Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer.
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.
Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA, mahahuss@med.umich.edu.
Maha
M
Hussain
Michael A
MA
Carducci
Susan
S
Slovin
Jeremy
J
Cetnar
Jiang
J
Qian
Evelyn M
EM
McKeegan
Marion
M
Refici-Buhr
Brenda
B
Chyla
Stacie P
SP
Shepherd
Vincent L
VL
Giranda
Joshi J
JJ
Alumkal
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D007610:Kallikreins / Q000097:blood; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy*; D000077204:Temozolomide; D016896:Treatment Outcome
D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D000077204:Temozolomide