Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer

Leichman, Lawrence; Groshen, Susan; O’Neil, Bert H.; Messersmith, Wells A.; Berlin, Jordan; Chan, Emily; Leichman, Cynthia G.; Cohen, Steven J.; Cohen, Deirdre Jill; Lenz, Heinz Josef; Gold, Philip J.; Boman, Bruce M.; Fielding, Anitra; Locker, Gershon Y.; Cason, Ronald C.; Hamilton, Stanly R.; Hochster, Howard S.

doi:10.1634/theoncologist.2015-0319

Cited by 62 publications

(51 citation statements)

References 33 publications

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“…More recently, a phase II clinical trial investigated off‐label of use of PARPi in MSS and MSI CRCs to determine whether microsatellite status was a predictive marker of PARPi response. The results of this study suggested that PARPi alone did not affect patient outcomes regardless of microsatellite status (Leichman et al ., ). While PARPi have been approved for the treatment of other cancer types that exhibit HR deficiency, PARPi are not currently used for CRC patients.…”

Section: Targeting Dna Repair In Colorectal Cancermentioning

confidence: 99%

Exploiting DNA repair defects in colorectal cancer

et al. 2019

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Colorectal cancer ( CRC ) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC . At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair‐deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRC s. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma ( TCGA ‐ COAD ) and Rectal Adenocarcinoma ( TCGA ‐ READ ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair‐deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly( ADP )‐ribose polymerase are effectively used to treat cancers that carry mutations in BRCA 1 and/or BRCA 2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA 1/ BRCA 2 mutations but exhibiting BRCA ‐ like phenotypes. DNA repair‐targeting therapies, such as ATR and CHK 1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRC s to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients.

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Section: Targeting Dna Repair In Colorectal Cancermentioning

confidence: 99%

Exploiting DNA repair defects in colorectal cancer

et al. 2019

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“…This approach has been investigated using poly(ADP)ribose polymerase (PARP) inhibitors in BRCA gene‐mutated ovarian and breast cancers [20], [21]. A phase II study with the PARP inhibitor olaparib did not demonstrate activity in advanced CRC patients with MSS or MSI‐high tumors [22]. Nonetheless, POLE ‐deficient cancers encompass a different mechanism of failed DNA repair, and targeted therapies such as these may prove successful in the future.…”

Section: Molecular Tumor Boardmentioning

confidence: 99%

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Castellucci

Goldstein

et al. 2017

The Oncologist

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Two cases of metastatic colorectal cancer with a POLE mutation, both of which were ultramutated and microsatellite stable, are presented and discussed from the standpoint of the basic biochemical mechanisms leading to a unique phenotype in POLE deficiency, the challenges faced with interpreting the genomic profiling of tumors in this important subset of patients, and the potential clinical implications.

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“…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).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

Feng

Sundaram

et al. 2019

Intl Journal of Cancer

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PARP inhibitors (PARPis) have remarkable antitumor activity in BRCA mutant ovarian carcinoma. Emerging evidence has shown that responses to PARPis are not limited to BRCA mutant tumors, but could expand to other homologous recombination deficiency (HRD) carcinomas. However, relatively little is known about the efficacy of PARPis in patients with HRD when compared to non‐HRD carriers. In this systematic review, 13 clinical trials were included and analyzed for the treatment effect of PARPis on progression free survival (PFS) and overall survival (OS) for HRD (BRCA mutant HRD, n = 697; BRCA wild‐type HRD, n = 478) vs. non‐HRD (n = 1,417) patients. Pooled analyses of the effect of PARPis in both ovarian and nonovarian carcinoma groups showed significantly higher PFS rates at 6 months and 12 months (PFS6 and PFS12) in the HRD subgroup, as compared to the non‐HRD subgroup. Within the HRD subgroup, the BRCA‐mutant population achieved significantly higher PFS6 (OR: 2.29, 95% CI: 1.03–5.08) and PFS12 (OR: 1.95, 95% CI: 1.26–3.01) when compared to BRCA wild‐type patients. Furthermore, within BRCA wild‐type carcinomas, mutations in other HRD‐related genes also led to increased PFS6 (OR: 1.72, 95% CI: 1.27–2.43) and PFS12 (OR: 1.85, 95% CI: 1.31–2.62), as compared to non‐HRD counterparts. Therefore, patients with HRD carcinomas exhibited pronounced PFS advantages upon treatment with PARPis, as compared to non‐HRD carcinomas. In addition to BRCA mutations, other non‐BRCA HRD‐related aberrations may serve as novel biomarkers for the prediction of PARPi efficacy.

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Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer

Cited by 62 publications

References 33 publications

Exploiting DNA repair defects in colorectal cancer

Exploiting DNA repair defects in colorectal cancer

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

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