ENZAMET trial results to be presented at ASCO

The results of the 1,125-patient, randomized, double-blind ENZAMET trial are to be reported in a late-breaking abstract at the upcoming annual meeting of the American Society for Clinical Oncology (ASCO) in Chicago.

We can reasonably assume that the sponsors of this trial — the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group — would only have submitted the data to ASCO as a late-breaking abstract if they were either seriously positive or seriously negative. The completion of this trial appears to have occurred more than a year ahead of schedule.

The ENZAMET trial was designed to investigate treatment of men with metastatic, hormone-sensitive prostate cancer (mHSPC) using either

  • Standard androgen deprivation therapy (ADT, with a bilateral orchiectomy or with an LHRH agonist) + enzalutamide (160 mg once daily) or
  • Standard ADT (with a bilateral orchiectomy or with an LHRH agonist) + a placebo

The study enrolled the 1,125 patients at 82 centers — all but one in Australia, New Zealand, Canada, Ireland, and the UK, starting in 2014, and was projected to report initial results in September 2020. The patients could only have had received any form of standard ADT for treatment of mHSPC for a maximum of 12 weeks prior to trial enrollment. The primary study endpoint is overall survival.

Obviously, your sitemaster has no advance knowledge as to the outcome of this trial. However, his suspicion is that the result will be positive. The question will therefore be just how positive.

It is worth bearing in mind that the final results of the LATITUDE trial (as published by Fizazi et al. in Lancet Oncology at the beginning of this month) showed that the combination of standard ADT + abiraterone acetate + prednisone extended median overall survival by 16.5 months as compared to standard ADT + two placebos. Specifically, median survival of the patients treated with standard ADT + the two placebos was 36.5 months compared to 53.3 months for the patients treated with standard ADT + abiraterone acetate + prednisone (hazard ratio [HR] = 0.66).

If the ENZAMET trial were to show a similar result but with a lower risk for side effects (because enzalutamide does not need to be given with prednisone), this could be very good news for patients.

9 Responses

  1. The prednisone given with abiraterone (5 mg qd) for mHSPC is a replacement dose to make up for the cortisol inhibited in the adrenals. The right replacement dose may vary among individuals, but at this low level it should not create any additional side effects.

  2. Dear Allen:

    While the intent of adding prednisone to abiraterone (and its similar use in association with many other forms of chemotherapy) is as a replacement for loss of cortisol, and short-term use of this drug is not usually associated with side effects, I can assure you that the long-term use, over years, presents a series of serious and not unusually very serious adverse effects. Oncologists have decades of experience with the use of this drug and understand these risks very well.

  3. I disagree — despite your assurances. Do you have any data to back up your assertion that long-term use of a replacement dose taken with Zytiga has untoward side effects? Janssen doesn’t list any. Oncologists cannot have “decades of experience” with this combination because Zytiga with prednisone has only been available for mHSPC since 2018. The only side effects I’ve seen are in men who have cut prednisone out with resultant adrenocortical insufficiency. There is a tendency among patients to fear prednisone because they are aware of long-term side effects in cases where it is not given just as a replacement dose – we have to be careful about feeding those unwarranted fears.

  4. This could be very good news for patients, as long as private insurance and Medicare Part C does not invoke step therapy for this subset of patients. One possibility is to first mandate Taxotere, then abiraterone acetate, then you get to try enzalutamide. If this is the case you might not might not see much of an impact in this patient population.

    I understand Medicare part C is considering a rule change that would allow this.

  5. Dear Allen:

    The use of prednisone at low and high doses in the treatment of cancer and a whole host of other conditions goes back decades. This has nothing to do with what drug it is being given in combination with. At the time of the original approval of abiraterone acetate + prednisone for the treatment of post-chemo mCRPC (when the use of abiraterone acetate in most patients would have been < 1 year) concerns about the use of prednisone were limited because of the short-term use.

    The concerns relate solely to the use of prednisone over longer time frames, when side effects are well known to occur even when low doses of the drug are administered. Exactly why this happens is unclear. And it does not occur in all patients.

    This paper by Fizazi et al. which reported no significant concerns related to low-dose prednisone in association with abiraterone acetate was based on patients being treated for up to about 30 months. I have yet to see a comparable paper related to data from the LATITUDE study, when some patients were on treatment for more like 5 years.

    No one that I am aware of is suggesting that “cutting pednisone out” is wise if one is being treated with abiraterone acetate. However, any patient who is being treated for long periods of time on even low-dose prednisone does need to be monitored with care for risk of the well-known side effects of corticosteroid therapy. The WARNINGS and PRECAUTIONS section of the prescribing information for Zytiga includes three bullet points, the first of which relates specifically to risk for mineralocortocoid excess in patient with cardiovascular conditions. Giving prednisone along with abiraterone acetate is a core risk factor for such mineralocorticoid excess.

  6. Dear Brad:

    Until we have data from the trial, I think we are simply speculating about all the possible things that might happen. It is perfectly possible that the data from the ENZAMET trial will be good but not good enough to justify the use of an LHRH agonist + enzalutamide prior to other forms of therapy. The bar has been set pretty high by the data from the STAMPEDE and LATTITUDE trials.

  7. You are ignoring the fact that that the dosage given for mHSPC is a REPLACEMENT dose and not EXTRA prednisone that one need worry about. The reason I am making an issue out of this is that some patients are fearful of taking abiraterone with prednisone for mHSPC, and your comments — with no evidence to support it — only serve to feed their fears.

    This paper explains how a replacement dose of prednisone PREVENTS mineralocorticoid excess (it does not CAUSE it, as you stated):

    “Glucocorticoid replacement therapy, as defined in this paper, has been shown to effectively REDUCE the incidence of mineralocorticoid-related adverse events in patients with mCRPC treated with abiraterone acetate. … In these settings, the main goal is to mimic normal cortisol production to restore normal physiology while minimizing adverse effects.”

    “Taken together, these findings indicate that the incidence of glucocorticoid-induced adverse events —- including bone loss, diabetes, central nervous system effects, and myopathy — are related to dose and choice of glucocorticoid, and these consequences tend to occur at doses much higher than those used in mCRPC.”

    “The systemic exposure attained with the recommended low-dose glucocorticoids is below the amount shown to inhibit immune cell proliferation in response to antigens.”

    “Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. … INCREASED dosage of corticosteroids may be indicated before, during and after stressful situations. (from the Zytiga prescribing info).

    It is worthwhile noting that the REPLACEMENT prednisone dose given for mHSPC is only 5 mg/ day, while the dose given for mCRPC is two 5 mg pills per day. It is entirely possible that the higher dose is unnecessary (as it may be when given with docetaxel), but the expected survival is also briefer. There may be some anti-cancer effect from the higher dose. As I said, the proper replacement dose is individual and might be affected by comorbidities. Oncologists should monitor BP and potassium levels and adjust prednisone up or down as appropriate.

  8. Dear Allen:

    With respect, I am not “ignoring” the “replacement” issue at all. Rather, I would suggest politely that a low dose of a drug like prednisone cannot be “standardized”. In other words basic biology tells us that one man’s “low” dose of “replacement” prednisone might be 7.5 mg/day whereas another man’s “low” dose might need to be much lower (perhaps 2.5 mg/day). Biology and pharmacology are not “one size fits all” forms of science. Indeed, you acknowledge this in your own comment when, at the end, you state that blood pressure and potassium levels should be monitored.

    Many men are going to do just fine on a 5 mg/day dose of prednisone along with their Zytiga, but some aren’t because their biological ability to make mineralocorticoids is not suppressed as much as most men’s or their biologically “normal” levels of corticosteroids are not as high as the average.

    The ways in which we dose all drugs have to be considered in the context of the individual patient, not the “average” patient. Look at the prescribing information for almost any drug you want to, and you will find that it includes language about the need to modify dose levels in individual patients for all sorts of reasons (including the one given in the Zytiga prescribing information). Indeed, I would argue that that just as the recommended 5 mg/day dose of prednisone may be too high for some men, there are probably men for whom it is too low, and those men might well need a slightly higher “replacement” dose of prednisone (e.g., 7.5 mg) on a daily basis.

    The message you should be sending to men who think that prednisone is “dangerous” and so they shouldn’t take it is that that is extremely unwise. Far better that they talk to their physician about whether 5 mg is the correct replacement dose for them. Patients’ mineralocorticoid levels are easily monitored over time, and this can allow a patient and his physician to ensure that they are getting a safe and effective dose of prednisone, not simply the dose that was found to be “right” for the “average”, patient who was being highly monitored in a sophisticated clinical trial (and who had had to meet all sorts of other criteria before he could even be entered into such a trial).

    Now what I certainly am saying is, why would one take a drug like abiraterone acetate that has to be taken with an additional drug (prednisone) if there is another drug that has the same therapeutic effects with a similar side effect profile but doesn’t need to be taken with prednisone. I don’t know that enzalutamide can do that yet, but there is increasing evidence that at least one of the other “super” antiandrogens may well be able to.

    That doesn’t make abiraterone acetate a “bad” drug. But read the specialized urologic oncology and medical oncology literature on the management of metastatic prostate cancer. It is rife with articles noting that we are still learning how and when to best use all these new drugs in the management of advanced disease. The STAMPEDE trials showed that we don’t need to give prednisone at all along with docetaxel in the treatment of newly diagnosed men with mCRPC.

    As far as I am concerned, the use of prednisone in the treatment of cancer of any type is one that always needs to be individualized. Just because trials indicate that a “low dose” is recommended on average is by no means the same thing as stating that every patient “has to” have a 5 mg/day dose of prednisone along with another specific drug. We have decades of data that make it very clear that dosing of prednisone needs to be titrated and monitored over time to maximize the benefits of this agent and to minimize the risks — especially when this drug is being used for the long term (which was the only point I was making from the beginning).

  9. What About Trials Comparing Combined Zytiga or Xtandi plus an LHRH Agonist or Antagonist versus Bicalutamide plus an LHRH Agonist or Antagonist for mCRPC?

    It is wonderful that we have these powerful new drugs, and it is clear that they do better in combination with testicular testosterone minimization (LHRH agonist/antagonist or orchiectomy) than just an LHRH agonist/antagonist or orchiectomy alone. But how much better are they than combos of bicalutamide, which is a whole lot less expensive, plus testicular testosterone minimization?

    There is at least one trial looking into this. It is run out of the University of Alabama, NCT02058706: “LHRH Analogue Therapy With Enzalutamide or Bicalutamide in Treating Patients With Metastatic Hormone Sensitive Prostate Cancer.” I have looked over the trial details, and it looks like data collection is over and the analysis/reporting phase is under way. Does anyone have any updates or know of similar trials?

    I was unable to find the dose of bicalutamide being used. I would assume that it would be 150 mg per day because the patients are metastatic and that is the dose for metastatic prostate cancer used by some of the doctors whose work I follow. It is also notable that that dose is mentioned favorably in the 2019 NCCN guidelines. However, when the trial was started in May 2014, the usual dose was 50 mg per day, and I doubt the NCCN guidelines would have mentioned a dose of 150 mg. (I was always on the lower dose for my non-metastatic case, but I am convinced the higher dose is more effective for patients who have especially challenging cases, including patients who are metastatic.)

    Thanks, Sitemaster, as always for posting this.

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