A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type, Advanced Triple-Negative Breast Cancer

Abstract

• Monotherapy with prexasertib demonstrated modest activity in BRCA wild-type, recurrent triple-negative breast cancer, highlighting the unmet need for combination treatment strategies. • Neutropenia, anemia, and thrombocytopenia are common with the use of prexasertib but are manageable with supportive care measures. Prophylactic use of granulocyte colony stimulating factor should be considered to avoid dose reductions or treatment delays. • Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells.

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“…However, the clinical efficacy of prexasertib was modest in advanced BRCA wild-type triple-negative breast cancer, despite similar molecular features with HGSOC (46). The posthoc analysis of HGSOC indicated that prexasertib activity might be associated with CCNE1 amplification and overexpression (45).…”

“…In patients who administered BI 2536 or volasertib, neutropenia was the most frequently observed adverse event, and about 30%-40% of the patients experienced grade 3 or 4 neutropenia (23)(24)(25)27,28). Similarly, hematological adverse events were frequently observed in the patients that were treated with prexasertib, and almost all the patients experienced grade 3 or 4 neutropenia (44)(45)(46)(47). Therefore, the hematological toxicity of these drugs should be kept in mind; however, it is important to also note that all clinical trials have concluded the safety profile.…”

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“…Similarly, prexasertib showed modest clinical efficacy in the subsequent phase II trial evaluating nine patients with BRCA-wt recurrent triple-negative breast cancer (TNBC). One patient exhibited PR, and four achieved SD; the median PFS was 86 days [145]. However, the results from a recent phase I study do not favor the combination of prexasertib with ralimetinib (p38 mitogen-activated protein-kinase inhibitor) in advanced or metastatic tumors, as of nine enrolled patients, three experienced serious DLTs G4, and only one patient had the best overall response of SD [147].…”

“…Indeed, prexasertib did well in several trials as a monotherapy, mainly in patients with advanced solid tumors. The monotherapy was tolerated with several DLTs where the most common treatment-related SAE G4 was neutropenia [143][144][145][146]. However, the neutropenia was transient and could be recovered (median duration of six days) without any supporting care [146].…”

“…The TP53 mutation proved to be a suitable synthetically lethal partner of CHK1i in the clinic [131,145]. In a small cohort study, prexasertib could show clinical efficacy in TNBC even though they were BRCA-wt [145]. In contrast, HR deficiency associated with BRCA1/2 mutation warranted CHK1i benefit in another trial [143].…”