Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer

Invest New Drugs. 2014 Oct;32(5):904-12. doi: 10.1007/s10637-014-0099-0. Epub 2014 Apr 26.

Abstract

Androgen receptor-mediated transcription is directly coupled with the induction of DNA damage, and castration-resistant tumor cells exhibit increased activity of poly (ADP-ribose) polymerase (PARP)-1, a DNA repair enzyme. This study assessed the efficacy and safety of low dose oral PARP inhibitor veliparib (ABT-888) and temozolomide (TMZ) in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) in a single-arm, open-label, pilot study. Patients with mCRPC progressing on at least one docetaxel-based therapy and prostate specific antigen (PSA) ≥ 2 ng/mL were treated with veliparib 40 mg twice daily on days 1-7 and TMZ once daily (150 mg/m(2)/day cycle 1; if well tolerated then 200 mg/m(2)/day cycle 2 onwards) on days 1-5 q28 days. Patients received 2 (median) treatment cycles (range, 1-9). The primary endpoint was confirmed PSA response rate (decline ≥ 30 %). Twenty-six eligible patients were enrolled, 25 evaluable for PSA response. Median baseline PSA was 170 ng/mL. Two patients had a confirmed PSA response (8.0 %; 95 % CI: 1.0-26.0), 13 stable PSA, and 10 PSA progression. The median progression-free survival was 9 weeks (95 % CI: 7.9-17) and median overall survival 39.6 weeks (95 % CI: 26.6-not estimable). The most frequent treatment-emergent adverse events (AEs) were thrombocytopenia (77 %), anemia (69 %), fatigue (50 %), neutropenia (42 %), nausea (38 %), and constipation (23 %). Grade 3/4 AEs occurring in > 10 % of patients were thrombocytopenia (23 %) and anemia (15 %). Veliparib and TMZ combination was well tolerated but with modest activity. Biomarker analysis supported the proof of concept that this combination has some antitumor activity in mCRPC.

Trial registration: ClinicalTrials.gov NCT01085422.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / adverse effects
  • DNA Repair / drug effects
  • Dacarbazine / administration & dosage
  • Dacarbazine / adverse effects
  • Dacarbazine / analogs & derivatives
  • Humans
  • Kallikreins / blood
  • Male
  • Middle Aged
  • Pilot Projects
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Temozolomide
  • Treatment Outcome

Substances

  • Benzimidazoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • veliparib
  • Dacarbazine
  • Kallikreins
  • kallikrein-related peptidase 3, human
  • Prostate-Specific Antigen
  • Temozolomide

Associated data

  • ClinicalTrials.gov/NCT01085422