Dutasteride in the “off-therapy” cycles of ADT

A poster at the Genitourinary Cancers Symposium yesterday will bring joy to Chuck Maack’s heart. It addressed the use of dutasteride in the off-therapy cycles of intermittent androgen deprivation therapy (ADT).

Now we have to be clear up front that this poster by Shevrin et al. was based on data from a very small number of patients. However, …

For the very first time, as far as we are aware, Shevrin and his colleagues conducted a randomized, placebo-controlled, Phase II clinical trial in which patients were maintained on either dutasteride or a placebo during the off-therapy (“re-growth phase”) cycles of intermittent ADT, and were also given prostate biopsies to actually try to measure the extent of tumor re-proliferation.

Eligible patients had to have metastatic, castrate-sensitive prostate cancer, have an intact prostate (i.e., no previous local ablative treatment like surgery or radiation therapy), and receive an initial 8 months of ADT. The men who responded well to ADT were then randomized to receive dutasteride (0.5 mg daily) or a placebo during their off-therapy phase. Once the patients’ serum testosterone had normalized, they were given a prostate biopsy and then resumed ADT. (In other words, normalization of serum testosterone was the trigger for resumption of ADT, not a specific PSA value.) Patients who responded well to a second cycle of intermittent ADT were then “crossed-over” to receive a placebo (if they had previously received dutasteride) or dutasteride (if they had previously received a placebo) during the second off-therapy phase. Once again, when the patients’ serum testosterone had re-normalized, a second prostate biopsy was carried out and the patients again resumed ADT. Patients’ PSA levels were measured monthly to determine their PSA doubling times. Patients’ tumor proliferation was measured using the Ki-67 index.

Here are the core findings reported by the investigators:

  • 21 men were initially enrolled into the study.
  • 16/21 men were actually randomized to dutasteride vs. placebo in the first off-therapy cycle.
  • 11/16 men actually underwent prostate biopsies.
  • Dutasteride therapy in the “off ADT” cycles appeared to inhibit tumor proliferation.
    • Ki-67 index = 3.65 ± 1.7 in men on dutasteride
    • Ki-67 index = 8.5 ± 2.3 in men on placebo, p=0.001).
  • Patients’ PSA doubling times during the “off ADT” re-growth phase was similar in the dutasteride and the placebo groups.
  • Dutasteride was reported to be well tolerated with no evidence of significant toxicities.

The investigators conclude, first, that, “clinical observation of an early inhibitory effect” of dutasteride (a 5α-reductase inhibitor or 5ARI) on tumor proliferation during of “off ADT” phase of a an ADT- treated prostate “is novel.”

They point out that this finding is analogous to findings from their earlier animal model of ADT. In that model they had shown that blockade of conversion of testosterone to dihydrotestosterone by a 5ARI had a more significant effect on tumor growth in a prostate that had previously been treated with ADT than in an untreated (“intact”) prostate. The animal model had also shown that 5ARI treatment was most effective in inhibiting tumor proliferation early in the regrowth phase.

Shevrin et al. also conclude that, “using a 5ARI during the regrowth phase of [ADT] and using [testosterone] normalization as the trigger for resumption of [ADT] may result in improved efficacy of this treatment.”

Chuck … Are you happy now?

4 Responses

  1. Never had a doubt. :-)

    I have many references to support this issue.

  2. Really good news!

    But I have a problem with the two, in my opinion, a little bit conflicting statements:

    “… Dut resulted in significant inhibition of tumor proliferation …” but “PSADT during the regrowth phase was similar between the 2 groups”.

    And there was a lot of disturbing information about 5ARIs in recent weeks, for example:

    — Murtola TJ, et al.: High-grade prostate cancer and biochemical recurrence after radical prostatectomy among men using 5α-reductase inhibitors and alpha-blockers, which states that: “Long-term users of finasteride or dutasteride had more often high-grade prostate cancer” and “The proportion of high-grade (Gleason 7-10) tumors was significantly elevated among men who had used 5-ARIs for 4 years or longer compared to the non-users (83.3% vs. 53.3%, respectively).”

    — Grubb et al.: The REDUCE follow-Up study: low rate of new prostate cancer diagnoses observed during a 2-year, observational, follow-up study of men who participated in the REDUCE trial, which includes ther statement, “Very few prostate cancers were detected during follow-up, but there were more in the former dutasteride group. Specifically, there were 14 cases among former dutasteride recipients compared to 7 among the former placebo group, …”

  3. Gunterman:

    Conversely, at 15+ years of follow-up of men in the PCPT study (treated with finasteride for 7 years), according to Goodman et al., there was no sign at all of excess deaths among men in the 5ARI arm of the trial as opposed to the placebo arm.

  4. Yes, I know! I already read this study and your information about this study. Thank you!

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