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

• Published in: Investigational new drugs Vol. 32; no. 5; pp. 904 - 912
• Main Authors: Hussain, Maha, Carducci, Michael A., Slovin, Susan, Cetnar, Jeremy, Qian, Jiang, McKeegan, Evelyn M., Refici-Buhr, Marion, Chyla, Brenda, Shepherd, Stacie P., Giranda, Vincent L., Alumkal, Joshi J.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-10-2014; Springer; Springer Nature B.V
• Subjects: Aged; Aged, 80 and over; Analysis; Androgens; Anemia; Antigens; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Biological and medical sciences; Cancer therapies; Cell cycle; Cell growth; Chemotherapy; Creatinine; Cytotoxicity; Dacarbazine - administration & dosage; Dacarbazine - adverse effects; Dacarbazine - analogs & derivatives; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA Repair - drug effects; Drug dosages; Gynecology. Andrology. Obstetrics; Humans; Kallikreins - blood; Male; Male genital diseases; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Oncology; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase I Studies; Pilot Projects; Poly(ADP-ribose) Polymerase Inhibitors; Prostate cancer; Prostate-Specific Antigen - blood; Prostatic Neoplasms, Castration-Resistant - blood; Prostatic Neoplasms, Castration-Resistant - drug therapy; Radiation; Review boards; Studies; Thrombocytopenia; Treatment Outcome; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Pilot study; Temozolomide; Combination therapy; Metastatic castration-resistant prostate cancer; Veliparib; Antineoplastic agent; Human; Urinary system disease; Prostate disease; Targeting; Metastasis; Malignant tumor; DNA repair; Resistance; Alkylating agent; Target; Castration; Benzimidazole derivatives; DNA; Advanced stage; Combined treatment; Male genital diseases; Prostate cancer; Cancer; Metastatic castration-resistantprostate cancer
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-014-0099-0

Summary
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.