TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC).

Abstract

93 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (a potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned interim analysis (IA; Dec 2019). Updated results at a Sep 4 2020 cut-off, available in November 2020, will be presented at the meeting. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal, or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to objective response; response duration; prostate-specific antigen (PSA) decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and <5 per 7.5 mL blood); time to PSA progression; radiographic progression-free survival (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed. Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cut-off Dec 12 2019); 75 pts were evaluable for IA, with DDRm, had measurable disease, received ≥16 weeks’ treatment, and were assessed for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All pts evaluable for IA had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Funding: Pfizer Inc. Clinical trial information: NCT03148795. [Table: see text]

Age Is Just a Number: Considerations for Older Adults in Cancer Clinical Trials

“…Thus, our general approach entails consideration of the epidemiology of the disease and design of studies that reflect the age distribution, beginning with no age exclusion. For example, in some of our recent trials recruiting heavily pretreated men with metastatic castration-resistant prostate cancer, which naturally implies an advanced age group, removal of upper age cutoffs from eligibly criteria and reliance on functional measures that have a scientific rationale allowed recruitment of a trial sample with a median age of 69 years and up to 84 years (TALAPRO-1, NCT03148795) ( 26 ). Beyond data from clinical trials, we also rely on real-world evidence studies to further our understanding of treatment patterns and functional and quality-of-life outcomes in older patients; for instance, the PalomAGE study (EUPAS23012) is a prospective observational study that we recently initiated specifically to understand experience of women aged 70 years and older with locally advanced or metastatic breast cancer ( 27 ).…”

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

“…Taza and colleagues found that PARP inhibitor activity was diminished in BRCA1 - versus BRCA2 -altered mCRPC in a cohort of 123 BRCA1/2 -altered mCRPC patients receiving the PARP inhibitor, and this differential activity was not explained by mutation origin (germline vs. somatic) or allelic status (mono- vs. biallelic) [ 120 ]. The phase II TALAPRO-1 trial reported results from the treatment with talazoparib in patients with mCRPC and associated DDR defects who had progressed after ARSi and taxane [ 99 ]. The overall response rates were 44% in patients harboring BRCA1/2 alterations, 33% in PALB2 and 12% in ATM, whereas the complete response rates were 76% in BRCA1/2 , 50% in PALB2 , and 28% in ATM.…”

Prostate cancer and PARP inhibitors: progress and challenges

“…No response was observed in the other HRR groups. Most common adverse events were slightly more frequent than other PARPi, namely anemia (42.5%, all grades) and nausea (32.7%, all grades) [53].…”

“…They have received at least one taxane-based chemotherapy regimen and one or more NHT. Interim results were recently reported with 113 patients having received talazoparib and 75 patients evaluable for the primary endpoint of ORR (41 BRCA1/2, 3 PALB2, 17 ATM and 14 patients with other HRR gene alterations) [52,53]. In the BRCA, PALB2 and the ATM groups, ORR was 43.9%, 33.3% and 11.8%, respectively.…”