TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort.

Konstantinopoulos, Panagiotis A.; Waggoner, Steven; Vidal, Gregory A.; Mita, Monica; Fleming, Gini F.; Holloway, Robert W.; Le, Linda Van; Sachdev, Jasgit C.; Chapman‐Davis, Eloise; Colón‐Otero, Gerardo; Penson, Richard T.; Matulonis, Ursula A.; Kim, Young B.; Moore, Kathleen N.; Swisher, Elizabeth M.; Dezube, Bruce J.; Wang, Jing Y.; Buerstatte, Nathan; Arora, Siddharth; Münster, Pamela N.

doi:10.1200/jco.2018.36.15_suppl.106

Cited by 118 publications

(85 citation statements)

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“…Based on dose finding in phase I, the recommended phase II dose of niraparib and pembrolizumab was 200 mg orally once daily and 200 mg intravenously 3-weekly, respectively. Among 60 patients evaluable for initial response assessment, 64% had platinum-resistant, 19% had platinum-refractory, and 17% had platinum-sensitive ovarian cancer, respectively [97]. The overall ORR and disease control rate were 25% and 68%, respectively, whilst in the BRCA1/2 mutant cohort they were higher (45% and 73%, respectively).…”

Section: Nct03426254mentioning

confidence: 97%

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

et al. 2020

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Genetic complexity and DNA damage repair defects are common in different cancer types and can induce tumor-specific vulnerabilities. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality and have emerged as promising anticancer therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA ) mutations. However, the utility of PARP inhibitors could be expanded beyond germline BRCA1/2 mutated cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. US Food and Drug Administration (FDA)-approved PARP inhibitors include olaparib, rucaparib, and niraparib, while veliparib is in the late stage of clinical development. Talazoparib inhibits PARP catalytic activity, trapping PARP1/2 on damaged DNA, and it has been approved by the US FDA for the treatment of metastatic germline BRCA1/2 mutated breast cancers in October 2018. The talazoparib side effect profile more closely resembles traditional chemotherapeutics rather than other clinically approved PARP inhibitors. In this review, we discuss the scientific evidence that has emerged from both experimental and clinical studies in the development of talazoparib. Future directions will include optimizing combination therapy with chemotherapy, immunotherapies and targeted therapies, and in developing and validating biomarkers for patient selection and stratification, particularly in malignancies with 'BRCAness'. Key PointsPARP inhibitors are a family of enzymes that play a role in DNA repair.

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Section: Nct03426254mentioning

confidence: 97%

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

et al. 2020

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“…140 There are presently no approved immune therapies for ovarian cancer. 141 Current approaches are ongoing to enhance the activity of checkpoint inhibitors, such as combination with anti-CTLA-4 and anti-PD-1, 142 or a combination of checkpoint inhibitors with chemotherapy, such as pegylated liposomal doxorubicin (JAVELIN Ovarian 200; NCT02580058) or weekly paclitaxel, 143 144 ] and MEDIOLA [NCT02734004] trials). After these early-phase trials, 5 large phase 3 trials have been leveraged in the front-line setting combining a PD-L1 inhibitor with chemotherapy and bevacizumab, potentially with the addition of a PARP inhibitor.…”

Section: Immunotherapymentioning

confidence: 99%

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

Lheureux

Braunstein

Oza

2019

CA A Cancer J Clinicians

1,053

867

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Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum‐based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP‐ribose) polymerase (PARP) molecules involved in the DNA damage‐repair process, which have been approved in a recurrent setting and recently in a first‐line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence‐based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.

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“…Results from the TNBC cohort showed promising activity with an ORR of 28% in the 46 evaluable patients, and durable responses irrespective of tumor BRCA status, PD-L1 status, or prior platinum exposure, although the highest ORR was observed in patients with tumor BRCA1 or BRCA2 mutations (60%; ref. 101). A randomized phase II trial comparing olaparib in combination with the PD-L1 inhibitor atezolizumab versus olaparib alone in patients with BRCA-associated metastatic TNBC is currently ongoing (NCT02849496).…”

Section: "Brcaness" In Sporadic Tnbcmentioning

confidence: 99%

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

2019

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Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat. To date, therapies directed to specifi c molecular targets have rarely achieved clinically meaningful improvements in outcomes of patients with TNBC, and chemotherapy remains the standard of care. Here, we seek to review the most recent efforts to classify TNBC based on the comprehensive profi ling of tumors for cellular composition and molecular features. Technologic advances allow for tumor characterization at ever-increasing depth, generating data that, if integrated with clinical-pathologic features, may help improve risk stratifi cation of patients, guide treatment decisions and surveillance, and help identify new targets for drug development.Signifi cance: TNBC is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other major breast cancer subtypes. The identifi cation of biomarkers that can help guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is key to the design of novel therapeutic strategies to help prevent the development of metastatic disease and, ultimately, to improve survival in this patient population. TNBC AND INTRINSIC BREAST CANCER SUBTYPESEarly transcriptomic profi ling of breast cancer using microarrays classifi ed tumors into fi ve intrinsic subtypes: luminal-A, luminal-B, HER2-enriched, basal-like, and a normal breast-like group ( 5,6 ). Although all intrinsic subtypes can be found within immunohistochemically defi ned triplenegative disease, basal-like tumors exhibit the greatest overlap with TNBC. Between 50% and 75% of TNBC have basal phenotype, and approximately 80% of basal-like tumors are ER-negative/HER2-negative ( Fig. 2 ; refs. 7, 8 ). Characterization Research.on August 1, 2020.

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TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort.

Cited by 118 publications

References 0 publications

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

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