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Treatment with the combination of talazoparib (Talzenna) and tazemetostat (Tazverik) produced expected levels of myelosuppression and an acceptable safety profile, and clinical benefit was observed in some biomarker-unselected patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from a phase 1a/1b trial (NCT04846478).
Findings presented at the 2025 ASCO Annual Meeting demonstrated that evaluable patients treated at the recommended phase 2 dose (RP2D; n = 12) experienced an overall response rate (ORR) of 8.3%, with the lone responder achieving an unconfirmed partial response. The stable disease rate was 33.3%, and the progressive disease rate was 58.3%. In patients with a prostate-specific antigen (PSA) level of at least 2 ng/dL who were evaluable for PSA response (n = 23), 13.1% experienced at least a 50% decline in PSA levels from cycle 1, day 1. Additionally, 17.4% of patients achieved a PSA decline of at least 30%.
Regarding safety, all evaluable patients treated at the RP2D (n = 27) experienced at least 1 treatment-related adverse effect (TRAEs). Grade 3 or higher TRAEs occurred in 59% of patients, with the most common comprising thrombocytopenia (29.6%), anemia (29.6%), fatigue (14.8%), neutropenia (11.1%), leukopenia (11.1%), lymphopenia (3.7%), and hyperglycemia (3.7%).
“In a heavily pretreated, biomarker-unselected population, talazoparib and tazemetostat at the RP2D was associated with expected myelosuppression but otherwise acceptable safety profile, with clinical benefit seen in a minority of patients,” lead study author Atish Choudhury, MD, PhD, and colleagues wrote in a poster presentation of the data. Choudhury is a senior physician and chair of the Gelb Center for Translational Research at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.
Phase 1 Trial Design
In designing the phase 1 study, investigators hypothesized that PARP inhibition with talazoparib and EZH2 inhibition with tazemetostat could be safely combined and produce clinical responses in patients with mCRPC.
The study enrolled patients with mCRPC of adenocarcinoma or neuroendocrine histology who experienced disease progression on prior treatment with an androgen receptor pathway inhibitor and taxane-based chemotherapy. Patients deemed inappropriate for a taxane were allowed to enroll. Prior treatment with a PARP inhibitor was permitted, and the population was not selected for biomarkers. Patients needed to be evaluable for response, defined as a PSA level of more than 2 ng/dL or measurable disease per RECIST 1.1 criteria.
During dose escalation in phase 1a, investigators evaluated 5 different dose levels of the combination, with 3 to 6 patients enrolled at each dose level:
- talazoparib at 0.5 mg once per day plus tazemetostat at 400 mg twice per day
- talazoparib at 0.5 mg once per day plus tazemetostat at 600 mg twice per day
- talazoparib at 0.75 mg once per day plus tazemetostat at 600 mg twice per day
- talazoparib at 0.75 mg once per day plus tazemetostat at 800 mg twice per day
- talazoparib at 1 mg once per day plus tazemetostat at 800 mg twice per day
The dose level selected for expansion was talazoparib at 0.75 mg once per day plus tazemetostat at 800 mg twice per day.
Safety/tolerability was a primary end point, measured via dose-limiting toxicities and grade of AEs. Determining the RP2D was the other primary end point. ORR was a secondary end point; other efficacy measures, such as duration of response, progression-free survival, and clinical benefit rate, were exploratory end points.
In the total population (n = 32), patients had a median age of 68 years (range, 53-81). The majority of patients had an ECOG performance status of 0 (65%) and received prior docetaxel (53%). Gleason scores at baseline comprised 6 (6%), 7 (28%), 8 (9%), 9 to 10 (47%), and not applicable (9%). Patients received a median of 6 prior lines of therapy (range, 1-10), and they had a median baseline PSA level of 24.7 ng/dL (range, 0-3287).
In patients treated at the RP2D (n = 27), median treatment duration was 3.4 months (range, 0.9-17.7); 22.2% of patients remained on treatment for more than 270 days, and at data cutoff, 7.4% of patients remained on treatment. Reasons for treatment discontinuation included radiographic disease progression (48.2%), clinical/symptomatic progression (25.9%), PSA progression (7.4%), physician decision (3.7%), consent withdrawal (3.7%), and unacceptable AEs (3.7%).
Additional Safety Data
At the RP2D, 51.9% of patients required dose modifications, including 25.9% who needed modifications for talazoparib and 48.1% who needed adjustments for tazemetostat.
The most common any-grade TRAEs reported at the RP2D consisted of decreased platelet count (74.1%), anemia (63.0%), fatigue (55.6%), nausea (48.1%), decreased neutrophil count (40.7%), decreased white blood cell count (18.5%), dizziness (18.5%), increased aspartate aminotransferase levels (14.8%), diarrhea (14.8%), vomiting (11.1%), dyspnea (7.4%), headache (7.4%), hypophosphatemia (7.4%), hypocalcemia (7.4%), decreased lymphocyte count (7.4%), and anorexia (7.4%).
Reference
Choudhury A, Zhong C, Xie W, et al. A phase Ia/Ib study of talazoparib in combination with tazemetostat in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2025;43(suppl 16):5042. doi:10.1200/JCO.2025.43.16_suppl.5042