Talazoparib plus enzalutamide as a first-line treatment in patients with mCRPC, regardless of HRR gene alteration status

In the TALAPRO-2 study, talazoparib plus enzalutamide demonstrated statistically significant and clinically meaningful improvement in radiographic progression-free survival over standard of care enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) regardless of HRR status, while delaying time to worsening in global health status and quality of life.

To date, metastatic castration-resistant prostate cancer (mCRPC) remains an aggressive disease and novel therapies are needed. Enzalutamide (ENZA), a potent androgen receptor signalling inhibitor, is a current standard-of-care treatment for mCRPC. Talazoparib (TALA) is a potent poly(ADP-ribose) polymerase inhibitor (PARPi) that traps PARP on single-strand DNA breaks, preventing DNA repair. Co-inhibition of the androgen receptor and PARP may be efficacious in tumours with or without HRR gene alterations. TALAPRO-2 is the first phase III study to combine the PARPi inhibitor TALA with the androgen receptor inhibitor ENZA in patients with mCRPC unselected for homologous recombination repair (HRR) status.

Study design

Patients unselected for genetic alterations in DNA damage repair pathways, directly or indirectly involved with HRR, received either TALA (0.5 mg) + ENZA (160 mg daily) or placebo + ENZA (160 mg daily) as first-line treatment for mCRPC. Patients were stratified by prior abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. In order to be eligible for the trial, patients must have mild or asymptomatic mCRPC with disease progression at study entry, an ECOG performance status score ≤1, ongoing androgen deprivation therapy and no prior life-prolonging therapy for CRPC. Primary endpoint of the trial is radiographic progression-free survival (rPFS) by blinded independent central review (BICR).

Results

In total, 402 patients were randomised to TALA+ENZA and 403 patients to placebo+ENZA. Baseline demographics and disease characteristics were well-balanced between treatment arms. Biomarker status was prospectively informed by tumour tissue for 99.9% of patients. HRR gene alterations were well-balanced between treatment arms and consistent with prior reports. Treatment with TALA+ENZA resulted in a 37% reduced risk of progression or death (HR[95%CI]: 0.63[0.51-0.78], p< 0.001). Median rPFS was not reached for the talazoparib group and was 21.9 months for the placebo group. A consistent treatment effect with TALA+ENZA was seen in prespecified subgroups, including age, ECOG performance status, Gleason score, stage at diagnosis, site of metastasis, HRR status and prior treatment with abiraterone or docetaxel. rPFS was significantly improved in HRR-deficient (HR[95%CI]: 0.46[0.30–0.70], p< 0.001), HRR-non-deficient or unknown (HR[95%CI]: 0.70[0.54–0.89], p= 0.004), and HRR-nondeficient patients by tumour tissue testing (HR[95%CI]: 0.66[0.49–0.91], p= 0.009) in the TALA+ENZA vs. placebo+ENZA arm. Overall survival (OS) data are still immature (31% maturity) but demonstrate a trend in favour of the TALA+ENZA combination (HR[95%CI]: 0.89[0.69-1.14], p= 0.35). In addition, TALA+ENZA prolonged time to PSA progression (HR[95%CI]: 0.72[0.58-0.89], p= 0.002). Benefits of TALA+ENZA were consistently observed across other secondary endpoints, including time to cytotoxic chemotherapy (p< 0.001) and PFS2 (p= 0.04). Objective response rates were 61.7% for TALA+ENZA and 43.9% for placebo+ENZA (p= 0.005). In addition, higher rates of complete response (37.5% vs. 18.2%) suggest a cooperative effect of TALA+ENZA treatment.

Overall, 71.9% (TALA+ENZA) and 40.6% (placebo+ENZA) had grade 3-4 treatment-emergent adverse events (TEAEs). Myelodysplastic syndrome was reported in one patient during the safety reporting period and acute myeloid leukaemia was reported in one patient during the follow-up period (both in the TALA+ENZA arm). Furthermore, pulmonary embolism was reported in 10 (2.5%) patients in the TALA+ENZA arm (grade 3 in 9 patients) and in 3 (0.7%) patients in the placebo plus enzalutamide arm (all grade 3). TEAEs led to discontinuation of TALA in 19.1% of patients (vs. placebo in 12.2%). The most common TEAEs leading to a dose reduction of talazoparib were anaemia (43.2%), neutropenia (15.1%) and thrombocytopenia (5.5%). Grade 3-4 anaemia were reported in 46.5% of men and 8.3% discontinued talazoparib due to anaemia. However, the median relative dose intensity of talazoparib remained above 80%. Finally, TALA+ENZA significantly prolonged time to definitive clinically meaningful deterioration in global health status/ quality of life (HR[95%CI]: 0.78[0.62-0.99], p= 0.04).

Conclusion

Talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in rPFS by BICR over placebo plus enzalutamide across the all-comers populations and prespecified subgroups in the first-line mCRPC setting. The safety profile of talazoparib plus enzalutamide was consistent with individual profiles, and TEAEs were generally managed through dose modifications and supportive measures. Time to definitive clinically meaningful deterioration in GHS/QoL was significantly longer with talazoparib plus enzalutamide versus placebo plus enzalutamide.

Reference

Agarwal N, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Presented at ASCO GU 2023; Abstract LBA17.