Therapeutic Potential of Olaparib in Combination With Pembrolizumab in a Young Patient With a Maternally Inherited BRCA2 Germline Variant: A Research Report

Waddington, T. C.; Mambetsariev, Isa; Pharaon, Rebecca; Fricke, Jeremy; Baroz, Angel Ray; Romo, Hannah; Ghanem, Bassam; Gray, Stacy W.; Salgia, Ravi

doi:10.1016/j.cllc.2021.01.009

Cited by 6 publications

(4 citation statements)

References 28 publications

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“…PARP inhibitors have been used successfully in clinical trials in breast and ovarian cancer patients with mutations in the BRCA gene, but no large clinical studies have been conducted to confirm whether these drugs can be used in lung cancer. So far, three case reports (20)(21)(22) showed that the PARP inhibitor Olaparib is effective in patients with BRCA1/2 mutations in non-small cell lung cancer, but all of them were lung adenocarcinoma or lung carcinoid tumors, whereas our study reported lung squamous cell carcinoma.…”

Section: Discussioncontrasting

confidence: 53%

BRCA2 mutation in advanced lung squamous cell carcinoma treated with Olaparib and a PD-1 inhibitor: a case report

et al. 2023

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BackgroundMutations in the human breast cancer susceptibility gene 2 (breast cancer 2, BRCA2) increase the risk of breast, ovarian and other cancers. Olaparib, an oral poly[adenosine diphosphate (ADP)–ribose] polymerase (PARP) inhibitor, is usually prescribed to treat BRCA mutated tumors, especially breast and ovarian cancers. Programmed cell death-1 (PD-1) inhibitors have revolutionized the treatment of lung cancer and many other cancers by destroying the interaction between receptors with ligands in the tumor-immune microenvironment and enabling T cells to recognize and attack cancer cells.Case descriptionIn our study, we report a patient with advanced BRCA2 lung squamous cell carcinoma who received platinum-based chemotherapy combined with paclitaxel. Seven months later, the disease progressed. BRCA2 mutations were detected in peripheral blood by next-generation sequencing. After 2 months of treatment with Olaparib combined with Cindilimab, the patient was in partial remission and the progression-free survival (PFS) lasted for 6 months, but the patient developed immune renal damage.ConclusionsThis study adds to the clinical data for the treatment of BRCA2 mutant non-small cell lung cancer by demonstrating that lung squamous cell carcinoma has a good response to PARP inhibitors. It also serves as a reminder that there may still be some negative effects from targeted superimposed immunotherapy.

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Section: Discussioncontrasting

confidence: 53%

BRCA2 mutation in advanced lung squamous cell carcinoma treated with Olaparib and a PD-1 inhibitor: a case report

et al. 2023

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“…In addition to monotherapy for cancers with HRD, PARP inhibitors are under clinical assessment in combination with other antitumor agents referred for chemotherapy, targeted therapy, and immunotherapy ( Plummer et al, 2013 ; Norris et al, 2014 ; Matulonis and Monk, 2017 ; Tomao et al, 2017 ; Friedlander et al, 2019 ; Lee and Konstantinopoulos, 2019 ; Lampert et al, 2020 ; Palaia et al, 2020 ; Bizzaro et al, 2021 ; Waddington et al, 2021 ). Similar to other PARP inhibitors, YHP-836 also potentiates chemotherapy agents against various tumor cells.…”

Section: Discussionmentioning

confidence: 99%

A Novel PARP Inhibitor YHP-836 For the Treatment of BRCA-Deficiency Cancers

Zhang

Zhou

et al. 2022

Front. Pharmacol.

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PARP inhibitors have clinically demonstrated good antitumor activity in patients with BRCA mutations. Here, we described YHP-836, a novel PARP inhibitor, YHP-836 demonstrated excellent inhibitory activity for both PARP1 and PARP2 enzymes. It also allosterically regulated PARP1 and PARP2 via DNA trapping. YHP-836 showed cytotoxicity in tumor cell lines with BRCA mutations and induced cell cycle arrest in the G2/M phase. YHP-836 also sensitized tumor cells to chemotherapy agents in vitro. Oral administration of YHP-836 elicited remarkable antitumor activity either as a single agent or in combination with chemotherapy agents in vivo. These results indicated that YHP-836 is a well-defined PARP inhibitor.

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“…This suggests that NSCLC patients with BRCA1/2 mutations may have non-BRCA related alterations, leading to patients’ benefitting from the addition of PARPi therapy. Further supporting this, a 26-year-old woman with stage 4 adenocarcinoma found to have a germline mutation in BRCA2 (S497*) without other targetable mutations had an excellent clinical response to combination pembrolizumab and olaparib [ 70 ]. Importantly, preclinical data have offered evidence that olaparib upregulates PD-L1 expression, suggesting potential therapeutic synergy with checkpoint blockade [ 71 ].…”

Section: The Clinical Relevance Of Targeting Hr Pathway In Patients W...mentioning

confidence: 95%

The Prognostic and Therapeutic Potential of DNA Damage Repair Pathway Alterations and Homologous Recombination Deficiency in Lung Cancer

Khaddour

Fernandez

Khabibov

et al. 2022

Cancers

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Lung cancer remains the second most commonly diagnosed cancer worldwide and the leading cause of cancer-related mortality. The mapping of genomic alterations and their role in lung-cancer progression has been followed by the development of new therapeutic options. Several novel drugs, such as targeted therapy and immunotherapy, have significantly improved outcomes. However, many patients with lung cancer do not benefit from existing therapies or develop progressive disease, leading to increased morbidity and mortality despite initial responses to treatment. Alterations in DNA-damage repair (DDR) genes represent a cancer hallmark that impairs a cell’s ability to prevent deleterious mutation accumulation and repair. These alterations have recently emerged as a therapeutic target in breast, ovarian, prostate, and pancreatic cancers. The role of DDR alterations remains largely unknown in lung cancer. Nevertheless, recent research efforts have highlighted a potential role of some DDR alterations as predictive biomarkers of response to treatment. Despite the failure of PARP inhibitors (main class of DDR targeting agents) to improve outcomes in lung cancer patients, there is some evidence suggesting a role of PARP inhibitors and other DDR targeting agents in benefiting a distinct subset of lung cancer patients. In this review, we will discuss the existing literature on DDR alterations and homologous recombination deficiency (HRD) state as predictive biomarkers and therapeutic targets in both non-small cell lung and small cell lung cancer.

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Therapeutic Potential of Olaparib in Combination With Pembrolizumab in a Young Patient With a Maternally Inherited BRCA2 Germline Variant: A Research Report

Cited by 6 publications

References 28 publications

BRCA2 mutation in advanced lung squamous cell carcinoma treated with Olaparib and a PD-1 inhibitor: a case report

BRCA2 mutation in advanced lung squamous cell carcinoma treated with Olaparib and a PD-1 inhibitor: a case report

A Novel PARP Inhibitor YHP-836 For the Treatment of BRCA-Deficiency Cancers

The Prognostic and Therapeutic Potential of DNA Damage Repair Pathway Alterations and Homologous Recombination Deficiency in Lung Cancer

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