TOPACIO/Keynote-162: Niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial.

Vinayak, Shaveta; Tolaney, Sara M.; Schwartzberg, Lee S.; Mita, Monica; McCann, Georgia A.; Tan, Antoinette R.; Hendrickson, Andrea E. Wahner; Forero‐Torres, Andres; Anders, Carey K.; Wulf, Gerburg M.; Dillon, Patrick M.; Lynce, Filipa; Zarwan, Corrine; Erban, John K.; Dezube, Bruce J.; Zhou, Yinghui; Buerstatte, Nathan; Arora, Siddharth; Achour, Haroun; Telli, Melinda L.

doi:10.1200/jco.2018.36.15_suppl.1011

Cited by 68 publications

(49 citation statements)

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“…Taken together, the available preclinical and translational data strongly support combining PARP inhibition and ICB, and based on these data, a number of clinical trials are currently ongoing (Table 1). Up to now, data from three different PARP inhibitor/anti-PD-1/L1 combinations are available: olaparib/ durvalumab (98,99), niraparib/pembrolizumab (100,101), and BGB-A317/BGB-290 (102). Both of the first combinations were well tolerated, with toxicities in line with those observed for the relevant agents in monotherapy settings.…”

Section: Combining Parp Inhibition and Checkpoint Blockadementioning

confidence: 86%

Development of PARP and Immune-Checkpoint Inhibitor Combinations

2018

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PARP inhibitors drive increased DNA damage, particularly in tumors with existing defects in DNA repair. This damage not only promotes immune priming through a range of molecular mechanisms, but also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. In this context, PARP inhibition and programmed cell death 1 (PD-1)/PD-L1-targeting antibodies represent a rationale combination. In this review, we detail the basic and translational science underpinning this promising new combination, summarize available clinical data, and discuss the key questions that remain to be addressed during future development. Cancer Res; 78(24); 6717-25. Ó2018 AACR.

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Section: Combining Parp Inhibition and Checkpoint Blockadementioning

confidence: 86%

Development of PARP and Immune-Checkpoint Inhibitor Combinations

2018

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“…TOPACIO/KEYNOTE-162 was a study combining the PARP inhibitor niraparib with pembrolizumab in TNBC, with initial data on 45 patients showing an ORR = 29%, with a disease control rate of 49%. Among BRCA mutant patients, the ORR was 67% with a disease control rate of 75% [53]. Studies with durvalumab plus olaparib in metastatic TNBC are also ongoing (NCT03167619, NCT03801369).…”

Section: Immunotherapy With Other Targeted Therapiesmentioning

confidence: 99%

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

Kim

Sanchez

McArthur

et al. 2019

Curr Breast Cancer Rep

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Purpose of Review Immunotherapy is emerging as an effective treatment option for metastatic triple-negative breast cancer. In this review, we summarize clinical data of immunotherapy in triple-negative breast cancer and comment on future directions in the field. Recent Findings IMpassion130 was a phase III trial that demonstrated progression-free survival benefit, and potentially overall survival benefit, of first-line chemotherapy (nab-paclitaxel) plus anti-programmed death ligand 1 (PD-L1) atezolizumab, among PD-L1-positive metastatic triple-negative breast cancers. Studies are ongoing to evaluate other combination therapies with immune checkpoint blockade in TNBC, and to evaluate efficacy in PD-L1-negative tumors and in later lines of therapy. Summary Immunotherapy is now a standard option in the treatment of triple-negative breast cancer. Ongoing trials may expand the degree of clinical benefit. Further work is ongoing to identify novel predictive biomarkers, which in the future may enable a personalized approach of combination immunotherapy.

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“…A phase II (MEDIOLA) trial in relapsed gastric cancer with a 4-week run in of olaparib, followed by combination with durvalumab failed to show efficacy (DCR at 12 weeks was 26%) due to early PD during the run-in period [99]. Combination of niraparib and pembrolizumab in a phase II trial (TOPACIO/Keynote-162) in triple negative breast cancer (TNBC) and recurrent ovarian cancer patients showed that the combination is safe and effective, irrespective of the platinum exposure or BRCA 1/2 or PD-L1 status [100,101]. A phase I study involving a combination of olaparib, durvalumab, and the vascular endothelial factor receptor (VEGFR)-1 inhibitor cediranib in ovarian/endometrial/TNC patients showed that the combination is safe; there was an efficacy signal with DCR of 67% [102].…”

Section: Parpi In Combination With Immunotherapymentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibitors in Pancreatic Cancer: A New Treatment Paradigms and Future Implications

Gupta

Iyer

Fountzilas

2019

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy. Most of the patients of PDAC present at later stages of disease and have a five-year survival rate of less than 10%. About 5–10% PDAC cases are hereditary in nature and have DNA damage repair (DDR) mutations such as BRCA 1 and 2. Besides having implications on screening and prevention strategies, these mutations can confer sensitivity to platinum-based therapies and determine eligibility for poly(ADP-ribose) polymerase inhibitors (PARPi). In the presence of DDR mutations and PARPi, the cells are unable to utilize the error-free process of homologous recombination repair, leading to accumulation of double stranded DNA breaks and cell death eventually. Various PARPi are in clinical development in PDAC in different subgroup of patients as monotherapies and in combination with other therapeutics. This review would focus on the mechanism of action of PARPi, history of development in PDAC, resistance mechanisms and future directions.

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TOPACIO/Keynote-162: Niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial.

Cited by 68 publications

References 0 publications

Development of PARP and Immune-Checkpoint Inhibitor Combinations

Development of PARP and Immune-Checkpoint Inhibitor Combinations

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

Poly(ADP-Ribose) Polymerase Inhibitors in Pancreatic Cancer: A New Treatment Paradigms and Future Implications

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