Skip to main content

Advertisement

SpringerLink
Log in

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

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dantzer F, de La Rubia G, Ménissier-De Murcia J, Hostomsky Z, de Murcia G, Schreiber V (2000) Base excision repair is impaired in mammalian cells lacking poly (ADP-ribose) polymerase-1. Biochemistry 39(25):7559–69

    Article  CAS  PubMed  Google Scholar 

  2. Schreiber V, Amé JC, Dollé P et al (2002) Poly (ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277(25):23028–36

    Article  CAS  PubMed  Google Scholar 

  3. Annunziata CM, O’Shaughnessy J (2010) Poly (ADP-ribose) polymerase as a novel therapeutic target in cancer. Clin Cancer Res 16(18):4517–26

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Tomoda T, Kurashige T, Moriki T, Yamamoto H, Fujimoto S, Taniguchi T (1991) Enhanced expression of poly (ADP-ribose) synthetase gene in malignant lymphoma. Am J Hematol 37(4):223–7

    Article  CAS  PubMed  Google Scholar 

  5. Shiobara M, Miyazaki M, Ito H et al (2001) Enhanced polyadenosine diphosphate-ribosylation in cirrhotic liver and carcinoma tissues in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 16(3):338–44

    Article  CAS  PubMed  Google Scholar 

  6. de Murcia JM, Niedergang C, Trucco C et al (1997) Requirement of poly (ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A 94(14):7303–7

    Article  PubMed Central  PubMed  Google Scholar 

  7. Masutani M, Nozaki T, Nakamoto K et al (2000) The response of Parp knockout mice against DNA damaging agents. Mutat Res 462(2–3):159–66

    Article  CAS  PubMed  Google Scholar 

  8. de Murcia MJ, Ricoul M, Tartier L (2003) Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J 22(9):2255–63

    Article  PubMed Central  PubMed  Google Scholar 

  9. Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–34

    Article  CAS  PubMed  Google Scholar 

  10. Fong PC, Yap TA, Boss DS et al (2010) Poly (ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28(15):2512–9

    Article  CAS  PubMed  Google Scholar 

  11. Tutt A, Robson M, Garber JE et al (2010) Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376(9737):235–44

    Article  CAS  PubMed  Google Scholar 

  12. Audeh MW, Carmichael J, Penson RT et al (2010) Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376(9737):245–51

    Article  CAS  PubMed  Google Scholar 

  13. Plummer R, Jones C, Middleton M et al (2008) Phase I study of the poly (ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 14(23):7917–23

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Kummar S, Ji J, Morgan R et al (2012) A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res 18(6):1726–34

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Schiewer MJ, Goodwin JF, Han S et al (2012) Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov 2(12):1134–49

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Penning TD, Zhu G-D, Gandhi VB et al (2009) Discovery of the poly (ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J Med Chem 52(2):514–23

    Article  CAS  PubMed  Google Scholar 

  17. Kummar S, Kinders R, Gutierrez ME et al (2009) Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 27(16):2705–11

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Li X, Delzer J, Voorman R, de Morais SM, Lao Y (2011) Disposition and drug-drug interaction potential of veliparib (ABT-888), a novel and potent inhibitor of poly (ADP-ribose) polymerase. Drug Metab Dispos 39(7):1161–69

    Article  CAS  PubMed  Google Scholar 

  19. Barreto-Andrade JC, Efimova EV, Mauceri HJ et al (2011) Response of human prostate cancer cells and tumors to combining PARP inhibition with ionizing radiation. Mol Cancer Ther 10(7):1185–93

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Liu SK, Coackley C, Krause M, Jalali F, Chan N, Bristow RG (2008) A novel poly (ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia. Radiother Oncol 88(2):258–68

    Article  CAS  PubMed  Google Scholar 

  21. Palma JP, Wang YC, Rodriguez LE et al (2009) ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumors. Clin Cancer Res 15(23):7277–90

    Article  CAS  PubMed  Google Scholar 

  22. Donawho CK, Luo Y, Luo Y et al (2007) ABT-888, an orally active poly (ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 13(9):2728–37

    Article  CAS  PubMed  Google Scholar 

  23. Palma JP, Rodriguez LE, Bontcheva-Diaz VD et al (2008) The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo. Anticancer Res 28(5A):2625–35

    CAS  PubMed  Google Scholar 

  24. Molina JR ND, Erlichman C, Lensing JL, Luo Y, Giranda V. Ongoing Phase 1 Studies of a Novel PARP Inhibitor, ABT-888: Pharmacokinetics, Safety and Anti-Tumor Activity [abstract]. Proceedings of the 100th Annual Meeting of the American Association for Cancer Research. 2009 Apr 18–22; Denver, CO. AACR; 2009. Abstract nr 3602.

  25. Petrylak DP, Ankerst DP, Jiang CS et al (2006) Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99–16. J Natl Cancer Inst 98(8):516–21

    Article  PubMed  Google Scholar 

  26. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the united states, national cancer institute of Canada. J Natl Cancer Inst 92(3):205–16

    Article  CAS  PubMed  Google Scholar 

  27. Rudin CM, Hann CL, Garon EB et al (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18(11):3163–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Cristofanilli M, Budd GT, Ellis MJ et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–91

    Article  CAS  PubMed  Google Scholar 

  29. Gandhi L, Camidge DR (2011) Ribeiro de Oliveira M, et al. Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29(7):909–16

    Article  CAS  PubMed  Google Scholar 

  30. Shaffer DR, Leversha MA, Danila DC et al (2007) Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin Cancer Res 13(7):2023–9

    Article  CAS  PubMed  Google Scholar 

  31. Scher HI, Jia X, de Bono JS et al (2009) Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 10(3):233–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Locker GY, Hamilton S, Harris J et al (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 24(33):5313–27

    Article  CAS  PubMed  Google Scholar 

  33. Kumar-Sinha C, Tomlins SA, Chinnaiyan AM (2008) Recurrent gene fusions in prostate cancer. Nat Rev Cancer 8(7):497–511

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Tomlins SA, Rhodes DR, Perner S et al (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310(5748):644–8

    Article  CAS  PubMed  Google Scholar 

  35. Brenner JC, Ateeq B, Li Y et al (2011) Mechanistic rationale for inhibition of poly (ADP-Ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19(5):664–78

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Haffner MC, Aryee MJ, Toubaji A et al (2010) Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 42(8):668–75

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. van Brussel JP, Busstra MB, Lang MS, Catsburg T, Schröder FH, Mickisch GH (2000) A phase II study of temozolomide in hormone-refractory prostate cancer. Cancer Chemother Pharmacol 45(6):509–12

    Article  PubMed  Google Scholar 

  38. Panteleakou Z, Lembessis P, Sourla A et al (2009) Detection of circulating tumor cells in prostate cancer patients: methodological pitfalls and clinical relevance. Mol Med 15(3–4):101–14

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Doyen J, Alix-Panabières C, Hofman P et al (2012) Circulating tumor cells in prostate cancer: a potential surrogate marker of survival. Crit Rev Oncol Hematol 81(3):241–56

    Article  PubMed  Google Scholar 

  40. Feuer JA, Lush RM, Venzon D et al (1998) Elevated carcinoembryonic antigen in patients with androgen-independent prostate cancer. J Investig Med 46(2):66–72

    CAS  PubMed  Google Scholar 

  41. Haffner MC, De Marzo AM, Meeker AK, Nelson WG, Yegnasubramanian S (2011) Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target? Clin Cancer Res 17(12):3858–64

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Statistical analyses were performed by Matt Dudley, PhD and medical writing assistance by Keith J. Gaddie, PhD of AbbVie. Medical writing assistance was provided by Mukund Nori, PhD, MBA, CMPP and Helen Varley, PhD, CMPP of UBC-Envision Group; financial support for this service was provided by AbbVie.

Disclosures

AbbVie provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data as well as the writing, review and approval of the manuscript.

Conflict of interest

Jiang Qian, Evelyn McKeegan, Marion Refici-Buhr, Brenda Chyla. Stacie Shepherd and Vincent Giranda are employees and stock owners of AbbVie. Maha Hussain, Michael Carducci, Susan Slovin, Jeremy Cetnar, and Joshi Alumkal have no conflicts to disclose.

Financial support

Trial registration ID: NCT01085422.

This study was sponsored by AbbVie Inc. The institutions of authors Maha Hussain, Michael Carducci, Susan Slovin, Jeremy Cetnar, and Joshi Alumkal received funding support from AbbVie to conduct this study. This trial was conducted by the Prostate Cancer Clinical Trials Consortium (PCCTC), a program of the Prostate Cancer Foundation and the Department of Defense Prostate Cancer Research Program (PCRP).

Author information

Author notes

  1. Jeremy Cetnar

    Present address: Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA

Authors and Affiliations

  1. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Maha Hussain

  2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA

    Michael A. Carducci

  3. Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Susan Slovin

  4. Department of Medicine, Carbone Cancer Center, University of Wisconsin, Madison, WI, USA

    Jeremy Cetnar

  5. AbbVie Inc, North Chicago, IL, USA

    Jiang Qian, Evelyn M. McKeegan, Marion Refici-Buhr, Brenda Chyla, Stacie P. Shepherd & Vincent L. Giranda

  6. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Joshi J. Alumkal

  7. Division of Hematology/Oncology, University of Michigan, 1500 E Medical Center Dr., 7314 Cancer Center, Ann Arbor, MI, 48109-0946, USA

    Maha Hussain

Authors
  1. Maha Hussain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael A. Carducci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susan Slovin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeremy Cetnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiang Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Evelyn M. McKeegan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marion Refici-Buhr
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Brenda Chyla
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stacie P. Shepherd
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vincent L. Giranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Joshi J. Alumkal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maha Hussain.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hussain, M., Carducci, M.A., Slovin, S. et al. Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Invest New Drugs 32, 904–912 (2014). https://doi.org/10.1007/s10637-014-0099-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-014-0099-0

Keywords

Search

Navigation