Should you be adding abiraterone acetate to your ADT?


The data previously reported from the STAMPEDE trial and the LATITUDE trial over the past couple of days were from men newly diagnosed with high-risk and/or metastatic forms of prostate cancer, but …

They raise an interesting new question that only occurred to your sitemaster this morning, and which has never came up in any discussion about these data that he has heard to date. The question is this one:

If a prostate cancer patient is already on a standard form of androgen deprivation therapy (ADT) for either high-risk, TxN0M0, but potentially micrometastatic prostate cancer, for node-positive prostate cancer, or for metastatic prostate cancer, then should he be talking to his doctor about adding abiraterone acetate to his ADT now, as opposed to waiting until he becomes castration resistant?

This is going to be a difficult question to answer immediately, because:

  • We will only have the data from the men in the control arms of the LATITUDE and the STAMPEDE trials who were switched from ADT alone to ADT + abiraterone acetate on which to be able to make that decision.
  • It will probably take quite a while before data from those patients are available.
  • If we were to find that those patients on standard ADT should, in fact, be adding abiraterone to their standard ADT early, the costs are going to be enormous (at least until abiraterone becomes available as a generic drug, which will be relatively soon).
  • We really don’t know what all the risks are of early, long-term use of abiraterone acetate, but they certainly include
    • The potential problems of long-term therapy with prednisone (even at just 5 mg/day) for 6 or more years
    • The potential risk of early induction of neuroendocrine forms of prostate cancer in some men with advanced disease (who, at least at present, we cannot identify in advance as being at risk for such a transition)

While the benefits of early use of abiraterone acetate along with ADT seem to be clear among men who are newly diagnosed with more advanced forms of prostate cancer, this does come with risks.

The use of abiraterone acetate in this scenario is not yet approved by the US Food and Drug Administration, and so neither Medicare nor insurance companies are going to be legally or otherwise “compelled” to cover the costs associated with such treatment — even though it is almost certainly appropriate.

The question raised above is therefore one more added complication that will need to be addressed by physicians, payers, and all of the relevant patients over the next 12 months or so.

6 Responses

  1. Thanks for posing this question. I am new to this site, but I suspect I am one of those persons with the unintended consequence of developing a second neuroendocrine cancer as a result of treatment with enzalutimide + chemotherapy. My PSA did go dormant while under this double treatment. But when the treatment stopped I soon had a shift that added a second (neuroendocrine) cancer. I was scheduled for prostate immunotherapy, but now this choice is off the table.

    I am now starting a second round of chemotherapy specifically targeted for my neuroendocrine mutation.

    The discoveries by Dr. Snuffy Myers seem particularly relevant to my particular cancer history and I appreciate this site indicating this new lead. Any other leads will be welcome. I live in Vancouver, BC, Canada, so must live within this medical model with specific protocols and procedures.

    I hope to become educated on the growing edge of personalized, specific approaches to each person’s particular cancer.

    I am now going for a second opinion to a medical oncologist who works in an integrative community health center. My hope is that he may have alternative ways to navigate standard practices and have me enrolled in these emerging new therapies. My first step is to enter the questions such as the one posed here at this InfoLink.

    Thank you for your commitment to keeping open this site. I feel it may become a lifeline for community support and education.

    Thanks,

    Larry

  2. Type of ADT in STAMPEDE as a major confounder?

    Thanks as always for your thoughts, Sitemaster.

    As a former veteran of intermittent ADT3 for just over 14 years, I became fairly savvy with issues involving ADT. From that perspective, I am puzzled by the study design, which permits many variations of ADT “according to local practice.”

    The STAMPEDE Definition of ADT: Here’s the description of permitted ADT from one of the relevant papers (James et al., Lancet, 2012): “The permitted methods of hormone therapy were LHRH analogues (with short-term antiandrogens to cover disease flare when necessary), maximum androgen blockade [which probably means, in practical terms, LHRH-agonists (analogues) plus long-term antiandrogens, but very likely not the further addition of a 5-alpha reductase inhibitor drug, which was my ADT3 therapy], LHRH antagonists, orchidectomy, or, in patients without metastasis, bicalutamide monotherapy (150 mg daily); choice of hormone therapy was based on clinician and patient preference.” This definition of ADT applies to both the control arm in the study and for the ADT element in each of the intervention arms.

    Key Problem — Variability in Effectiveness of Types of ADT: A key problem here is that these different types of ADT almost certainly have different degrees of effectiveness. As just one example, that has been proven for antiandrogen monotherapy compared to LHRH agonist therapy. (However, such monotherapy can be suitable for patients where the need for cancer control is not as urgent as the need to minimize side effects of more robust ADT, such as is often the case for elderly patients, per experts.) Therefore, adding abiraterone acetate (Zytiga) to one of these different foundations is bound to result in different outcomes just because the foundation is different, apart from any impact of abiraterone acetate.

    Another Problem: Moreover, abiraterone acetate is fairly similar to an LHRH agonist or antagonist in action. Therefore, it could be duplicative with those drugs, but strongly complementary with an antagonist, where the overlap in function is much lower, per my layman’s impression.

    My main point is there is a lot going on in this interesting and innovative trial, and all that activity seems likely to me to produce a substantial confounding factor.

    A Possible Solution, A Little Late: One approach to better equalize the playing field before considering abiraterone acetate would have been to have an induction phase for the control and intervention groups with an eligibility requirement that all patients must achieve a reduction in PSA to 0.05 or lower in order to continue. That level is routinely achieved by many ADT3 patients, and my impression is that quite a few patients on ADT2, and even some on single ADT by castration or an LHRH-agonist achieve it, as well as probably a hefty proportion more on an LHRH antagonist. At that point, after successful induction, abiraterone acetate could have been added to the intervention group. There is nothing sacred about the threshold of 0.05; it could be somewhat higher, though that strikes me as objectionably loose, or it could be lower, such as < 0.05, 0.01, or < 0.01. Most men who are going to respond well to ADT will hit such a low point within just a few months. (Not me, but I finally made it.)

    But Maybe Not Too Late: Though it's too late to crank such a scheme into the randomization process, something like this solution could be done as a secondary analysis. Perhaps the control group could be split, for that analysis, into those achieving the low point and those not. (It's very likely that the vast majority of those in the ADT plus abiraterone acetate arm will achieve such success.) The secondary comparison would then yield a suggestion whether the intervention was better than ADT alone where men were able to achieve the low point, and it would also yield a comparison of the intervention versus those who could not achieve the low point on ADT alone.

    If no one deflates my suggestion, I intend to pass it on to Dr. James, the trial director.

  3. Mike,

    You continue to amaze me with your work!

    Stan R.

  4. Dear Jim:

    (a) Since the whole point of the trial was to investigate whether ADT of any reasonable type along with abiraterone (when initiated together) was better that ADT of any reasonable type alone, it wouldn’t have been feasible to have an induction phase.

    (b) You are mistaken in your belief that abiraterone “is fairly similar to an LHRH agonist or antagonist in action”. That is not the case at all. It acts on a completely different biochemical pathway.

    (c) We have no data at all that indicates that men with high-risk M0 or M1 disease at time of diagnosis, and whose PSA goes to (say) < 0.05 ng/ml on initiation of continuous ADT will have better overall or prostate cancer-specific survival rates than men whose PSA only goes to (say) < 1.0 ng/ml. Why don't we? Because (rightly or wrongly) the standard that has been used for the past 40+ years to define "castrate" has been a serum testosterone level of < 50 ng/dl and not a PSA level. Thus …

    (d) If we wanted to test your hypothesis, the right way to do it would be to measure the serum T levels and the serum DHT levels of all patients every 3 months in a similar trial and then use those data to assess whether the men who had lower serum T and serum DHT levels sooner on each specific type of ADT (with or without the abiraterone) were the ones who got a greater survival benefit. Now it might be possible for Dr. James and his colleagues to go back and do this retrospectively because they may have retained serum samples on all of the patients in this trial over time, but I don’t know the answer to that question.

  5. Superiority of outcomes where PSA falls to < 0.05 versus higher level?

    Dear Sitemaster,

    Thank you for your reply of June 6, 2017 at 8:57 am in which you wrote the following paragraph (c):

    "(c) We have no data at all that indicates that men with high-risk M0 or M1 disease at time of diagnosis, and whose PSA goes to (say) < 0.05 ng/ml on initiation of continuous ADT will have better overall or prostate cancer-specific survival rates than men whose PSA only goes to (say) < 1.0 ng/ml. Why don't we? Because (rightly or wrongly) the standard that has been used for the past 40+ years to define "castrate" has been a serum testosterone level of < 50 ng/dl and not a PSA level. Thus …"

    Though I have followed developments in ADT (a.k.a. hormonal therapy) closely and have used the available evidence in shaping my own therapy choices (IADT3 for more than 14 years total before a possible cure with radiation), I too am not aware of any gold standard evidence that would stand against your first sentence. Moreover, I am not aware of any evidence that would apply, regarding achievement of a PSA of < 0.05, with the exact conditions you include (high-risk M0 or M1 disease at time of diagnosis). However, for those patients, like me who have high-risk M0 or M1 disease at diagnosis, there is one important published guidepost, as well as some informal evidence.

    The published report comes from the peer-reviewed journal Urology in 2007. Due to a quirky dispute, the authors used the awkward term “testosterone inactivating pharmaceuticals” for ADT, but combined ADT is what they were researching. The key finding was a stunning survival advantage for patients who achieved a PSA nadir of < 0.05 or lower versus those who did not. Here are the key sentences from the results section of the abstract:

    “… Death from prostate cancer was far more common (78% versus 11%) and accelerated (median of 4 years versus 7 years) for men with a PSA nadir greater than 0.05 ng/mL than for those with a lower nadir. Multivariate Cox regression analysis indicated that the hazard ratio for prostate cancer-specific mortality in men with a PSA nadir greater than 0.05 ng/mL was 11.6 (P < 0.0001)….” In order to make the study more relevant to the then current post-PSA era where fewer men were being diagnosed with well-advanced diseases, they excluded from their chart review cases men with bone metastases and PSAs greater than 100. All men were on combined blockade: an LHRH agonist and an antiandrogen. This was a fairly risky group, with 60% having a Gleason of 7 or higher, and 56% having a PSA doubling time of 12 or fewer months. While the title mentions “intermittent” therapy, the complete paper indicates that ADT was stopped only if men achieved a nadir of 0.05 or lower. What we now call castration-resistant prostate cancer (CRPC) was defined in the study as the first in a series of PSA elevations greater than 0.05 with testosterone less than 50 ng/mL (as is the usual practice today for the testosterone level). This study clearly lacked the rigor of a prospective, gold-standard type clinical trial, but it is an impressive clinical series.

    The practical import is that the authors and like-minded physicians start using other tactics at the point that their patients are unable to achieve a nadir of 0.05 or lower (or, today, perhaps < 0.01 due to the availability of superior ultrasensitive tests). They do this regardless of whether the patient has proven to be castrate resistant. We would love to have clinical trials that conclusively resolve this question, but in their absence, I, as a patient with my life on the line, found the study most useful. Of course it is another question whether the researchers involved in STAMPEDE would be impressed.

    I hope to follow with some thoughts on your paragraph (d). There may be some ways around the difficulties you note for a secondary analysis in the STAMPEDE study.

  6. Dear Jim:

    There is no doubt in my mind that we need high-quality data from a randomized clinical trial to prove or disprove the hypothesis that Scholtz et al. (and many other others) have been arguing for years. However, I don’t happen to find their case series nearly as impressive as you do because these were all carefully selected patients and all sorts of bias come into effect when one looks at data of this type. Also (as far as either of us seem to be aware), no one else seems to have been able to replicate the results of that one paper in a comparable, large case series over the past many years now.

    Of course such a study alone still wouldn’t resolve the question that Dr. de Bono is asking about.

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