About 18 months ago, at the 2011 Genitourinary Cancer symposium in Orlando, Florida, Klotz et al. presented data from a large trial of intermittent (IADT) versus continuous androgen deprivation therapy (CADT) in the management of men with progressive prostate cancer after prior treatment with first- or second-line radiation therapy. We reported their data at the time.
The full report on the structure and results of this trial has now been published in the New England Journal of Medicine. Unfortunately, only the abstract is available on line unless you are a subscriber to the journal. As far as we can tell, however, there is no significant difference between the published data and the data originally presented by Klotz in February 2011.
As many readers will already be aware, the results of this trial (that IADT was non-inferior to CADT in these patients) are in sharp contrast to the results of the trial reported by Hussain and her colleagues at the annual meeting of the American Society of Clinical Oncology earlier this year. It is not entirely clear at this time how to resolve these differences in outcome in the best interests of individual patients. It also needs to be realized, however, that there were some very real differences between the ways that these two trials were conducted and the eligibility criteria for participation in the two studies.
Clearly, there are men for whom IADT is not appropriate under any circumstances. Their disease is too aggressive and their PSA does not fall to a low enough nadir level during the first period on androgen deprivation, prior to any period off androgen deprivation.
The problem is whether there are men for whom IADT is entirely appropriate, how to pick these men out from the general population of men with a rising PSA who are candidates for androgen deprivation therapy, and how to then manage their intermittent protocol to optimize their outcome. There is a whole list of still unanswered questions:
- Do these men need to exhibit a nadir PSA level of < 0.1 ng/ml after 6 or 9 months of “lead in” androgen deprivation (or is any level < 4.0 ng/ml good enough)?
- Do these men need to exhibit a nadir serum testosterone level of < 20 ng/dl after 6 to 9 months of “lead in” androgen deprivation (or is any level < 50 ng/dl good enough)?
- What is the most appropriate and effective type of IADT?
- A brief period of an antiandrogen (e.g., bicalutimide) followed by an LHRH agonist alone during the “on therapy” cycles but no treatment at all during the “off therapy cycles” (IADT1)?
- Continuous two-drug androgen deprivation with an LHRH agonist and an antiandrogen during the “on therapy” cycles but no treatment at all during the “off therapy cycles” (IADT2)?
- Continuous three-drug androgen deprivation with an LHRH agonist, an antiandrogen, and a 5α-reductase inhibitor (e.g., dutasteride) during the “on therapy” cycles but no treatment at all during the “off therapy cycles” (IADT3)?
- Continuous three-drug androgen deprivation with an LHRH agonist, an antiandrogen, and a 5α-reductase inhibitor (e.g., dutasteride) during the “on therapy” cycles and continued treatment with the 5α-reductase inhibitor during the “off therapy cycles” (IADT3+)?
- Something else that we haven’t even tried yet (e.g., forms of IADT that include early use of drugs like enzalutamide)?
- What is the most appropriate signal to restart androgen deprivation in a man with a rising PSA after a period off full androgen suppression?
- What are acceptable nadir PSA and nadir serum testosterone levels after second, third, and subsequent “on therapy” cycles of androgen deprivation?
We know that there are men who appear to do extraordinarily well on all the different forms of IADT. We also know that there are some men who started out with “challenging” cases of progressive prostate cancer who appear to have done extraordinarily well on IADT3+ (and we fully expect at least one of those men to comment on this post). We also think that we know why the different forms of IADT fail, and it is the same reason regardless of type of IADT — because the patients’ cancers are progressing too rapidly into the realm of androgen resistance.
The problem is what we don’t know:
- Why do the men who do well on the different types of IADT respond so well?
- Are forms of IADT like IADT3+ truly superior to IADT1 and IADT2 — or is this a mirage because we are only really aware of the most outstanding positive responses?
And then, of course, there is the issue of whether, if we take another decade or so to conduct studies that might be able to answer these questions, we will continue to get conflicting information.
So what does an individual patient do, faced with the current challenges? He is going to have to make a very personal choice after careful discussion with his doctors.
For men who want to be sure that they have the longest possible survival, regardless of side effects of therapy, this is a no-brainer: the Hussain-reported data and the data just published in the New England Journal of Medicine both suggest strongly that CADT with an LHRH agonist alone or with an LHRH agonist + an antiandrogen has an overall survival benefit when the responses of all patients who initially respond well to androgen deprivation are assessed (even if that that overall survival benefit is very small).
However, for those men who see quality of life as being a significant factor in their decision process, the decision is going to be much more difficult, and at this point in time we do not believe that there is clinically documented evidence that can categorically be used to demonstrate that any one form of IADT is superior to any other in terms of overall survival, prostate cancer-specific survival, or long-term quality of life. Furthermore, few clinicians actually have significant experience with the more sophisticated forms of IADT, which means that persuading one’s doctors to even consider such options can be — in itself — a challenge.
In the world of prostate cancer, the importance of becoming a well-informed patient who is able and willing to make tough choices is only becoming more evident. Your doctor may be able to guide you and help you understand and interpret the available data, but in the end only you may be able to make some of the actual decisions in the most appropriate manner that suits your personal goals.