Results and Exploratory Biomarker Analyses of a Phase II Study CHANGEABLE: Combination of PD-1 Inhibitor and Niraparib in GErm-Line-mutAted Metastatic Breast Cancer

Abstract

This phase II trial evaluated the efficacy and safety of combining niraparib with the PD-1 inhibitor HX008 in patients with metastatic breast cancer who had germline DNA damage response (DDR) mutations. The study included 37 patients, divided into a primary cohort of HER2-negative individuals with germline BRCA1/2 or PALB2 mutations (n = 29) and an exploratory cohort of patients who were either HER2-negative with other DDR mutations, had brain metastases, or were HER2-positive (n = 8). The main cohort achieved an objective response rate (ORR) of 76% and a disease control rate (DCR) of 97%, with a median progression-free survival (PFS) of 7.3 months. The exploratory cohort had an ORR of 25% and a DCR of 75%, while patients with brain metastases showed a 40% ORR. Among treatment-related adverse events of Grade 3 or higher, the most frequently observed were anemia (35.1%), thrombocytopenia (10.8%), and neutropenia (8.1%). No treatment-related deaths were reported. Somatic XPO1 mutations correlated with better response. Somatic TP53 mutations significantly correlated with shorter PFS, while ASXL1 mutations correlated with longer PFS. This chemotherapy-free regimen demonstrates promising efficacy and a tolerable safety profile in patients with metastatic breast cancer and germline DDR mutations, providing a novel therapeutic option for this patient population, even those with brain metastases.

Keywords

BRCA mutation / homologous recombination deficiency / metastatic breast cancer / niraparib / programmed cell death protein 1 (PD-1) inhibitor

References

[1] H. Farmer, N. McCabe, C. J. Lord, et al., “Targeting the DNA Repair Defect in BRCA Mutant Cells as a Therapeutic Strategy,” Nature 434, no. 7035 (2005): 917–921.

[2] N. McCabe, N. C. Turner, C. J. Lord, et al., “Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition,” Cancer Research 66, no. 16 (2006): 8109–8115.

[3] M. Robson, S. A. Im, E. Senkus, et al., “Olaparib for Metastatic Breast Cancer in Patients With a Germline BRCA Mutation,” New England Journal of Medicine 377, no. 6 (2017): 523–533.

[4] L. M. Spring, H. Han, M. C. Liu, et al., “Neoadjuvant Study of Niraparib in Patients With HER2-Negative, BRCA-Mutated, Resectable Breast Cancer,” Nature Cancer 3, no. 8 (2022): 927–931.

[5] N. C. Turner, J. Balmaña, C. Poncet, et al., “Niraparib for Advanced Breast Cancer With Germline BRCA1 and BRCA2 Mutations: The EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study,” Clinical Cancer Research 27, no. 20 (2021): 5482–5491.

[6] S. Vinayak, S. M. Tolaney, L. Schwartzberg, et al., “Open-Label Clinical Trial of Niraparib Combined with Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer,” JAMA Oncology 5, no. 8 (2019): 1132–1140.

[7] R. Liu, W. Li, Y. Meng, S. Gao, J. Zhang, and X. Hu, “Phase I Study of Pucotenlimab (HX008), an Anti-PD-1 Antibody, for Patients With Advanced Solid Tumors,” Therapeutic Advances in Medical Oncology 13 (2021): 17588359211020528.

[8] J. Cao, B. Wang, J. Zhang, Z. Tao, L. Wang, and X. Hu, “Phase 1b Clinical Trial of pucotenlimab (HX008), a Novel Anti-PD-1 Monoclonal Antibody, Combined With Gemcitabine and Cisplatin in the First-Line Treatment of Metastatic Triple-Negative Breast Cancer,” Frontiers in Oncology 12 (2022): 837963.

[9] C. Pantelidou, O. Sonzogni, O. De, M. Taveira, et al., “PARP Inhibitor Efficacy Depends on CD8(+) T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer,” Cancer Discovery 9, no. 6 (2019): 722–737.

[10] T. Reisländer, E. P. Lombardi, F. J. Groelly, et al., “BRCA2 Abrogation Triggers Innate Immune Responses Potentiated by Treatment With PARP Inhibitors,” Nature Communications 10, no. 1 (2019): 3143.

[11] T. G. Meijer, N. S. Verkaik, A. M. Sieuwerts, et al., “Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer beyond BRCA Gene Defects,” Clinical Cancer Research 24, no. 24 (2018): 6277–6287.

[12] T. Sen, B. L. Rodriguez, L. Chen, et al., “Targeting DNA Damage Response Promotes Antitumor Immunity Through STING-Mediated T-Cell Activation in Small Cell Lung Cancer,” Cancer Discovery 9, no. 5 (2019): 646–661.

[13] R. A. Stewart, P. G. Pilié, and T. A. Yap, “Development of PARP and Immune-Checkpoint Inhibitor Combinations,” Cancer Research 78, no. 24 (2018): 6717–6725.

[14] S. M. Domchek, S. Postel-Vinay, S. A. Im, et al., “Olaparib and Durvalumab in Patients With Germline BRCA-mutated Metastatic Breast Cancer (MEDIOLA): An Open-Label, Multicentre, Phase 1/2, Basket Study,” Lancet Oncology 21, no. 9 (2020): 1155–1164.

[15] C. Corti, G. Antonarelli, C. Criscitiello, et al., “Targeting Brain Metastases in Breast Cancer,” Cancer Treatment Reviews 103 (2022): 102324.

[16] R. Uceda-Castro, A. S. Margarido, J. Y. Song, et al., “BCRP Drives Intrinsic Chemoresistance in Chemotherapy-Naïve Breast Cancer Brain Metastasis,” Science Advances 9, no. 42 (2023): eabp9530.

[17] D. P. Kodack, V. Askoxylakis, G. B. Ferraro, D. Fukumura, and R. K. Jain, “Emerging Strategies for Treating Brain Metastases From Breast Cancer,” Cancer Cell 27, no. 2 (2015): 163–175.

[18] P. Schmid, S. Adams, H. S. Rugo, et al., “Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer,” New England Journal of Medicine 379, no. 22 (2018): 2108–2121.

[19] J. K. Litton, H. S. Rugo, J. Ettl, et al., “Talazoparib in Patients With Advanced Breast Cancer and a Germline BRCA Mutation,” New England Journal of Medicine 379, no. 8 (2018): 753–763.

[20] X. W. Meng, B. D. Koh, J. S. Zhang, et al., “Poly(ADP-Ribose) Polymerase Inhibitors Sensitize Cancer Cells to Death Receptor-Mediated Apoptosis by Enhancing Death Receptor Expression,” Journal of Biological Chemistry 289, no. 30 (2014): 20543–20558.

[21] E. E. Parkes, S. M. Walker, L. E. Taggart, et al., “Activation of STING-Dependent Innate Immune Signaling by S-Phase-Specific DNA Damage in Breast Cancer,” Journal of the National Cancer Institute 109, no. 1 (2017): djw199.

[22] S. Jiao, W. Xia, H. Yamaguchi, et al., “PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression,” Clinical Cancer Research 23, no. 14 (2017): 3711–3720.

[23] L. Pusztai, C. Yau, D. M. Wolf, et al., “Durvalumab With Olaparib and Paclitaxel for High-Risk HER2-Negative Stage II/III Breast Cancer: Results From the Adaptively Randomized I-SPY2 Trial,” Cancer Cell 39, no. 7 (2021): 989–998.

[24] M. E. Robson, N. Tung, P. Conte, et al., “OlympiAD Final Overall Survival and Tolerability Results: Olaparib versus Chemotherapy Treatment of Physician's Choice in Patients With a Germline BRCA Mutation and HER2-Negative Metastatic Breast Cancer,” Annals of Oncology 30, no. 4 (2019): 558–566.

[25] J. K. Litton, S. A. Hurvitz, L. A. Mina, et al., “Talazoparib Versus Chemotherapy in Patients With Germline BRCA1/2-Mutated HER2-Negative Advanced Breast Cancer: Final Overall Survival Results From the EMBRACA Trial,” Annals of Oncology 31, no. 11 (2020): 1526–1535.

[26] M. J. Sambade, A. E. D. Van Swearingen, M. B. McClure, et al., “Efficacy and Pharmacodynamics of Niraparib in BRCA-mutant and Wild-Type Intracranial Triple-Negative Breast Cancer Murine Models,” Neuro-Oncology Advances 1, no. 1 (2019): vdz005.

[27] J. Wang, T. Sun, Z. Meng, et al., “XPO1 inhibition Synergizes With PARP1 inhibition in Small Cell Lung Cancer by Targeting Nuclear Transport of FOXO3a,” Cancer Letters 503 (2021): 197–212.

[28] K. S. Lee, W. J. Lee, H. Chae, et al., “Co-Mutation of ATM and ASXL1 and Relationship to Durable Response of a Novel PARP1/2 Inhibitor, Venadaparib, in Patients With Pancreatic Cancer,” Journal of Clinical Oncology 41, no. 16_suppl (2023): e15019.

[29] T. Collot, J. Niogret, M. Carnet, et al., “PARP Inhibitor Resistance and TP53 Mutations in Patients Treated With Olaparib for BRCA-Mutated Cancer: Four Case Reports,” Molecular Medicine Reports 23, no. 1 (2021): 75.

[30] J. W. Carlisle, N. T. Nho, C. Kim, et al., “Impact of TP53 Mutations on Efficacy of PD-1 Targeted Immunotherapy in Non-Small Cell Lung Cancer (NSCLC),” Journal of Clinical Oncology 36, no. 15_suppl (2018): e21090.

[31] K. Jin, J. Xu, X. Su, et al., “TP53 Disruptive Mutation Predicts Platinum-Based Chemotherapy and PD-1/PD-L1 Blockade Response in Urothelial Carcinoma,” Journal of Pathology 263, no. 2 (2024): 139–149.

[32] Z. Y. Dong, W. Z. Zhong, X. C. Zhang, et al., “Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma,” Clinical Cancer Research 23, no. 12 (2017): 3012–3024.

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