Dr Yap on Saruparib/Camizestrant in Advanced ER+, HER2-Negative or HER2-Low Breast Cancer

“There were no dose-limiting toxicities of note, and in particular, the drug discontinuation rate was very low with this particular combination; no overlapping or concerning toxicities [were] observed.”

Timothy A. Yap, MBBS, PhD, FRCP, a professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, presented findings from module 6 of the phase 1/2a PETRA study (NCT04644068) evaluating the combination of the next-generation, PARP1-selective inhibitor saruparib and the oral selective estrogen receptor degrader (SERD) camizestrant in patients with advanced or relapsed estrogen receptor (ER)–positive, HER2-negative or HER2-low breast cancer.

PETRA module 6 was designed to explore whether selective inhibition of PARP1 could be effectively paired with ER degradation to enhance antitumor activity while potentially improving tolerability compared with earlier PARP inhibitor strategies. Unlike first-generation PARP inhibitors, which inhibit both PARP1 and PARP2 and are associated with hematologic toxicity, saruparib was developed to selectively target PARP1, the primary mediator of synthetic lethality in homologous recombination–deficient tumors. This selectivity was hypothesized to preserve efficacy while reducing off-target adverse effects, thereby enabling rational combination approaches.

The study enrolled patients with heavily pretreated ER-positive/HER2-negative or HER2-low metastatic breast cancer, including individuals with prior exposure to endocrine therapy and CDK4/6 inhibitors. Importantly, enrollment was not restricted to patients with germline BRCA mutations. Camizestrant was selected as the endocrine backbone based on its potent ER degradation and activity in endocrine-resistant disease.

Early efficacy signals from PETRA module 6 demonstrated encouraging antitumor activity for the combination. Findings presented at the 2025 San Antonio Breast Cancer Symposium demonstrated that evaluable patients (n = 38) achieved an objective response rate (ORR) of 22.9% (80% CI, 13.8%-34.5%), which was comprised exclusively of partial responses. The median duration of response was 5.5 months (80% CI, 5.3-not calculable), and the disease control rate was 57.1%. Notably, patients harboring eligible germline or somatic alterations (n = 9) experienced an ORR of 33.3%. The median PFS in these 2 respective populations was 4.4 months (80% CI, 2.0-5.6) and 6.1 months (80% CI, 4.4-7.3).

From a safety perspective, the combination was generally manageable and consistent with the known profiles of each agent. Hematologic toxicities, a common limitation of earlier PARP inhibitors, were relatively infrequent and predominantly low grade, aligning with the PARP1-selective design of saruparib. Nonhematologic adverse effects were also manageable with standard supportive care and dose modifications, supporting the feasibility of this regimen in a heavily pretreated population.