TALAPRO-1: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA).

Abstract

119 Background: Phase 2 and 3 studies with poly(ADP-ribose) polymerase inhibitors (PARPi) have demonstrated antitumor activity in patients (pts) with mCRPC with DDRmut who were previously treated with novel hormonal therapy (NHT). We report the first IA of a Phase 2 study of TALA, a potent inhibitor and trapper of PARP. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRmut likely to sensitize to PARPi (including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) and progressed on ≥1 NHT (enzalutamide/abiraterone acetate). Pts receive oral TALA 1 mg/d (moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or consent withdrawal. Primary endpoint is objective response rate (ORR; blinded independent review). Secondary endpoints are time to OR, duration of response, prostate-specific antigen (PSA) decrease ≥50%, circulating tumor cell (CTC) count conversion (to CTC = 0 and <5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival (rPFS), overall survival, safety, pt-reported outcomes, and pharmacokinetics. A planned IA of safety and efficacy was performed after 20 pts with BRCA1/2 mutations were on treatment for ≥8 wks. Results: 81 pts received TALA as of June 5, 2019; 43 pts enrolled by Feb 12, 2019 were evaluable for the primary endpoint (20 BRCA1/2, 2 PALB2, 14 ATM, 7 other). All had received docetaxel and 49% prior cabazitaxel. Overall ORR (95% CI) was 25.6% (13.5–41.2), ORRBRCA1/2 50.0% (27.2–72.8), ORRATM 7.1% (0.2–33.9). Overall median (95% CI) rPFS was 5.6 months (mo) (3.5–8.2), rPFSBRCA1/2 8.2 mo (5.6–NE), rPFSATM 3.5 mo (1.7–8.1). Most common treatment-emergent adverse events (≥20%) were anemia, nausea, asthenia, decreased appetite, constipation, and platelet count decreased. Conclusions: TALA monotherapy demonstrates encouraging antitumor activity in docetaxel-pretreated mCRPC pts, especially those with BRCA1/2mut, and was generally well tolerated. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03148795.

Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

“…One avenue is on targeting DDRd. Besides platinum compounds, PARPi have shown very promising results in Phase 1 and 2 trials 21‐23 . Recently, these findings were validated in the Phase III PROfound trial 2 .…”

“…PARPi have shown very promising results in Phase 1 and 2 trials. [21][22][23] Recently, these findings were validated in the Phase III PROfound 26,27 Although not yet confirmed in a clinical setting, PTEN alterations in an in vitro setting appear to influence homologous repair, in such a way that PTEN-deficient prostate cancer cells are susceptible to treatment with PARPi. 28,29 Moreover, a preclinical study demonstrated in vitro and in vivo, that a senescence response to PARPi triggered by PTEN deficiency in prostate cancer cells, transformed to apoptosis in case of additional p53 dysfunction.…”

Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

“…One milligram of talazoparib daily is being tested in the open-label phase II trial TALAPRO-1 (NCT03148795) in patients with mCRPC with mutations in ATM , ATR , BRCA1 , BRCA2 , CHEK2 , FANCA , MLH1 , MRE11A , NBN , PALB2 , or RAD51C who progressed despite androgen-receptor-targeted therapy and taxane-based chemotherapy [ 54 ]. Preliminary data for 43 patients (20 BRCA1/2 , 14 ATM , 2 PALB2 , 7 other) showed an overall response rate of 25.6% (13.5–41.2), with an ORR of 50% (27.2–72.8) in the BRCA1/2 subgroup and 7.1% (0.2–33.9) in the ATM subgroup.…”

Safety, Pharmacokinetics, and Preliminary Efficacy of Talazoparib in Japanese Patients With Advanced Solid Tumors: Phase 1 Study

“…Talazoparib (oral 1 mg, once daily [QD]) is approved in the US, EU, and other countries as monotherapy for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with a germline BRCA 1/2 mutation [12,13], and is under investigation in other tumor types [14,15]. Findings from the phase 3 EMBRACA trial demonstrated that treatment with talazoparib 1 mg QD signi cantly improved progression-free survival (hazard ratio [HR] 0.54 [95% con dence interval (CI)] 0.41 to 0.71; P < 0.001) and patient-reported outcomes compared with chemotherapy in patients with HER2negative advanced breast cancer and a germline BRCA1/2 mutation [16,17].…”