Real-world effectiveness of PARP inhibitors after CDK4/6 inhibitor therapy in BRCA-mutated HR-positive/HER2-negative advanced breast cancer
Poly(ADP-ribose) polymerase inhibitors (PARPi) are established as standard-of-care therapy for patients with hormone receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC) who harbor germline BRCA1/2 likely pathogenic or pathogenic variants (LP/PV). However, the real-world efficacy of PARPi following tumor progression on first-line (1 L) cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) remains inadequately explored. In this cohort of 81 patients with HR+/HER2- aBC harboring germline BRCA LP/PV, 64 (79%) received 1 L treatment with CDK4/6i plus ET. Considering the subsequent therapy administered after tumor progression on 1 L CDK4/6i, patients treated with PARPi showed a significantly longer median real-world PFS (11.8 months) compared to those receiving ET, monochemotherapy, or polychemotherapy. This benefit was confirmed in a multivariable analysis, supporting PARPi as the preferred option in eligible patients. Our findings suggest that PARPi should be prioritized in the post-CDK4/6i treatment sequence for BRCA LP/PV carriers with HR+/HER2 aBC and highlight the critical role of germline BRCA testing.
Authors
- Giuseppe Curigliano (ORCID: https://orcid.org/0000-0003-1781-2518)
- Gennady Landa (ORCID: https://orcid.org/0000-0002-2693-9572)
- Claudio Vernieri (ORCID: https://orcid.org/0000-0003-1577-8176)
- Emma Zattarin (ORCID: https://orcid.org/0000-0002-3445-9245)
- Angela Toss
- Martina Manni (ORCID: https://orcid.org/0000-0001-8097-9922)
- Emilio Bria (ORCID: https://orcid.org/0000-0002-2333-704X)
- Valentina Guarneri (ORCID: https://orcid.org/0000-0002-2375-8397)
- Massimo Dominici (ORCID: https://orcid.org/0000-0002-4007-1503)
- Riccardo Cuoghi Costantini (ORCID: https://orcid.org/0000-0002-9116-5198)
- Letizia Pontolillo (ORCID: https://orcid.org/0009-0006-3363-8512)
- Elena Tenedini (ORCID: https://orcid.org/0000-0003-0285-765X)
- Caterina Sposetti (ORCID: https://orcid.org/0000-0003-3211-8516)
- Federica Caggia
- Elena Barbieri (ORCID: https://orcid.org/0000-0002-3480-7983)
- Laura Cortesi
- Arianna Daneri
- Antonella Palazzo (ORCID: https://orcid.org/0000-0002-8371-7087)
- Matteo Lambertini (ORCID: https://orcid.org/0000-0003-1797-5296)
- Maria Grazia Razeti
- Gaia Griguolo (ORCID: https://orcid.org/0000-0002-8782-4509)
- Ornella Ponzoni
- Antonio Marra (ORCID: https://orcid.org/0000-0002-7310-7824)
- Matteo De Monte
- Julian Etessami
Institutions
- University of Modena and Reggio Emilia (IT)
- Harvard University (US)
- University of Padua (IT)
- University of Milan (IT)
- Cornell University (US)
- Agostino Gemelli University Polyclinic (IT)
- Azienda Unita' Sanitaria Locale Di Modena (IT)
- Azienda Sanitaria Unità Locale di Reggio Emilia (IT)
- Azienda Ospedaliero-Universitaria di Modena (IT)
- Istituto Oncologico Veneto (IT)
- Dana-Farber Cancer Institute (US)
- Ospedale Policlinico San Martino (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Weill Cornell Medicine (US)
- European Institute of Oncology (IT)
- University of Genoa (IT)
Publication Details
- Journal
- npj Breast Cancer
- Published
- 2025-12-13
- DOI
- https://doi.org/10.1038/s41523-025-00859-z
- Citations
- 2
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 3.04