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

Maha Hussain, Michael A. Carducci, Susan Slovin, Jeremy Cetnar, Jiang Qian, Evelyn M. McKeegan, Marion Refici-Buhr, Brenda Chyla, Stacie P. Shepherd, Vincent L. Giranda, Joshi Alumkal

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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/m2/day cycle 1; if well tolerated then 200 mg/m2/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.

Original languageEnglish (US)
Pages (from-to)904-912
Number of pages9
JournalInvestigational New Drugs
Volume32
Issue number5
DOIs
StatePublished - Apr 26 2014

Fingerprint

temozolomide
Castration
Prostate-Specific Antigen
DNA Repair
Prostatic Neoplasms
docetaxel
Thrombocytopenia
Anemia
DNA Repair Enzymes
Androgen Receptors
Constipation
veliparib
Neutropenia
Nausea
DNA Damage
Disease-Free Survival
Fatigue
Therapeutics

Keywords

  • Combination therapy
  • Metastatic castration-resistant prostate cancer
  • Pilot study
  • Temozolomide
  • Veliparib

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology
  • Medicine(all)

Cite this

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

In: Investigational New Drugs, Vol. 32, No. 5, 26.04.2014, p. 904-912.

Research output: Contribution to journalArticle

Hussain, M, Carducci, MA, Slovin, S, Cetnar, J, Qian, J, McKeegan, EM, Refici-Buhr, M, Chyla, B, Shepherd, SP, Giranda, VL & Alumkal, J 2014, 'Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer', Investigational New Drugs, vol. 32, no. 5, pp. 904-912. https://doi.org/10.1007/s10637-014-0099-0
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. / Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. In: Investigational New Drugs. 2014 ; Vol. 32, No. 5. pp. 904-912.
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abstract = "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/m2/day cycle 1; if well tolerated then 200 mg/m2/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.",
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AU - Slovin, Susan

AU - Cetnar, Jeremy

AU - Qian, Jiang

AU - McKeegan, Evelyn M.

AU - Refici-Buhr, Marion

AU - Chyla, Brenda

AU - Shepherd, Stacie P.

AU - Giranda, Vincent L.

AU - Alumkal, Joshi

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