Ketoconazole plus mitoxantrone in metastatic castration-resistant prostate cancer progressing after docetaxel treatments, "Beyond the Abstract," by Robert J. Amato, DO

BERKELEY, CA (UroToday.com) - Prostate cancer is the second most common cancer among men, with almost 240 000 cases expected to be diagnosed in 2013.[1] Although patients with localized prostate cancer have a good prognosis, this is not the case for metastatic disease. Castration-resistant prostate cancer (CRPC) remains a significant problem for clinicians: present treatment regimens have high rates of adverse reactions, and treatment failure occurs often, usually within a median of 18-24 months.

The current standard of care for primary CRPC during study enrollment was docetaxel plus prednisone. Since then, abiraterone and sipuleucel-T have been added to first-line therapies. Cabazitaxel, which has tumor action similar to docetaxel, was approved for second-line therapy of CRPC in 2010.[2] Abiraterone was approved in late 2012 as a second- and third-line treatment for CRPC. This androgen signaling inhibitor was shown to improve overall and progression-free survival.[3] The androgen receptor inhibitor enzalutamide also increases overall survival.[4] Although these new treatments are encouraging, once resistance to these regimens develop, questions remain about second-line options, given that CRPC tumors do develop serial resistance.

The anti-cancer agent, mitoxantrone, plus prednisone is FDA-approved (and was originally the first-line standard of care), but it produces only a palliative effect and no survival benefit.[5] Mitoxantrone has a mechanism of action similar to the commonly used agent doxorubicin, but it causes less cardiac toxicity. Because of its lower toxicity, we sought to determine agents that could be combined with mitoxantrone to provide yet another option for patients.

The anti-androgenic agent ketoconazole has been used both alone and in combination with anti-tumor agents to decrease prostate-specific antigen (PSA) levels and thus provide clinical benefit. This agent is generally well tolerated, causing grade ≥ 3 toxicities in < 25% of patients. It has been used in combination with doxorubicin in the past,[6] giving us a rationale for using it along with mitoxantrone.

One of our areas of strong research interest is the immune therapy of prostate cancer. Granulocyte macrophage-colony stimulating factor (GM-CSF) has been shown to stimulate dendritic cells to take up tumor antigens. GM-CSF can cause noticeable decreases in PSA levels, and toxicities associated with its use are almost always mild (grade 1).

We combined the immune-stimulating effect of GM-CSF with mitoxantrone and ketoconazole with the thought that the three agents would work synergistically, attacking CRPC cells from three directions at once.

Although the study cohort was small (28 patients), we found that patients responded well to the treatment combination. Fifty percent of the patients with soft-tissue disease had an objective clinical response to the regimen, including 4 with a partial response and 3 with stable disease. Only one patient had an adverse effect serious enough to prompt removal from the final analysis group. Otherwise, the regimen was well tolerated, and toxicities faded after treatment cycles were completed.

Patients whose PSA levels decreased the most during the treatment had the best improvements in overall and progression-free survival. The median overall survival for the whole cohort was 18.03 months. This compares with 14.8 months for abiraterone,[3] 15.1 months for cabazitaxel,[2] and 18.4 months for enzalutamide.[4] However, for patients whose PSA levels decreased by ≥ 80%, median overall survival was 27 months.

These results show two things: (1) our combination of mitoxantrone with ketoconazole and GM-CSF is comparable to current second-line therapies with an acceptable, or even improved, toxicity profile; and (2) marked decreases in PSA levels are a potential indicator of prognosis. Given the urgent need for additional salvage therapies in prostate cancer, further studies in larger patient cohorts should be conducted to verify our results.

References:

  1. Siegel R, Naishadham D, Jamal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11-30.
  2. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment; a randomised open-label trial. Lancet 2010; 376(9747): 1147-54.
  3. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364(21): 1502-12.
  4. Loblaw DA, Walker-Dilks C, Winquist E, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: a systematic review. Clin Oncol 2013; 25(7): 406-30.
  5. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15): 1502-12.
  6. Sella A, Kilbourn R, Amato R, et al. Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer. J Clin Oncol 1994; 12(4): 683-8.

 

Written by:

Robert J. Amato, DO 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.

The University of Texas Health Science Center at Houston
Medical School
Department of Internal Medicine
Division of Oncology
6410 Fannin, Suite 830
Houston, TX

Phase II trial assessing granulocyte-macrophage-colony stimulating factor, ketoconazole plus mitoxantrone in metastatic castration-resistant prostate cancer progressing after docetaxel treatments - Abstract

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