Effects of ketoconazole, abiraterone, and chemotherapy in men with CRPC

Studies to be presented at the ASCO meeting next week suggest that: (a) high-dose ketoconazole has very limited activity in the treatment of men who have already been treated with abiraterone acetate; (b) men treated with either high-dose ketoconazole or abiraterone acetate (or both) can still respond to docetaxel-based chemotherapy. These findings are ones that most knowledgeable readers of this blog might reasonably have expected, given the mechanisms of action of abiraterone acetate and ketoconazole in advanced prostate cancer.

In the first of the two studies, Aggarwal et al. report data from men with chemotherapy-naïve, castration-resistant prostate cancer (CRPC) who were treated in early (Phase I and Phase II) trials of abiraterone acetate, progressed on treatment with abiraterone, and subsequently went on to be treated with either ketoconazole or docetaxel-based chemotherapy (at the discretion of the investigators and the patients). Their study data show that:

  • 6 patients were subsequently treated with ketoconazole.
  • 14 patients were subsequently treated with docetaxel-based chemotherapy
  • 11/14 patients treated with docetaxel-based chemotherapy (79 percent) had been treated with ketoconazole before any treatment with abiraterone.
  • The 20 patients were otherwise similar with respect to a variety of baseline factors.
  • Among the 6 men treated with ketoconazole
    • 0/6 showed a decline in their PSA level.
    • 0/6 showed any improvement in their bone scans
    • 0/6 showed any other objective response to treatment.
    • 6/6 demonstrated disease progression within 12 weeks of starting ketoconazole.
  • Among the 14 men treated with docetaxel-based chemotherapy,
    • 10/14 (71 percent) showed a decline in their PSA level
    • 6/14  (43%) showed a mazimum decline in their PSA level of > 50 percent.
    • 2/6 (33 percent) with measurable disease showed an objective response.
    • The median time to disease progression was 129 days (range, 60 to 294 days).

The authors conclude that men with CRPC who progress on treatment with abiraterone acetate are highly unlikely to respond to further androgen synthesis inhibition with ketoconazole, but that they do appear to to respond at a high level to docetaxel-based chemotherapy. (This latter finding is in contrast to some earlier data.)

The second study, by Small et al., looked at data from a cohort of men initially enrolled in the randomized clinical trial (CALGB 90401) that was designed to test the benefit of bevacizumab in combination with docetaxel + prednisone as compared to a placebo + docetaxel + prednisone. All patients entered into this trial had metastatic CRPC and were previously chemotherapy naïve.

 Within this cohort of 1,050 patients, Small et al. looked specifically at the impact of prior ketoconazole therapy on overall survival, progression-free survival, PSA decline, and objective response rates. Their result show that:

  • 277/1,050 patients (26 percent) had received high-dose ketoconazole therapy prior to chemotherapy.
  • Baseline characteristics were generally balanced between the men who had and who had not received prior ketoconazole therapy.
  • Levels of LDH and PSA were higher in the ketoconazole-pretreated patients.
  • There were no statistically significant differences in outcome between the ketoconazole-treated and the non-ketoconazole-treated patients with regards to
    • Overall survival (21.1 vs. 22.3 months, p = 0.643)
    • Progression-free survival (8.1 vs. 8.6 months, p = 0.394 )
    • Numbers of men showing a >50 percent decrease in their PSA levels (61 vs. 66 percent, p = 0.112)
    • Objective response to treatment (39 vs. 43 percent, p = 0.34).

The data from these two studies start to suggest some facts that may be relevant to the appropriate sequencing of the newer agents as their use becomes more widespread (although it would be helpful to see some of these data confirmed in prospective, randomized clinical studies). Specifically, it is starting to look as though:

  • If a patient with CRPC is to be treated with ketoconazole at all, it should be done before the patient is treated with abiraterone acetate (although the value of any high-dose ketoconazole treatment is now questionable by comparison with immediate treatment with abiraterone acetate in such patients).
  • If a patient with CRPC progresses after treatment with ketoconazole or abiraterone acetate or both, it is reasonable to expect about half of those men to show a meaningful response to docetaxel-based chemotherapy (although we do not know today if there is a survival benefit associated with docetaxel-based chemotherapy in men who have previously been treated with abiraterone acetate + prednisone).

One Response

  1. These are indeed interesting findings.

    Re “it should be done before the patient is treated with abiraterone acetate” … I am not sure of this conclusion. The Phase II abiraterone acetate trials concluded that the effects of abiraterone acetate are less pronounced if the patients had prior ketoconazole treatments. That’s one reason why J&J excluded patients who were exposed to ketoconazole from its Phase III trials.

    Re “it is reasonable to expect about half of those men to show a meaningful response to docetaxel-based chemotherapy” … If I am not mistaken, 50% is about what we expected from prior docetaxel trials.

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