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The Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial: Lower baseline prostate-specific antigen Is associated with a greater overall survival benefit from sipuleucel-T, "Beyond the Abstract," by Philip W. Kantoff, MD

BERKELEY, CA (UroToday.com) - The phase III IMPACT trial (Immunotherapy for Prostate Adenocarcinoma Treatment; D9902B; NCT00065442) showed that sipuleucel-T treatment in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) significantly increased survival and reduced the risk of death by almost 23%.[1] The results of this pivotal trial supported the approval of sipuleucel-T for the treatment of patients with mCRPC by the US Food and Drug Administration.[2]

We recently reported retrospective subanalyses of the IMPACT trial, which explored the potential predictive value of baseline variables in patients treated with sipuleucel-T vs control.[3] An overall survival (OS) benefit was observed with sipuleucel-T across all subgroups based on the baseline variables used in the Halabi score (prostate-specific antigen (PSA), lactate dehydrogenase (LDH), hemoglobin, Eastern Cooperative Oncology Group performance status (ECOG PS), alkaline phosphatase, and Gleason score); however, a trend towards a greater magnitude of OS benefit was observed among patients with better baseline prognostic characteristics (in particular, PSA and LDH values at or below the median and ECOG PS 0). When patients were further subdivided into quartiles by baseline PSA, we found that those with lower (≤ 22.1 ng/mL) versus higher (> 134 ng/mL) baseline PSA values not only generally lived longer, but also achieved a greater benefit with sipuleucel-T. The estimated improvement in median survival with sipuleucel-T vs control was 13.0 months in the lowest baseline PSA quartile and 2.8 months in the highest quartile.[3] Furthermore, the risk of death for patients in the lowest baseline PSA quartile was reduced by 49%, compared with 16% for patients in the highest PSA quartile.[3]

Although retrospective, the subanalyses reported in Urology[3] together with the primary IMPACT analysis[1] suggest that patients with less advanced disease – particularly those with more favorable baseline factors such as low PSA – may benefit the most from sipuleucel-T treatment, and provide a rationale for immunotherapy as an early treatment strategy in sequencing algorithms for mCRPC. Indeed, patients with a lower disease burden may have a more robust immune system due to less tumor-mediated immunosuppression and fewer prior immunosuppressive treatments,[4, 5] as well as having more time to allow the immune system to mount an effective response.[6] Other active agents in mCRPC treatment (docetaxel, abiraterone acetate in the pre- and post-chemotherapy settings, and enazlutamide in the post-chemotherapy setting) seem to work reasonably effectively independent of tumor burden as measured by PSA.[7, 8, 9, 10, 11, 12] Again, these retrospective findings suggest that earlier implementation of sipuleucel-T should be considered. Patients with more advanced disease may not derive much benefit. New immune biomarkers that are tied to the mechanism of action of sipuleucel-T hold promise to identify those patients with the greatest potential to benefit from an immune-based therapy.[13,14] Until such markers become available, disease burden as represented by baseline PSA appears to serve as a useful marker to integrate into a clinician’s assessment of therapeutic options for patients with mCRPC.

References:

  1. Kantoff PW, Higano CS, et al. (2010). “Sipuleucel-T immunotherapy for castration-resistant prostate cancer.” N Engl J Med 363(5): 411-422.
  2. PROVENGE® (sipuleucel-T) Prescribing Information. Seattle, Washington: Dendreon Corporation.
  3. Schellhammer PF, Chodak G, et al. (2013). “Lower Baseline PSA is Associated with a Greater Overall Survival Benefit from Sipuleucel-T in the IMPACT Trial.” Urology 81(6): 1297-302.
  4. Töpfer K, Kempe S, et al. (2011). “Tumor evasion from T cell surveillance.” J Biomed Biotechnol 2011:918471.
  5. Whiteside TL. (2008). “The tumor microenvironment and its role in promoting tumor growth.” Oncogene 27(45): 5904-5912.
  6. Bilusic M and Gulley JL. (2012). “Endpoints, patient selection, and biomarkers in the design of clinical trials for cancer vaccines.” Cancer Immunol Immunother 61(1): 109-117.
  7. Berthold DR, Pond GR, et al. (2008). “Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study.” J Clin Oncol 26(2): 242-245.
  8. Berthold DR, Pond G, et al. (2007). “Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival of the TAX 327 study [Meeting Abstracts].” J Clin Oncol 25(18 suppl):5005.
  9. Tannock IF, de Wit R, et al. (2004). “Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.” N Engl J Med 351(15): 1502-1512.
  10. Ryan CJ, Smith MR, et al. (2012). “Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).” J Clin Oncol 30(suppl); abstr LBA4518.
  11. de Bono JS, Logothetis CJ, et al. (2011). “Abiraterone and increased survival in metastatic prostate cancer.” N Engl J Med 364(21): 1995-2005.
  12. Scher HI, Fizazi K, et al. (2012). “Increased survival with enzalutamide in prostate cancer after chemotherapy.” N Engl J Med 367(13): 1187-1197.
  13. Sheikh NA, Petrylak S, et al. (2012). “Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer.” Cancer Immunol Immunother 62(1):137-47.
  14. McNeel D, Lin D, et al. (2012). “Correlation of increased eosinophil count following sipuleucel-T treatment with outcomes in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).” J Clin Oncol 30(suppl); abstr 4650.

Written by:
Philip W. Kantoff, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Department of Medical Oncology
Dana-Farber Cancer Institute
Harvard Medical School
Boston, MA 02115, USA
Email:

Funding, contributions and financial disclosure:
The IMPACT study was sponsored by Dendreon Corporation. Medical writing assistance was provided by Emma Warr of Gardiner-Caldwell Communications and funded by Dendreon Corporation. Philip W. Kantoff is a paid consultant to Dendreon Corporation.

Lower baseline prostate-specific antigen Is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial - Abstract

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