A phase Ia/Ib study of talazoparib in combination with tazemetostat in metastatic castration-resistant prostate cancer (mCRPC).

5042 Background: Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in metastatic castration-resistant prostate cancer (mCRPC), and is linked to lineage plasticity and therapy resistance. In pre-clinical studies, EZH2 directly regulates DNA damage repair (DDR) gene expression, and inhibition of EZH2 sensitizes prostate cancer cells to genotoxic stress as induced by poly-ADP ribose polymerase (PARP) inhibition. Here we report results of a Phase 1a/1b study of the combination of the PARP inhibitor talazoparib (tala) with the EZH2 inhibitor tazemetostat (taz) in mCRPC. Methods: Eligible patients (pts) had progressive disease after at least one secondary hormonal therapy and taxane-based chemotherapy (or felt not to be more appropriate for taxane), disease evaluable for response (PSA ≥ 2 ng/ml or measurable disease by RECIST 1.1) and a metastatic lesion amenable to biopsy adequate for next generation sequencing. The starting dose level (DL 0) in Phase 1a was tala 0.75 mg QD + taz 600 mg BID with dose escalation/de-escalation of both agents by up to 2 dose levels based on a 3+3 design to define the recommended phase 2 dose (RP2D). In Phase 1b, an additional 20 pts were treated at the RP2D to assess preliminary safety and efficacy. Results: 12 pts were treated in Phase 1a, of whom 2 of 11 DLT-evaluable pts experienced DLT (both Grade 4 thrombocytopenia): 0 of 3 at DL 0, 1 of 6 at DL +1 (tala 0.75 mg QD + taz 800 mg BID), and 1 of 2 at DL +2 (tala 1 mg QD + taz 800 mg BID). The other pt treated at DL +2 experienced Grade 3 anemia requiring transfusion just outside the DLT period, so DL +1 was selected as the RP2D. 27 pts were treated at the RP2D: 7 in Phase 1a (1 of whom was replaced due to progression prior to completion of the DLT period) and 20 pts in Phase 1b. Median PSA at enrollment was 21.8 ng/ml (range 0-3287), and median number of prior treatments was 4 (range 1-10). Grade ≥3 treatment-related AEs were reported in 59% of pts (16/27), including thrombocytopenia (8/27, 29.6%), anemia (8/27, 29.6%), fatigue (4/27, 14.8%), neutropenia (3/27, 11.1%), lymphopenia (1/27, 3.7%), and hyperglycemia (1/27, 3.7%). 14 of 27 pts (51.8%) required dose reduction. Confirmed PSA50 response was seen in 3 of 23 PSA-evaluable pts (13.0%), and PSA30 in 4 of 23 (17.4%). 1 of 12 pts with measurable disease (8.3%) experienced unconfirmed radiographic response, and 6 of 27 pts (22.2%) remained on study treatment for > 270 days. Conclusions: In a heavily pretreated biomarker-unselected population, the RP2D of talazoparib 0.75 mg daily and tazemetostat 800 mg BID was associated with expected myelosuppression but otherwise acceptable safety profile, with clinical benefit seen in a minority of patients. Companion blood and tissue-based correlative studies to characterize pharmacodynamic biomarkers of combined PARP+EZH2 inhibition and biomarkers of response and resistance are ongoing. Clinical trial information: NCT04846478 .