survival (OS), the precise role of HRD as a predictive biomarker has not been well established.…”

“…To date, the clinical results of tumor response and prognosis in different HRD cancer populations appear to be inconsistent. 13,14 In terms of long-term clinical benefit, such as progression-free survival (PFS) and overall survival (OS), the precise role of HRD as a predictive biomarker has not been well established. While multiple prospective randomized controlled studies are currently on the way to best address these questions, we aim to provide an evidence-based systematic review on available clinical studies.…”