Phase III study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer

Dièras, Véronique; Han, Heather; Kaufman, Bella; Wildiers, Hans; Friedlander, Michael; Ayoub, Joseph; Puhalla, Shannon; Bondarenko, Igor; Campone, Mario; Jakobsen, Erik; Jalving, Mathilde; Oprean, Cristina; Palácová, Markéta; Park, Y.H.; Shparyk, Yaroslav; Yáñez, Eduardo; Dudley, Matthew W.; Ratajczak, Christine K.; Maag, David; Arun, Banu K.

doi:10.1093/annonc/mdz394.008

Cited by 38 publications

(45 citation statements)

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“…Whether the addition of PARPi to platinum‐ or nonplatinum‐based chemotherapy would further improve the treatment outcome in patients with gBRCA mutations or HR defects, is an area of active research. The recently presented GeparOLA study and BROCADE‐3 study have already shown the feasibility of this approach, with quite encouraging efficacy results. Likewise, the combination of PARPi and anti‐PD‐1/ PD‐L1 agents looks quite effective in pre‐clinical models .…”

Section: Discussionmentioning

confidence: 94%

“…However, in situations where PARPi are not accessible/affordable, then first‐line carboplatin would stand as a rational treatment option as indicated by the TNT study. More recently, the combination of carboplatin and paclitaxel was shown to provide remarkable efficacy results in gBRCA‐mutant mBC, with a mPFS of 12 months and a mOS of >24 months, and hence it can be also considered as another evidence‐based treatment option in these patients (Table ).…”

Section: Exploring Genetic Events To Tailor Therapy Of Mtnbcmentioning

confidence: 99%

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Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

et al. 2019

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Compared with other breast cancer subtypes, patients with triple‐negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This—in return—has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti‐PD‐L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key—practice changing—clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.

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Section: Discussionmentioning

confidence: 94%

Section: Exploring Genetic Events To Tailor Therapy Of Mtnbcmentioning

confidence: 99%

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

et al. 2019

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“…In phase III trial, veliparib significantly improved progression-free survival in BRCA-mutated or HRD cohort compared to carboplatin plus paclitaxel (NCT02470585) [44]. In phase III trial of veliparib with carboplatin and paclitaxel in advanced HER2-negative breast cancer with germline BRCA mutation, median PFS in patients treated with veliparib plus carboplatin and paclitaxel was 14.5 months compared to 12.6 months in placebo plus carboplatin and paclitaxel (BROCADE3; NCT02163694) [45].…”

Section: Parp1 Parp2mentioning

confidence: 99%

“…Veliparib, in addition to carboplatin and paclitaxel, also significantly improved PFS to patients with HER2-negative advanced or metastatic breast cancer with germline BRCA-mutation in a phase III trial. The rate of 3-year PFS was 26 percent on veliparib addition group when the placebo group showed 11 percent [45]. Although veliparib is not yet approved to FDA on any indications, these data could accelerate the application of veliparib in the clinics.…”

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confidence: 91%

PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

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2020

Cancers

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Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application. However, the antitumor activities of PARP inhibitors in clinical development are different, due to PARP trapping activity beyond blocking PARylation reactions. In this review, we comprehensively address the current state of knowledge regarding the mechanisms of action of PARP inhibitors. We will also discuss the different effects of PARP inhibitors in combination with cytotoxic chemotherapeutic agents regarding the mechanism of regulating PARylation.Cancers 2020, 12, 394 2 of 16 be true, PARP inhibitors that inhibit DDR resulted in improved clinical benefits and became standard therapy [9][10][11]. To date, four PARP inhibitors have been approved by the FDA and are being applied clinically. However, while all PARP inhibitors inhibit PARP catalytic activities, they have different cytotoxicities. Therefore, the anti-tumor effects of the PARP inhibitors have been suggested to be due to PARP trapping, as well as the inhibition of the enzymatic activities [12,13].The catalytic inhibition and trapping effects of PARP are tightly regulated, and the cytotoxicity of each mechanism can cause different reactivities. Therefore, in this review, based on mechanisms of PARP, we intend to examine the difference of anti-tumor effect of the PARP inhibitors and the current aspect of the roles in combination treatment. PARPs and PARylationPoly (ADP-ribose) polymerase (PARP) is a family of 17 proteins in mammals, encoded by different genes, but with a conserved catalytic domain. Other than the catalytic domain, PARP family members contain one or more other motifs or domains, including zinc fingers, a breast cancer-susceptibility protein (BRCA) C-terminus-like (BRCT) motifs, ankyrin repeats, macro domains, and WWE domains [14] ( Figure 1A). PARP1 was the first family member identified and has a critical role in SSB repair through the metabolism of recruiting and dissociating repair proteins by PARylation. In addition to DNA damage repair, PARP1 has important roles in a various range of cellular processes from cell proliferation to cell death, due to having diverse substrates like nuclear proteins involved in transcriptional regulation, apoptotic cell death, chromatin decondensation, inflammation, and cell cycle regulation [15,16]. PARP1 has a total molecular weight of 113 kDa and contains seven independent domains ( Figure 1B) [5,17]. The N-terminus is the DNA binding domain (residues 1-353), which contains three zinc-finger DNA-binding domains, ZnFI, ZnFII, and ZnFIII, which are responsible for recognizing sites of damaged DNA and binding through allosteric activation. ...

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“…Studie hinzugekommen, welche den PARP-Inhibitor Veliparib in Kombination mit Carboplatin und Paclitaxel mit der Chemotherapie allein verglich. Auch in dieser Studie hatte die Therapie mit dem PARP-Inhibitor ein signifikant besseres progressionsfreies Überleben (HR = 0,705; 95 %-KI 0,566-0,877; p = 0,002) [19]. In der PARP-Inhibitor-Gruppe konnte in dieser Population nach 3 Jahren eine progressionsfreie Überlebenswahrscheinlichkeit von 26 % beobachtet werden [19], während diese bei den anderen beiden Studien bei 10 % oder niedriger lag [5], [6].…”

Section: Parp-inhibitorenunclassified

Update Mammakarzinom 2020 Teil 2 – fortgeschrittenes Mammakarzinom: neue Substanzen und Einzug diagnostikabhängiger Therapien

Lüftner

Schneeweiß

Hartkopf

et al. 2020

Senologie - Zeitschrift für Mammadiagnostik und -therapie

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ZusammenfassungFür Patientinnen mit einem lokal fortgeschrittenen bzw. metastasierten Mammakarzinom wurden in den letzten Jahren neue und effektive Therapien wie CDK4/6-Inhibitoren, PARP-Inhibitoren und ein PD‑L1-Inhibitor eingeführt. In dieser Übersichtsarbeit wird ein Update zu den vorhandenen Studien mit ihrer Datenlage gegeben. Ebenso werden 2 innovative Anti-HER2-Therapien dargestellt (Trastuzumab-Deruxtecan und Tucatinib), für die die Ergebnisse aus neuen Studien berichtet worden sind. Molekulare Tests bieten die Möglichkeit, Patientinnenpopulationen zu definieren oder auch Therapieverläufe zu monitorieren. Dieses kann helfen, Patientinnen mit spezifischen Eigenschaften zu identifizieren, um diesen eine individuelle zielgerichtete Therapie im Rahmen von Studien zukommen zu lassen. In einer großen Studie konnte der Nutzen einer solchen Biomarker-Studie zum ersten Mal beschrieben werden.

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Phase III study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer

Cited by 38 publications

References 0 publications

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

Update Mammakarzinom 2020 Teil 2 – fortgeschrittenes Mammakarzinom: neue Substanzen und Einzug diagnostikabhängiger Therapien

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