Intermittent ADT “non-inferior” to continuous ADT in randomized Phase III trial

It has been suspected for many years that intermittent androgen deprivation (ADT) might have the same or a better impact on survival of prostate cancer patients as continuous ADT, with potentially superior effects on other factors such as quality of life.

NCIC CTG PR.7 was a large, randomized Phase III Intergroup trial designed to compare intermittent ADT to continuous ADT in the treatment of prostate cancer patients with PSA recurrence after first- or second-line radical radiation therapy (RRT).

To be eligible to participate in this trial, patients had to have a rising PSA > 3.0 ng/ml at least 1 year after initial or salvage RRT for the treatment of localized prostate cancer. The patients could also have received up to 1 year of neoadjuvant and/or adjuvant ADT in conjunction with their RRT, so long as this course of ADT had been completed at least 1 year prior to enrollment in the current study.

To ensure that patients were comparable between the two study arms, they were stratified according to four factors:

  • Time since RRT (1-3 vs >3 years)
  • Original, initial PSA level (<15 vs >15 ng/ml)
  • Prior radical prostatectomy
  • Prior neoadjuvant and/or adjuvant ADT

Patients randomized to the intermittent ADT arm of the trial were initially treated with ADT for 8 months in each cycle; ADT was restarted (for another 8 months) when their PSA level reached >10 ng/ml when they were off treatment.

The results of this trial available to date (based on the abstract to be presented by Klotz et al. at the upcoming Genitourinary Cancer Symposium) are as follows:

  • 1,386 patients were randomized to ADT.
    • 690 patients received intermittent ADT.
    • 696 patients received continuous ADT.
  • The two arms of the trial were balanced for all important baseline factors.
  • Average (median) follow up was 6.9 years.
  • Patients in the intermittent ADT arm of the trial completed a median of two 8-month cycles on therapy (range,  1 to 9 cycles).
  • 524 deaths were observed (268 on intermittent ADT vs 256 on continuous ADT).
  • Median overall survival was 8.8 years on intermittent ADT vs 9.1 years on continulous ADT (hazard ratio [HR] = 1.02)
  • There were more prostate cancer-related deaths in the intermittent ADT arm of the trial than the continuous ADT arm (122 vs 97).
  • There were fewer prostate cancer-unrelated deaths in the intermittent ADT arm of the trial than the continuous ADT arm (134 vs 146) deaths.
  • Time to devellopment of hormone-refractory disease significantly improved among patients on intermittent ADT compared to those on continuous ADT (HR = 0.80; p = 0.024).
  • Patients receiving intermittent ADT had fewer hot flashes, but there was no evidence of other differences in adverse events.

Klotz and his colleagues conclude that, in patients with a PSA recurrence after RRT  for localized prostate cancer, intermittent ADT “is non-inferior” to continuous ADT with respect to overall survival.

Some people will be disappointed by the results of this trial. There had been hope in some quarters that good randomized clinical trials would show a clear survival benefit for intermittent ADT compared to continuous ADT. However, it is worth noting that patients in this study certainly included a significant percentage of intermediate- and high-risk patients. The high-risk patients may well have been poor candidates for any type of ADT.

It is also not clear yet exactly what type of ADT was being given to these patients, but it was probably just an LHRH agonist with (at most) brief period of antiandrogen therapy to prevent the LHRH agonist flare reaction. Again, we may be wiser when we are able to hear the entire presentation on Thursday.

2 Responses

  1. Please clarify what you mean when you state that the “high risk candidates may well have been poor candidates for any type of ADT.” What other non-experimental treatment should a post-RRT/post-RP, high-risk patient with rising PSA only be considering? I am under the impression that ADT is the standard treatment in this context, whether intermittent or continous. Thank you.

  2. Dear Richard:

    ADT absolutely is the “standard” recommended treatment for any man who has failed other forms of first- and second-line therapy. However, we know that there is a significant subgroup of men who progress rapidly on ADT. What we don’t know is why. What we do know, however, (as an example) is that younger men with a rapidly rising PSA (a low PSA doubling time) after failing first- and second-line therapy are at higher than average risk for progression on ADT.

    If I was such a young man (of say 55 years of age or younger), who had had surgery followed by radiation therapy and still had a PSA that was rising with a doubling time of 6 months or less, I think that I would want to consider something other that just standard ADT (intermittent or continuous). My personal choice would be to go looking for clinical trials of development-stage agents that might be able to do more than ADT. For example, could I find a trial of ADT + chemotherapy or ADT + early enzalutimide or similar, or a trial of one of the development-stage vaccines?

    Just because something is a “standard” does not mean it is right for everyone. A standard therapy may be “right” (i.e., established based on good scientific data) for most people of the type you describe … but there are certainly many specialists who believe that younger men with a short PSA doubling time of the type that I describe above should consider clinical trials as their next step as opposed to “standard” ADT.

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