The randomized, double-blind, Phase III ENZAMET trial was designed to investigate whether the combination of enzalutamide + standard androgen suppression had superior outcomes than a non-steroidal antiandrogen + standard androgen suppression in men with metastatic, hormone-sensitive prostate cancer (mHSPC).
The results of this trial were presented this afternoon at the annual meeting of the American Society for Clinical Oncology (ASCO) in Chicago. They are both positive and difficult to interpret from the perspective of clinical practice. The full results of this trial, as reported by Davis et al., were also just published on line in the New England Journal of Medicine.
The ENZAMET trial enrolled a total of 1,125 men with newly diagnosed mHSPC between March 31, 2014, and March 24, 2017. The patients were randomized to either
- Standard testosterone suppression + enzalutamide or
- Standard testosterone suppression + a non-steroidal antiandrogen (i.e., bicalutamide, nilutanide, or flutamide)
Patients could also receive early treatment with docetaxel, as shown to be effective in patients with high tumor burden in the CHAARTED trial in 2014.
Patients were also stratified to the two arms of this trial based on
- The volume of their disease (high versus low, as specific in the CHAARTED trial)
- Planned use of early docetaxel therapy
- Planned use of early anti-resorptive therapy (to prevent fractures)
- Comorbid conditions
- Study site
The patients were largely enrolled in Australia, England, and Ireland.
Criteria for early reporting were met at the first interim assessment of the study data (on February 28, 2019) after an average (median) follow-up of 33 months.
The estimated effects of treatment at 3 years of follow-up were that:
- Average (median) overall survival (OS) for greater for all patients in the enzalutamide arm
- 79 percent in the enzalutamide arm
- 72 percent in the non-steroidal antiandrogen arm
- Significantly more patients were still on their initially assigned treatment in the enzalutamide arm
- 64 percent of patients in the enzalutamnide arm
- 36 percent of patients in the nonsteroidal antiandrogen arm
- Patients receiving planned pre-treatment with docetaxel did not show a significant OS benefit
- 73 percent in the enzalutamide arm
- 74 percent in the non-steroidal antiandrogen arm
- Serious adverse events within 30 days of study treatment occurred in
- 42 percent of patients in the enzalutamide arm
- 34 percent of patients in the non-steroidal antiandrogen arm
In presenting these data today, Dr. Sweeney and the subsequent commentator, Dr. Dorff, both made the point that interpretation of these data was complex because of the increase in risk for serious side effects in the enzalutamide arm and the fact that patients pre-treated with docetaxel did not seem to benefit greatly from the use of enzalutamide as opposed to treatment with a non-steroidal antiandrogen.
On the other hand, this study is the first to compare the effects of what used to be known as “complete” or “maximal” androgen deprivation to standard testosterone suppression + a super-antiandrogen (enzalutamide). Previous studies with other drugs have compared investigational therapies like enzalutamide and apalutamide only to standard androgen suppression with an orchiectomy or an LHRH agonist.
However, what this study does do is expand the options for treatment for men initially being diagnosed with mHSPC. The most appropriate treatment for any individual patient will be — at least for the time being — a matter for shared decision-making between the individual patient and his doctor(s).
Our options for the initial treatment of mHSPC are liable to continue to expand over the next 5 years. A key issue will be whether we can better define the patients whose outcomes can be improved the most based on genetic/genomic and clinical factors that may allow us to better categorize these patients over time.
Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: antiandrogen, enzalutamide, ENZAMET, hormone-sensitive, metastatic, mHSPC, non-steroidal, overall, survival |
THE "NEW" PROSTATE CANCER INFOLINK 
Correction: They only showed 3-year overall survival (in percent) so far. Median time (months) of survival was not reached in either arm (median follow-up was 34 months). There is a handy chart with the ASCO abstract.
Sitemaster,
The doctor also should be prepared to discuss the relative costs of treatments during the shared decision-making conference. The doctor should have specific estimates in hand (e.g., for 36 months of enzalutamide, the cost of the drug will be about $_____) and advise the patient to consider the relative out of pocket costs before making any final treatment decisions. Or am I wrong about that — cost is not the doctor’s responsibility to explain (which seems to be the case in my experience)? Thank you.
Best regards,
Richard
Thank you for the corrections Allen. They have been duly incorporated above. I shouldn’t try to write these updates in a vast dark hall surrounded by 7,000 other people any more!
Richard:
At least here in the US, the precise cost of any particular medication to an individual patient is always going to depend on the type of insurance that a patient has (and other factors). And so the doctor will usually refer the patient to a nurse administrator who will discuss the costs of specific options with the patient and then work with that patient to secure the best cost for the most appropriate form of treatment.
It is simply not practical for the doctor to be able to spend time having that discussion with the patient. On the other hand, the doctor will be able to tell the patient which forms of treatment should be relatively low-cost because they use generically available drugs and which forms of treatment will be high-cost because they are newer, branded medications.
On top of all of that, the various manufacturers will be offering all sorts of different ways to facilitate coverage for their individual products which can become extremely complex, and most large oncology prac tices now have specialist nurse administrators who will work with individual patients to address all of this.
Richard,
I agree with you in principle. Many doctors brush off such questions as if such matters were beneath them. Imagine buying a car where there was no list price. These drugs are quite expensive — they list for about $12,000 per month (non-negotiated price). A new federal rule requires list prices to be announced on all advertising. There is a growing awareness of “financial toxicity” among doctors — I hope they will get more involved.
Abiraterone, especially when a generic version comes out, or if taken with food, lists for somewhat less (about $9,000-$10,000/mo.) than these newer drugs, and may be equally effective. There is a STAMPEDE trial (UK gov’t sponsored) that will compare it to enzalutamide for mHSPC. However, pharmaceutical manufacturers are usually loathe to sponsor comparative drug trials.
Critical Question: Dose of the non-steroidal antiandrogen (NSAA, especially Casodex) in the ENZAMET trial?
I dearly hope the researchers did not set this up so that they were shooting ducks in a pond, tilting the likely outcome toward enzalutamide. That would be the case if the dose of the NSAA, which is highly likely to have been Casodex/bicalutamide for the vast majority of patients, was only 50 mg. My strong impression after following medical thought for more than 19 years and being on mostly Casodex, 50 mg daily over three rounds over years of IADT3, but for 18 months on flutamide for my last round due to a suspected androgen receptor mutation (ARM), is that a higher dose of 150 mg of Casodex is much more effective than 50 mg for patients who have had metastasis detected. Assuming that impression is true, then patients in this trial who were on Casodex should have been on the 150 mg dose!
The dose of the NSAA is not stated in any of the links. Frankly, I’m disappointed that it was omitted and consider that a significant flaw, but hopefully one that is fixable. I suspect, however, that the lower dose was used because the study details at clinicaltrials.gov, while that link does include the dose for enzalutamide, it does not include doses/regimens for the NSAA drugs, instead simply referring to them as “conventional NSAA.”
If the higher dose of 150 mg for at least Casodex was used, then that would bolster this study as substantial evidence that enzalutamide offered a benefit that was arguably worth the extra cost. (The NSAA drugs are now all generic, and cost has dropped a lot over the years. My wallet was happy about that.)
I am not aware of any study that has looked at 150 mg of Casodex (or arguably appropriate higher doses of either of the other more problematic drugs) vs. enzalutamide for mHSPC patients.
(Thank you very much Sitemaster for your service in attending this conference and selecting these key abstracts for reports!)
Sitemaster and Allen,
Coincidentally, I read an article today published in connection with ASCO 2019 which addresses new ASCO initiatives “focusing on increased physician-patient dialogue [and] informed patient decision-making” with respect to the cost of cancer treatments. The article states, in part, that “ASCO believes that physicians have a responsibility to both patients and society to be effective stewards of healthcare resources”, and one of ASCO’s goals for informed patient decision-making is “[P]atients will have more immediate access to both clinical and cost information when choosing a treatment algorithm with their physician.” I support this goal.
Best regards,
Richard
Dear Richard:
No one is arguing with the fact that every oncology practice should have well-designed systems to ensure that patients are fully informed about the costs of differing treatment options for specific forms of cancer. However, when ASCO says that “[P]atients will have more immediate access to both clinical and cost information when choosing a treatment algorithm with their physician,” they do not mean that all of that discussion will be with the actual physician. They mean that the physician will make sure that the patient is fully informed about and helped to deal with these issues by that physician and other staff in his or her practice.
If we were to require physicians themselves to be the people having detailed discussions about every possible financial option related to their care, then in oncology most physicians would probably only be able to see a couple of new patients a day. These conversations can take several hours. The paperwork that needs to get completed is complex for many patients whose insurance options are probably a great deal less generous that yours, and in any case the physicians are simply not trained to be able to explain all of the details for the hundreds of different drugs that are now available, and which can have very different systems for reimbursement, depending on a multitude of variables.
Just as it is not the physician who is going to actually administer your infusion of docetaxel, in most cases it is not going to be the physician who sits down with a patient for 2 hours to try to work out whether a specific patient who is ideally going to get treated with drug X (as agreed between the physician and the patient) is going to be able to get drug X paid for by their insurer for the treatment of cancer type Y. It is going to be someone who has specialized in helping patients to navigate the increasingly complex world of treatment cost coverage in this country.
Dear Jim:
I suggest you get yourself a copy of the paper from the New England Journal of Medicine, where I am sure that the actual dosing regimens for the NSAAs will have been included. This was not, for most patients, a US-based trial. However, as far as I am aware, 150 mg dosing of bicalutamide (Casodex) has never been approved in any country in combination with any form of standard testosterone suppression (an orchiectomy or an LHRH agonist). It’s use in the 150 mg formulation has only ever been approved as monotherapy (whatever you may think about that personally).
Thus, my bet is that when bicalutamide was used in this trial, it would have been used at the 50 mg/d dose, which would also have corresponded to standard forms of dosing with flutamide or nilutamide. Even if the trialist had wanted to do this, I suspect that a trial that used 150 mg doses of bicalutamide would not have been acceptable to regulatory authorities. You will remember that the FDA refused to approve dosing of bicalutamide even as monotherapy because they felt the benefit was insufficient to counterbalance the risk of some fairly significant side effects for most patients.
Re bicalutamide (Casodex) at 150 mg dose – European approval, favorable mention in the current NCCN guidelines – building on my comment of 6/4 12:49 pm and Sitemaster response of 6/5 11:38 pm
Thank you as always Sitemaster for your response during this extremely busy time for you. I am trying to get that full article you linked in the NEJM.
My impression of non-approval status for the 150 mg dose in the US was the same as yours (which I just confirmed), though I had heard that Europe had approved that dose, which at least this source confirms. However, I thought I’d recalled that the 150 mg dose had been mentioned favorably in the 2019 update of the NCCN guidelines, and indeed it has been, not that that constitutes “approval.”
I just checked the NCCN physician guidelines on treatment of prostate cancer at with a search for bicalutamide. (I am not a professional/physician but a survivor.) (Adding 150 mg before or after, and searching for Casodex, did not yield comprehensive results.) There were three favorable occurrences (text, excluding updates) to bicalutamide at the 150 mg dose, including two in combination with radiation after post-prostatectomy recurrence and one with 150 mg as monotherapy. There were at least a couple of occurrences regarding the inferiority of bicalutamide at 50 mg to enzalutamide at 160 mg (STRIVE and TERRAIN trials). I could provide specific references, but the search goes fast as there is just a handful of results.
I’m not sure what to make of what I believe is an update, probably in recent years, in the NCCN guidelines that is now favorable to use of bicalutamide at a dose of 150 mg. I’m not sure how this relates to a possible “approval” versus possibly growing enthusiasm for off-label use at the 150 mg dose; obviously the NCCN favorable mentions do not constitute formal FDA approval of bicalutamide at 150 mg for specific indications. In fact, the FDA is blunt about non-approval at that dose.
However, more than one of the doctors whose publications I follow uses the drug at that dose. For example, in his book (with 29 others) The Key to Prostate Cancer, Mark Scholz, MD, in a section he wrote that is headed “Using Milder Therapy in Older Men” (see p. 332), states that:
“One common maneuver for reducing side effects from hormonal therapy is to substitute Casodex for Lupron. Casodex is about two-thirds as effective as Lupron but with one-third the side effects. In higher doses (three pills per day [i.e., 150 mg]), Casodex is almost as effective as Lupron.”
Elsewhere he refers to the higher dose in support of radiation therapy that was picked up in the NCCN guidelines.
The documented success of bicalutamide at a dose of 150 mg, as indicated in the NCCN guideline text and associated trial references, does suggest, to me at least, that a trial of enzalutamide vs. bicalutamide at 150 mg/day is needed.
If you have time, your thoughts?
Dose of the non-steroidal antiandrogen (NSAA, especially Casodex) in the ENZAMET trial – confirmation that dose of Casodex was 50 mg
This is a follow up to the exchange involving my initial comment of June 4, 2019 at 12:49 pm, Sitemaster’s response of June 5, 2019 at 11:38 am, and my response to Sitemaster of June 5, 2019 at 3:45 pm.
I obtained the paper, but the dose of the non-steroidal anti-androgen, which would primarily have been Casodex, as previously discussed, was not stated anywhere in the paper.
I contacted lead author Dr. Ian Davis, and here is his response: “We only used the 50 mg dose of bicalutamide and not the 150 mg dose (which is more commonly used in Europe and without other treatment).”
This confirms the concern expressed in the initial comment: the higher dose of Casodex, 150 mg, was not tested against enzalutamide, which leaves open the possibility that far less costly Casodex might be much more effective than the Casodex used in the trial at the 50 mg dose.
Dear Jim:
I repeat my criticism of your comments on this issue. The long-term use of 150 mg of bicalutanide (alone or in combination with an orchiectomy or an LHRH agonist) is not a “standard” form of androgen suppression, and the whole premise of the ENZAMET trial was that it would compare “standard” testosterone suppression + a placebo to “standard” testosterone suppression + enzalutamide.
If you wanted to argue that bicalutamide monotherapy at daily 150 mg dose was equivalent to known “standard” forms of testosterone suppression, then we would need large clinical trials to prove that. Such trials have never been carried out. The same would be true if you wanted to suggest that using an orchiectomy or an LHRH agonist + a 150 mg daily dose of bicalutamide should be a “standard’ forms of testosterone suppression.
This doesn’t mean that one cannot use 150 mg daily dosing of bicalutamide appropriately in some patients, but such a dose does significantly impact the side effects associated with bicalutamide, and — as indicated earlier — it is not approved for use at this dose level in the USA.
Trial of Enzalutamide vs. Bicalutamide at 150 mg Needed/Unlikely; Financial Toxicity’s Role
I agree with all points in your response to me of 11:12, and thank you for your thoughts and summary.
I doubt we will ever see that trial of enzalutamide/Xtandi at 160 mg vs. bicalutamide at 150 mg, the latter probably dosed early, at mid-day, and at bedtime, but such a trial would be relevant to many survivors of metastatic prostate cancer because of the high cost of Xtandi, which is simply not affordable to those without adequate insurance unless they are covered under the company’s compassionate use program. The high cost of Xtandi, like the high cost of other wonderful, modern drugs, is also a drain on the resources of Medicare and our insurers, which we pay for, of course, via higher premiums.
Jim:
I give up. We are talking about two utterly different issues.
If you want to see a head to head trial of bicalutamide ALONE at a dose of 150 mg/d vs enzalutamide ALONE at a dose of 160 mg/d in men with ADT-naive prostate cancer, that’s fine. They might be willing to consider that in Europe, but that has nothing whatsoever to do with the ENZAMET trial, which was testing a completely different hypothesis.
Dear Jim:
There are dozens of different trials that I would like to see done. However, trials like this are extremely expensive (probably at least US$5 million or more). There is no motivation for Pfizer and Astellas to conduct a trial of bicalutamide monotherapy at a dose of 150 mg a day vs. enzlautamide monotherapy at a dose of 160 mg a day. Since Pfizer and Astellas aren’t going to do this trial, and the percentage of patients being treated currently with bicalutamide at 150 mg/day (off label in the USA and on label in Europe) is small, I don’t have a clue who else would be willing to pay for such a trial.
The “endorsement” of the 150 mg dose of bicalutamide in the NCCN guidelines merely indicates that it is one of many possible ways to treat some patients. It is not exactly a “recommendation” for any well-defined set of patients.