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

Pishvaian, Michael J.; Slack, Rebecca; Jiang, Wei; He, Aiwu Ruth; Hwang, Jimmy J.; Hankin, Amy; Dorsch-Vogel, Karen; Kukadiya, Divyesh; Weiner, Louis M.; Marshall, John L.; Brody, Jonathan R.

doi:10.1002/cncr.31309

Cited by 49 publications

(39 citation statements)

References 52 publications

(130 reference statements)

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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%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

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%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

Feng

Sundaram

et al. 2019

Intl Journal of Cancer

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Efficacy of Adding Veliparib to Temozolomide for Patients With MGMT-Methylated Glioblastoma

Sarkaria,

Ballman,

Kizilbash

et al. 2024

JAMA Oncol

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ImportanceThe prognosis for patients with glioblastoma is poor following standard therapy with surgical resection, radiation, temozolomide, and tumor-treating fields.ObjectivesTo evaluate the combination of veliparib and temozolomide in glioblastoma based on preclinical data demonstrating significant chemosensitizing effects of the polyadenosine diphosphate-ribose polymerase 1/2 inhibitor veliparib when combined with temozolomide.Design, Setting, and ParticipantsPatients with newly diagnosed glioblastoma with MGMT promoter hypermethylation who had completed concomitant radiation and temozolomide were enrolled between December 15, 2014, and December 15, 2018, in this Alliance for Clinical Trials in Oncology trial. The data for this analysis were locked on April 21, 2023.InterventionsPatients were randomized and treated with standard adjuvant temozolomide (150-200 mg/m2 orally, days 1-5) combined with either placebo or veliparib (40 mg orally, twice daily, days 1-7) for 6 cycles.Main Outcomes and MeasuresThe primary end point for the phase 3 portion of the trial was overall survival (OS).ResultsThere were 322 patients randomized during the phase 2 accrual period and an additional 125 patients randomized to complete the phase 3 accrual, for a total of 447 patients in the final phase 3 analysis. The median (range) age for patients was 60 (20-85) years and 190 patients (42.5%) were female. The median OS was 24.8 months (90% CI, 22.6-27.7) for the placebo arm and 28.1 months (90% CI, 24.3-33.3) for the veliparib arm (P = .17). The difference in survival did not meet the prespecified efficacy end point. However, there was a separation of the survival curves that favored the veliparib arm over 24 to 48 months of follow-up. The experimental combination was well tolerated with an acceptable elevation in grade 3 or 4 hematologic toxic effects.Conclusions and RelevanceThis trial found that adding veliparib to adjuvant temozolomide did not significantly extend OS in patients with newly diagnosed, MGMT-hypermethylated glioblastoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02152982

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

Cited by 49 publications

References 52 publications

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

Efficacy of Adding Veliparib to Temozolomide for Patients With MGMT-Methylated Glioblastoma

Exploiting DNA repair defects in colorectal cancer

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