The combination of the PARP inhibitor rucaparib with sacituzumab govitecan, a conjugate of SN-38 with a humanized antibody targeting Trop-2, has shown promising antitumor activity in six patients enrolled in the SEASTAR trial, a phase Ib study with the primary aim to determine the maximum tolerated dose and recommended phase II dose. Results were recently published as case reports in JCO Precision Oncology.
Six patients with previously treated, locally advanced or metastatic triple negative breast cancer or urothelial cancer or relapsed, platinum-resistant ovarian cancer were treated with sacituzumab govitecan (twice per cycle, on day 1 and 8 of each cycle) and rucaparib once or twice daily, with a starting dose of 300 mg; treatment interruptions and/or dose reductions were permitted in the event of toxicity. All patients experienced at least one treatment-emergent adverse event, with neutropenia the most common, but they all continued treatment for ≥ 12 weeks. All patients had an investigator-assessed best response of RECIST v1.1 stable disease or better and three patients had a confirmed RECIST v1.1 partial response; they were all previously treated with a PARP inhibitor until disease progression and there were non differences in tumors with and without homologous recombination repair gene mutations. Results from the SEASTAR study thus provide proof-of-concept clinical evidence supporting further development of PARP inhibitors in combination with antibody-drug conjugates carrying Topo1-inhibitor payloads. «Targeted delivery of SN-38 to cancer cells through an antibody-drug conjugate is a rational and effective strategy for combination therapy with a PARP inhibitor by potentially reducing off-target and additive toxicity», write authors. «No optimal recommended phase II dose was established in the current study, but these data suggest that combination trials are warranted to investigate intermittent dosing of PARP inhibitors together with sacituzumab govitecan or other antibody-drug conjugate to reduce myelosuppression and optimize antitumor efficacy». Rucaparib is approved in the United States and European Union for treatment or maintenance treatment of patients with recurrent ovarian cancer, in the United States for patients with metastatic castration-resistant prostate cancer too; sacituzumab govitecan is approved in the United States for the treatment of patients with metastatic triple-negative breast cancer and urothelial cancer.