PARP inhibitors stumble in breast cancer

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

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Abstract 1181: Neratinib induces synthetic lethality with PARP inhibitors in triple negative breast cancer cellsin vitroandin vivo

10.1158/1538-7445.am2021-1181 ◽

2021 ◽

Author(s):

Chuan Xing ◽

Zhuo Zhang ◽

Deborah Della Manna ◽

Irmina Diala ◽

Lisa Eli ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Synthetic Lethality ◽

Parp Inhibitors

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Practice-Changing Interventions in the Systemic Management of Breast Cancer

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2020.5006 ◽

2020 ◽

Vol 18 (7.5) ◽

pp. 941-944

Author(s):

William J. Gradishar

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Breast Cancer Subtype ◽

Metastatic Breast ◽

Parp Inhibitors ◽

Targeted Agents ◽

Her2 Positive ◽

Nccn Guidelines ◽

Estrogen Receptor Positive ◽

Treatment Paradigm

Systemic treatment for metastatic breast cancer now incorporates many targeted agents and a plethora of combinations specific to the breast cancer subtype. New to the treatment paradigm are fam-trastuzumab deruxtecan-nxki, and tucatinib for HER2-positive disease; the PI3K inhibitor alpelisib in combination with fulvestrant for estrogen receptor–positive and PIK3CA-mutated tumors; PARP inhibitors for patients with germline BRCA1/2 mutations; and the anti–PD-L1 agent atezolizumab in combination with albumin-bound paclitaxel for triple-negative disease with PD-L1 mutations in tumors. In addition, for estrogen receptor–positive disease, the role of CDK4/6 inhibitors increased substantially during the past year, as overall survival results have emerged. These targeted agents are greatly improving patient outcomes, and thus have all been incorporated into the NCCN Guidelines for Breast Cancer.

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Poly(ADP-Ribose) Polymerase Inhibitors (PARPi) for Patients With Advanced Breast Cancer: a Meta-analysis of Randomized Controlled Trials

10.21203/rs.3.rs-48500/v1 ◽

2020 ◽

Author(s):

YongCheng Su ◽

XiaoGang Zheng

Keyword(s):

Breast Cancer ◽

Randomized Controlled Trials ◽

Fixed Effects ◽

Meta Analysis ◽

Parp Inhibitors ◽

Cochrane Library ◽

Controlled Trials ◽

Randomized Controlled ◽

Increased Risk ◽

Grade 3

Abstract BACKGROUND: Poly(ADP–ribose) polymerase (PARP) inhibitors are new class of drugs that are currently being studied in several malignancies. However, datas about the efficacy and safety of the PARP inhibitors are limited. Therefore, we conducted a meta-analysis of randomized controlled trials (RCT) in patients with breast cancer.METHODS: Pubmed/Medline, Embase, Cochrane Library, and abstracts presented at the annual meeting of the American Society of Clinical Oncology (ASCO) were searched for articles published from 2000 to June 2018.Summary incidences and the RR, HR with 95% confidence intervals, were calculated by using a random-effects or fixed-effects model.RESULTS: The summary HR indicated PARPi was not associated with OS (HR=0.83, 95%CI 0.66–1.06, Z=1.49, P=0.14), while it could significantly improve PFS ande time to deterioration (TTD) of global health status/quality of life(GHS/QoL) as compared with traditional standard therapy, the HR was 0.60(95%CI 0.50-0.72; Z=5.52, P＜0.00001) and 0.4 (95%CI 0.29–0.54,z=5.80 ,p=0.000),respectively.The RR of grade 3 or more anemia ,fatigue and headache was 3.02 (95% CI, 0.69–13.17;p = 0.14,,I2=90%),0.77 (95%CI, 0.34–1.73;p=0.52,I2=7%) and 1.13 (95% CI,0.30–4.18;p=0.86,I2=0%),respectively.CONCLUSION: The findings of this meta-analysis showed that PARPi has no significant effect on OS, while it could significantly improve in PFS and TTD of GHS/QoL for patients with advanced or metastatic breast cancer.Furthermore,our findings also demonstrated that the PARPi treatment is connected with an increased risk of grade 3 or more anemia adverse events.

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Rucaparib in patients presenting a metastatic breast cancer with Homologous Recombination Deficiency, without germline BRCA1/2 mutation

10.21203/rs.3.rs-78109/v1 ◽

2020 ◽

Author(s):

Anne Patsouris ◽

M'boyba Khadija DIOP ◽

Olivier Tredan ◽

Daniel Nenciu ◽

Anthony Goncalves ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Homologous Recombination ◽

Statistical Significance ◽

Objective Response ◽

Metastatic Breast ◽

Parp Inhibitors ◽

Small Subset ◽

Durable Response ◽

Homologous Recombination Deficiency

Abstract Breast cancer may present genomic alterations leading to homologous recombination deficiency. PARP inhibitors have proved their efficacy in patients with HER2-negative metastatic breast cancer (mBC) harboring germline (g) BRCA1/2 mutations. We conducted the phase 2 RUBY trial to assess the efficacy of rucaparib in HER2-negative mBC with high genomic loss of heterozygosity (LOH) score or somatic, without gBRCA1/2 mutation. 220 of 711 patients with mBC screened for LOH presented high LOH score which was associated with a higher likelihood of death (HR = 1.39, 95% CI: 1.11-1.75, p = 0.005). The primary objective was not reached with a clinical benefit rate (objective response or SD>16 weeks) of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (14 and 32 months). HRDetect tended to be associated with response to rucaparib, whithout reaching statistical significance (median HRDetect responders versus non responders: 0.465 versus, 0.040, p = 0.2135). Our data suggests that a small subset of patients with high LOH score could derive benefit from PARP inhibitors.

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The overview of modern approaches in treatment of triple negative breast cancer

Research n Practical Medicine Journal ◽

10.17709/2409-2231-2020-7-1-6 ◽

2020 ◽

Vol 7 (1) ◽

pp. 55-65

Author(s):

A. A. Kharitonova ◽

I. A. Smirnova ◽

M. V. Kiseleva

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Parp Inhibitors ◽

Morphological Response ◽

Chemotherapy Drugs ◽

Treatment Regimens ◽

Dose Dense ◽

Platinum Preparations ◽

Aggressive Subtype

By far the most aggressive subtype of breast cancer is triple negative cancer. The purpose of this review is to analyze current ideas about the pathogenesis, clinical characteristics of different subtypes of triple negative breast cancer, the nature of its metastasis, mechanisms of chemoresistance. The review presents the results of modern regimens of drug therapy of triple negative breast cancer according to the publications of domestic and foreign oncologists. On the basis of various clinical studies, the effectiveness of the use of anthracyclines, taxanes in the dose-dense regime, platinum preparations and other chemotherapy drugs for the treatment of triple-negative cancer has been shown. The presented treatment regimens allow to achieve a complete morphological response in 85% of patients, to increase the rates of relapse-free and overall survival, comparable with other subtypes of breast cancer. The review highlights the possibilities of modern targeted drugs-PARP inhibitors, chk1 inhibitors UCN‑01, immunotherapy possibilities for the treatment of this aggressive subtype of breast cancer.

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Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies

npj Precision Oncology ◽

10.1038/s41698-021-00232-w ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Marilyne Labrie ◽

Allen Li ◽

Allison Creason ◽

Courtney Betts ◽

Jamie Keck ◽

...

Keyword(s):

Breast Cancer ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Patient Specific ◽

Combination Therapies ◽

Breast Cancer Patients ◽

Effector Cells ◽

Basal Breast Cancer ◽

Rational Combination

AbstractIn a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.

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