A Phase I Study of ASTX727 plus Talazoparib in Patients with Triple Negative or Hormone Resistant/HER2-negative Metastatic Breast Cancer
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Background
Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective in patients with germline BRCA 1/2 and PALB2 mutations but have been largely ineffective as monotherapy in others. PARP interacts with, and is recruited to, DNA damage sites along with epigenetic factors, such as DNA methyltransferase 1 (DNMT1). In addition to increasing PARP-trapping, inhibitors of DNMT modulate ROS-cAMP/PKA signaling and induce a pathogen mimicry, inflammasome signaling response and a ‘BRCAness phenotype’ that further sensitizes cells to PARPi. In preclinical in vitro and in vivo studies, combined DNMTi + PARPi therapy was effective in both triple negative (TNBC) and hormone resistant (HRBC) models with intact BRCA.
Methods
We conducted a phase I study combining the oral DNMTi ASTX727 with the PARPi talazoparib in patients (pts) with previously treated TNBC or HRBC; pts with deleterious mutations of BRCA were excluded. Pts with TNBC had received at least one prior chemotherapy and pts with HRBC had received prior endocrine therapy with a cyclin-dependent kinase inhibitor for metastatic disease. An ECOG PS 0-1 and adequate organ function was required. A classical 3+3 design guided dose escalation/de-escalation with dose-limiting toxicity (DLT) defined as Grade 4 neutropenia or thrombocytopenia lasting ≥7 days, or clinically significant grade ≥3 non-hematologic toxicity in cycle 1; 28 days constituted each cycle. Serial peripheral blood mononuclear cells (PBMCs) were analyzed for changes in methylation using the Infinium Methylation EPIC BeadChip and LINE1 sequencing.
Results
34 evaluable pts were enrolled and treated in 8 dose cohorts. Median age was 59 years, 12% identified as Black. Myelosuppression was common with grade ≥3 neutropenia in 42% and grade 3 anemia and thrombocytopenia in 13%. DLT was limited to neutropenia. Efficacy was assessed in 29 pts. There were no objective responses, 6 pts had stable disease persisting for > 4 months in 3 pts. LINE1 demethylation ranged from ∼2-10% and immune-specific CpGs (methylation in immune cells) changed 1-5% by differential methylation locus analysis at Day 15. Methylation changes were not dose dependent.
Conclusions
ASTX727 plus talazoparib produces significant myelosuppression but is otherwise well tolerated. Low dose ASTX727 (10 mg decitabine: 100 mg cedazuridine) on Days 1,3,5 with talazoparib 0.5 mg daily on Days 1-21 of each 28-day cycle is recommended for phase II trials. Methylation changes in PBMCs were detected and some heavily pre-treated pts had prolonged stable disease despite the attenuated doses.
Statement of Translational Relevance
Inhibitors of poly (ADP-ribose) polymerase (PARPi) have significant clinical benefit in patients with advanced breast cancer who harbor deleterious mutations of BRCA1, BRCA2, or PALB2 but have had limited benefit in those without mutations. Similarly, epigenetic therapies such as the DNA methyltransferase inhibitors (DNMTi) slow disease progression in some hematologic malignancies and myelodysplastic syndromes but have not found a role in solid tumors. Despite limited clinical activity as monotherapy, the combination of PARP and DNMTi significantly inhibited tumor growth in several preclinical models with intact BRCA. In the first clinical trial combining talazoparib and ASTX727, myelosuppression limited drug exposure but the combination was otherwise well tolerated. Strategies to reduce myelosuppression with this combination should be explored. Despite the attenuated doses, methylation changes in peripheral blood mononuclear cells (PMBCs) and clinical benefit were observed; neither were clearly dose dependent.
