A pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation

Litton, Jennifer K.; Scoggins, Marion E.; Ramirez, David Luis; Murthy, Rashmi Krishna; Whitman, Gary J.; Hess, Kenneth R.; Adrada, Beatriz E.; Moulder, Stacy L.; Barcenas, Carlos H.; Valero, Vicente; Booser, Daniel J.; Gomez, J. Schwartz; Mills, Gordon B.; Piwnica‐Worms, Helen; Arun, Banu K.

doi:10.1093/annonc/mdw364.10

Cited by 17 publications

(10 citation statements)

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“…Recently Litton and colleagues have shown that talazoparib has marked antitumor efficacy in patients with germline BRCA mutations (38). Of the targeted agents tested in our PDX models, talazoparib seems to have the most potential as a single agent, and its utility appears to extend beyond BRCA1/2 germline deleterious mutations.…”

Section: Discussionmentioning

confidence: 99%

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors

Evans

Yuca

Akçakanat

et al. 2017

Clinical Cancer Research

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Background Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is a pressing need for novel targets and models for preclinical testing. Here we report characterization of breast cancer patient derived xenografts (PDXs) largely generated from residual tumors following neoadjuvant chemotherapy. Methods PDXs were derived from surgical samples of primary or locally recurrent tumors. Normal and tumor DNA sequencing, RNASeq and Reverse Phase Protein Arrays (RPPA) were performed. Phenotypic profiling was performed by determining efficacy of a panel of standard and investigational agents. Results Twenty-six PDXs were developed from 25 patients. Twenty-two were generated from residual disease following neoadjuvant chemotherapy, and 24 were from triple negative breast cancer (TNBC). These PDXs harbored a heterogeneous set of genomic alterations and represented all TNBC molecular subtypes. On RPPA, PDXs varied in extent of PI3K and MAPK activation. PDX also varied in their sensitivity to chemotherapeutic agents. PI3K, mTOR and MEK inhibitors repressed growth but did not cause tumor regression. PARP inhibitor talazoparib caused dramatic regression in 5 of 12 PDXs. Notably 4 of 5 talazoparib-sensitive models did not harbor germline BRCA1/2 mutations, but several had somatic alterations in homologous repair pathways, including ATM deletion and BRCA2 alterations. Conclusions PDXs capture the molecular and phenotypic heterogeneity of TNBC. Here we show that PARP inhibition can have activity beyond germline BRCA1/2 altered tumors, causing regression in a variety of molecular subtypes. These models represent an opportunity for the discovery of rational combinations with targeted therapies and predictive biomarkers.

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Section: Discussionmentioning

confidence: 99%

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors

Evans

Yuca

Akçakanat

et al. 2017

Clinical Cancer Research

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“…Most of clinical studies of veliparib were for combination therapy ( ) [ 81 , 82 , 83 ]. Talazoparib (BMN-673) has been reported to be used as both a mono-therapeutic and combination therapeutic drug with leukemia, Ewing’s sarcoma, BRCA-mutant and proficient ovarian carcinoma, breast carcinoma, and osteosarcoma [ 84 , 85 , 86 , 87 ]. It is a promising PARP1-based anticancer drug candidate, because its PARP–DNA complex trapping ability is almost 100-fold stronger than that of olaparib and rucaparib [ 88 ] ( Table 2 ).…”

Section: Parp1 Inhibitors Against Carcinomasmentioning

confidence: 99%

PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs

Wang

Liang

et al. 2017

IJMS

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Poly (ADP-ribose) polymerase 1 (PARP1), the best-studied isoform of the nuclear enzyme PARP family, plays a pivotal role in cellular biological processes, such as DNA repair, gene transcription, and so on. PARP1 has been found to be overexpressed in various carcinomas. These all indicate the clinical potential of PARP1 as a therapeutic target of human malignancies. Additionally, multiple preclinical research studies and clinical trials demonstrate that inhibition of PARP1 can repress tumor growth and metastasis. Up until now, PARP1 inhibitors are clinically used not only for monotherapy to suppress various tumors, but also for adjuvant therapy, to maintain or enhance therapeutic effects of mature antineoplastic drugs, as well as protect patients from chemotherapy and surgery-induced injury. To supply a framework for understanding recent research progress of PARP1 in carcinomas, we review the structure, expression, functions, and mechanisms of PARP1, and summarize the clinically mature PARP1-related anticancer agents, to provide some ideas for the development of other promising PARP1 inhibitors in antineoplastic therapy.

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“…Neoadjuvant talazoparib monotherapy has demonstrated promising activity in a pilot phase 2 study. Thirteen patients who had BRCA ‐mutant breast cancer received 2 months of talazoparib monotherapy, which resulted in 88% (range 30%‐98%) median tumor shrinkage by ultrasound . The study was halted early to allow for the expansion of neoadjuvant talazoparib as the only treatment before surgery to assess for the pCR rate …”

Section: Clinical Development In Breast Cancermentioning

confidence: 99%

“…Thirteen patients who had BRCA-mutant breast cancer received 2 months of talazoparib monotherapy, which resulted in 88% (range 30%-98%) median tumor shrinkage by ultrasound. 55 The study was halted early to allow for the expansion of neoadjuvant talazoparib as the only treatment before surgery to assess for the pCR rate. 56 The phase 3 OlympiA study will assess the safety and efficacy of up to 12 months of adjuvant olaparib (300 mg twice daily) versus placebo in patients with BRCA-mutant TNBC or hormone receptor-positive/ HER2-negative breast cancer.…”

Section: Clinical Development In Early Stage Diseasementioning

confidence: 99%

PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside

Turk

Wisinski

2018

Cancer

117

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Individuals with breast and ovarian cancer susceptibility gene 1 (BRCA1) or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA-mutant cancer cells have abnormal homologous recombination (HR) repair of DNA. In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate-ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA-mutant cells while sparing normal cells-a concept called synthetic lethality. PARP inhibitors are the first cancer therapeutics designed to exploit synthetic lethality. Recent clinical trials in BRCA-mutant, metastatic breast cancer demonstrated improved outcomes with single-agent PARP inhibitors (olaparib and talazoparib) over chemotherapy. However, resistance to PARP inhibitors remains a challenge. Primarily due to myelosuppression, the combination of PARP inhibitors with chemotherapy has been difficult. Novel combinations with chemotherapy, immunotherapy, and other targeted therapies are being pursued. In this review, the authors discuss current knowledge of PARP inhibitors in BRCA-mutant breast cancer and potential future directions for these agents. Cancer 2018;124:2498-506. © 2018 American Cancer Society.

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A pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation

Cited by 17 publications

References 0 publications

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors

PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs

PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside

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