What to do with a man with M0 or M1 disease who is progressing on treatment

Is the addition of enzalutamide (Xtandi) to an LHRH agonist now the appropriate standard of care for a man with M0 or M1 prostate cancer who starts to progress on treatment with an LHRH agonist alone? And should an antiandrogen be replaced by enzalutamide in men with Mo or M1 disease who are progressing on combined androgen deprivation with an LHRH agonist and and antiandrogen (e.g., bicalutamide)?

An article yesterday on the MedPage Today web site suggests these possibilities, but The “New” Prostate Cancer InfoLink would urge a little caution before we come to such conclusions, so let’s review what we actually do know.

It is clear from published data from the STRIVE and the TERRAIN trials (see below) that when men with Mo and M1 prostate cancer start to progress (and therefore start to become castration resistant) while on treatment with an LHRH agonist or orchiectomy alone, they do better in terms of progression-free survival (PFS) if they are treated with the addition of enzalutamide than they do if they are treated with the addition of the antiandrogen bicalutamide. Indeed, the improvement in PFS from adding enzalutamide is some two to three times better on enzalutamide than that seen from the addition of bicalutamide. So there is certainly a strong argument that there is a role for enzalutamide in this setting. However, …

  • Enzalutamide is not an appropriate form of therapy for any patient with a history of seizures (and such patients were specifically excluded from both these trials).
  • We do not yet know whether
    • The use enzalutamide instead of bicalutamide in such a setting has a true survival benefit
    • The use of bicalutamide first and then replacement with enzalutamide on a second progression (i.e., using the drugs sequentially) might have similar or better effects
    • The use of abiraterone acetate instead of bicalutamide or enzaluatmide might be at least as good an option
    • The use of bicalutamide first and then replacement with abiraterone acetate on a second progression (i.e., using these drugs sequentially) might have similar or better effects

As noted in the MedPage Today article (in a statement by Dr. David Penson, the lead author of the article on the STRIVE trial):

There is an ongoing phase III study of enzalutamide versus placebo in M0 patients, which if positive, would provide definitive proof of this agent in this space.

This trial is the PROSPER trial, which is currently enrolling about 1,560 patients and is expected to report results some time in 2019. The primary endpoint for the PROSPER trial will be metastasis-free survival (with overall survival as a secondary endpoint). But the trial is actually comparing the addition of enzalutamide to an LHRH agonist as opposed to the addition of a placebo, so it is arguable that the results of this study may be a foregone conclusion!

What is not being tested in any trial that we are aware of is the possibility of finding the best way to treat men who are progressing on an LHRH agonist alone or on an LHRH agonist + an antiandrogen. One reason for this is that there are multiple complex possibilities and it may not be in the interests of any of the drug manufacturers to identify that “best” solution. Why? Because it might severely limit the use of their particular drug if it got an unexpected result.

So while we congratulate Medivation and its partner Astellas for investing heavily in trying to learn whether the early use of enzalutamide has the potential for beneficial effects on progression-free and overall survival in not only metastatic and micrometastatic patients but also in high-risk patients progressing after first-line treatment (the EMBARK trial), we are also very realistic in our appreciation of what is not being learned along the way (which might have profound effects on the costs of treatment for men with progressive M0 and M1 disease).

Let us remember that bicalutamide is now a relatively cheap, generic drug. Abiraterone acetate (Zytiga) will also be a generic drug in the reasonably near future, and the cost of treatment with this product can also be expected to drop significantly. By comparison, enzalutamide has a long, future patent life. It costs about $70,000 a year for a course of treatment, and so 5 years on treatment with enzalutamide will cost some $350,000 (even if the price stays stable). At that price, in our opinion, patients deserve to know whether they are really getting the best form of care that is available. Most patients (including those on Medicare) will be paying a significant chunk of that $350,000 out of their own pockets, not to mention the impact on the Medicare budget (which we are all paying for in taxes).

We should also note that the side effect profile associated with treatment with enzalutamide appears to be at least slightly higher in risk that that associated with treatment with bicalutamide (see below).

To provide a quick summary of the published data from the STRIVE and the TERRAIN trials, these were both randomized, Phase II studies.

The STRIVE trial enrolled 396 men with either non-metasatic Mo disease (n = 139) or metastatic M1 disease (n = 257) who were progressing on an LHRH agonist. The patients were randomized to the addition of either enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Treatment with the LHRH agonist was continued in both arms. Penson et al. report that

  • Enzalutamide reduced the risk of progression or death by 76 percent compared with bicalutamide (hazard ratio [HR] = 0.24; P < 0.001).
  • Average (median) PFS was
    • 19.4 months with enzalutamide
    • 5.7 months with bicalutamide.
  • Compared to treatment with bicalutamide, treatment with enzalutamide resulted in significant improvements in
    • Time to PSA progression (HR = 0.19; P < 0.001)
    • Proportion of patients with a ≥ 50 percent PSA response (81 percent vs 31 percent; P < 0.001)
    • Radiographic PFS in metastatic patients (HR = 0.32; P < 0.001)
  • Beneficial effects from treatmnent with enzalutamide were observed in both non-metastatic and metastatic subgroups.
  • The observed adverse event profile was consistent with that from phase III trial of enzalutamide.
    • Serious, grade 3+, and fatal adverse events occurred in a similar proportion of patients in each group.
    • Fatigue, back pain, hot flushes, falls, hypertension, dizziness, and decreased appetite occurred more often (≥ 2 percent difference) with enzalutamide.
    • Constipation, diarrhea, anemia, and urinary tract infections were more common with bicalutamide.

The TERRAIN trial enrolled 375 men with M1 that had progressed on upfront ADT (with either a bilateral orchiectomy or LHRH agonist treatment). Patients were randomized to enzalutamide (n = 191) or bicalutamide (n = 184) and continued treatment until further progression. The primary endpoint was PFS. Shore et al. report that:

  • Median follow-up was 20.0 months in the enzalutamide arm and 16.7 months in the bicalutamide arm.
  • Enzalutamide reduced the risk of progression or death by 56 percent compared with bicalutamide (hazard ratio [HR] = 0.44; P < 0.0001).
  • Average (median) PFS was
    • 15.7 months with enzalutamide
    • 5.8 months with bicalutamide
  • Adverse events (all grades) that occurred more often with one drug than the other were
    • Fatigue (28 vs. 20 percent), back pain (19 vs. 18 percent), and hot flushes (15 vs. 11 percent) in the enzalutamide group
    • Nausea (17 vs. 14 percent) and arthralgia (16 vs. 10 percent) in the bicalutamide group
  • The most common grade 3+ adverse events (occurring in 3 percent or more of patients) were
    • Hypertension (7 percent), back pain (3 percent), pathological fracture (3 percent), and myocardial infarction (3 percent) in the enzalutamide group
    • Hypertension (4 percent) and hydronephrosis (4 percent),
  • Serious adverse events were reported by
    • 57/183 patients (31 percent) in the enzalutamide group
    • 44/189 patients (23 percent) in the bicalutamide group
  • Of the 12 deaths reported from all causes during the course of the trial
    • 1/9 deaths in the enzalutamide group (11 percent) was thought to be possibly related to treatment (due to systemic inflammatory response syndrome).
    • 0/3 deaths in the bicalutamide group (0 percent) were thought to be possibly related to treatment.

10 Responses

  1. Another very expensive possibility is the simultaneous use of both Xtandi and Zytiga. While they are both hormonal therapies, they have very different modes of actions, which may turn out to be complementary. There is a major Phase III randomized clinical trial for men with mCRPC (NCT01949337). A Phase II trial (60 men, without randomization) at M. D. Anderson (NCT01650194) was scheduled to complete last month, so we should see some results soon.

    Then we have newer hormonal agents, in test now, which may turn out to be still more effective in delaying progression, like ARN 509 or VT-464. How will we know which, if any, of these newer agents are most effective unless the trials are head-to-head, which they rarely are? And what about older medications like ketoconazole or estrogen patches? Ketoconazole, at a cost of less than $200/month, has a similar mode of action to Zytiga, but they have never been compared in a randomized trial, to my knowledge. Newer doesn’t always mean better, but it almost always means more expensive.

  2. Did the patients on these studies have their testosterone levels checked prior to entering the trial? One would expect that patients whose testosterone was not completely suppressed by the LHRH agonist could have a beneficial effect to bicalutamide as opposed to those with an unmeasurable testosterone.

  3. Richard:

    I can’t answer that question for you. I have only seen the abstracts of the papers, not the full text.

  4. I looked at the clinical trial specs. STRIVE (NCT01664923) had a requirement of “Serum testosterone level ≤ 50 ng/dL (1.73 nmol/L) at the Screening visit.” TERRAIN (NCT01288911) only required chemical or surgical castration. Perhaps the full texts include subgroup analyses.

  5. The elephant in the room, to which I think our Sitemaster may have been alluding, is whether early chemo trumps the lot — at least for men with M1 disease. I believe the CHAARTED and STAMPEDE results suggest that chemo prior to enzalutamide for men with M1 disease is optimal sequencing from what we know today.

    Am I missing something?

  6. Actually Rick, no. That wasn’t what I was referring to. That is, however, just one more in a long list of unanswered questions.

  7. You correctly state that the use of bicalutamide first and then replacement with enzalutamide on a second progression might have similar or better effects. Couldn’t this be determined with a retrospective pooled data analysis, since this has been the traditional treatment protocol for quite a few years now? This should have been the obvious third arm of these trials but I assume this was not done because Astellas had nothing to gain by doing this. It’s sad that money trumps truth and good clinical practice in so many trials.

  8. Dear Len:

    The sort of retrospective data analysis you envision can actually be extremely misleading for all sorts of reasons. The only accurate way to assess the relative merits of the two approaches is through a prospective, randomized trial in a well defined set of patients.

  9. Both the STRIVE and TERRAIN trials administered bicalutamide at 50 mg/d. Correct me if I am wrong, but I seem to recall that higher dose (e.g., 150 mg/d) of bicalutamide has been shown (or at least is suspected) to give better response than 50 mg/d. By that standard both these trials are tipping the scale in favor of enzalutamide. If I were going on bicalutamide in this setting, I would certainly want to be getting the higher dose.

  10. Dear Tom:

    Your argument is not an unreasonable one, but there are a number of things you need to bear in mind:

    (a) The data that led to the approval of bicalutamide at a dose of 150 mg/d in Europe was based on treatment of high-risk patients after first-line therapy and prior to any treatment with an LHRH agonist (i.e., not the same patients as were treated in the STRIVE and the TERRAIN trials).

    (b) Bicalutamide at a dose of 150 mg/d has never been approved here in America for any indication because the FDA and its advisory board felt that the risk for side effects was excessive, and so

    (c) Here in America the 50 mg/d dose is the accepted standard dose for bicalutamide (although some doctors will prescribe it at higher dose level for selected patients, and some payers will cover the costs associated with the higher dose for those patients).

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