Targeting resistant prostate cancer, with or without DNA repair defects, using the combination of ceralasertib (ATR inhibitor) and olaparib (the TRAP trial).

Abstract

88 Background: Men with metastatic, castration resistant prostate cancer (mCRPC) harboring DNA repair defects (̃20%) achieve a radiographic progression free survival of 7.4 months with PARP inhibitors (PARPi). Preclinical studies combining a PARPi (olaparib) and DNA damage checkpoint inhibitor (ATR inhibitor, ceralasertib) show synergy, providing the rationale to test this combination in men with mCRPC, including where single agent olaparib has been shown to be active. Methods: Two cohorts were accrued to a trial combining ceralasertib with olaparib in men a) with or b) without DNA repair defects. All patients progressed on ≥1 prior mCRPC therapy with no prior PARPi or platinum chemotherapy. The primary endpoint was disease response (confirmed PSA decline ≥50% and/or RECIST response), while disease progression was defined per Prostate Cancer Working Group 3 definition. Each cohort is analyzed independently for disease endpoints, while both groups were combined for toxicity assessments. Results: The 12 person DNA repair-deficient (DRDef) cohort allowed patients with germline BRCA2 loss (n = 4), somatic BRCA2 loss (n = 1) and ATM loss (n = 1 germline, n = 5 somatic and n = 1 somatic with unknown germline). 35 men without BRCA2/BRCA1 or ATM genomic loss were accrued to the DNA repair-proficient (DRPro) cohort. These men had next-generation sequencing (NGS) on contemporary biopsies (prior to enrolment without intervening therapy, 12), prior NGS on metastatic tissue (10), prior NGS on primary prostatic tissue (n = 3), or cell-free analyses (5). Five patients have incomplete cell-free analyses. At data cutoff (October 2021), in the DRDef cohort, the response rate by confirmed ≥50% PSA decline was 4/10 (40%) including 3 of 4 BRCA2 patients, and another is awaiting sufficient follow up; 1 of 6 ATM-deficient patients responded and another is awaiting sufficient follow up. All 4 DRDef responders remain on therapy (median of 8 months). For patients in the DRPro cohort who have completed therapy and response assessment (n = 21), 3 responded, one with a duration of 12 months, two with 6 months. An updated analysis will be presented. Conclusions: This analysis suggests potential activity of the doublet for DRDef (BRCA2 mainly) and DRPro mCRPC. Ongoing biomarker analysis (e.g. ATM IHC, contemporaneous cell-free DNA analysis rather than archived tissue) may help guide selection of patients most likely to benefit. Clinical trial information: NCT03787680.

PARP inhibitors in metastatic prostate cancer

“…In an in vitro study of olaparib and the ATR inhibitor ceralasterib, this therapeutic combination was shown to selectively cause cell death in ATM -deficient cells ( 59 ). This synergistic interaction was used as the basis for the TRAP trial, a 2-cohort study of patients with BRCA1 , BRCA2 , or ATM mutations or without any HRR alterations ( 26 ). In this study, olaparib was administered twice daily at a standard dose, and ceralasterib was administered daily on days 1-7 of a 28-day cycle.…”

Homologous Recombination Repair Gene Mutations in Prostate Cancer: Prevalence and Clinical Value

“…TRAP (NCT03787680) is a phase 2 study investigating olaparib in patients with mCRPC [ 91 , 92 ]. Patients with tumors that progressed after at least one more line of treatment were enrolled and treated with olaparib in combination with ceralasertib (AZD6738), an ATR inhibitor [ 91 ].…”

“…TRAP (NCT03787680) is a phase 2 study investigating olaparib in patients with mCRPC [ 91 , 92 ]. Patients with tumors that progressed after at least one more line of treatment were enrolled and treated with olaparib in combination with ceralasertib (AZD6738), an ATR inhibitor [ 91 ]. At data cutoff (DCO), the rate of confirmed ≥ 50% PSA decline was 33% (4/12) in patients who tested positive for DNA repair deficiency (defined as germline or somatic BRCA2 or ATM loss) and 11% (4/35) in patients who tested negative for DNA repair deficiency [ 91 ].…”

Hematological Toxicities with PARP Inhibitors in Prostate Cancer: A Systematic Review and Meta-Analysis of Phase II/III Randomized Controlled Trials

“…The reasons for full-text exclusion are shown in Figure 1. Specifically, the phase II trials, such as TOPARP-A, TOPARP-B, TRITON2, TALAPRO-1, GALAHAD, QUEST, NCT02484404, CheckMate 9KD, JAVELIN PARP Medley, and TRAP, were excluded during title/abstract or full-text review due to single arm design, non-randomization protocol, or being reported in conference abstracts [17,22,[44][45][46][47][48][49][50][51]. Table 1 demonstrates the main characteristics of the eight studies included in this study.…”