Enzalutamide shows positive outcome in TERRAIN trial

A media release issued today by Medivation and Astellas Pharma, based on data presented at the European Association of Urology meeting in Madrid, Spain, states that enzalutamide appears to extend progression-free survival (PFS) better than bicalutamide in the randomized, Phase II TERRAIN trial.

The TERRAIN trial enrolled 375 patients in North America and Europe. It was designed to compare the effects  of adding either enzalutamide (160 mg once daily) or bicalutamide (50 mg once daily) to the treatment regimen of men with metastatic, castration-resistant prostate cancer whose disease was progressing on treatment with an LHRH agonist alone.

According to the companies’ media release:

  • The study achieved its primary objective of a statistically significant increase of 9.9 months in PFS for enzalutamide compared to bicalutamide.
    • The median PFS in the enzalutamide arm was 15.7 months.
    • The median PFS in the bicalutamide arm was 5.8 months.
    • The hazard ratio (HR) = 0.44.
  • The median time to PSA progression was 13.6 months longer with enzalutamide (19.4 months) relative to bicalutamide treatment.
    • 19.4 months for the enzalutamide arm.
    • 5.8 months for the bicalutamide arm
    • HR = 0.28
  • The median time on enzalutamide treatment was 11.7 months compared to 5.8 months on bicalutamide.
  • Serious adverse events were reported in
    • 31.1 percent of patients treated with enzalutamide
    • 23.3 percent of patients treated with bicalutamide
  • Grade 3 or higher cardiac AEs were observed in
    • 5.5 percent of patients treated with enzalutamide
    • 2.1 percent of patients treated with bicalutamide
  • Seizures were reported in two patients treated with enzalutamide and one patient treated with bicalutamide.
  • Common AEs reported more frequently with enzalutamide compared to bicalutamide were
    • Fatigue (27.9 vs. 20.1 percent)
    • Back pain (19.1 vs. 18.0 percent)
    • Hot flushes (14.8 vs. 11.1 percent)
    • Hypertension (14.2 vs. 7.4 percent)
    • Diarrhea (11.5 vs. 9.0 percent)
    • Weight decrease (10.9 vs. 7.9 percent)
    • Pain in extremities (10.9 vs. 5.3 percent)

According to the media release:

The safety profile of the enzalutamide-treated patients in TERRAIN is consistent with the known safety profile of enzalutamide.

Dr. Axel Heidenreich of the Depratment of Urology, University Hospital, Aachen, Germany is quoted as stating that

The results of the TERRAIN trial, if confirmed, have the potential to impact the treatment landscape of metastatic castration-resistant prostate cancer. The study demonstrated an improvement with enzalutamide over the standard practice of the addition of bicalutamide to a luteinizing hormone-releasing hormone therapy.

6 Responses

  1. I see that the trial used the recommended daily dose of enzalutamide (160 mg), but not the usual monotherapy dose of bicalutamide (150 mg). Do you think the trial was a valid apples to apples comparison of the effectiveness of both drugs, especially considering enzalutamide costs about $9,000/month and bicalutamide costs about $50/month? Thanks. Richard

  2. It’s good to see this additional evidence for the success of enzalutamide.

    I am struck once again by the sharp difference in treatment approaches between the doctors I follow and much of the rest of the oncology world. For men with metastatic disease, the doctors I follow would in the past have given a dose of 150 mg of bicalutamide, and that would have been on top of an LHRH agonist and very likely also a 5-ARI drug, most likely Avodart, as well as supporting drugs as considered appropriate (for bone density protection, a statin, metformin, etc.). I was always on just 50 mg as I never had detectable metastatic disease. Because of the dosage effect, it is too bad more arms of study were not included with at least one getting a dose of 150 mg of bicalutamide. At least one well-known oncologist used to use even higher doses when needed to get the desired response, under careful monitoring. Now, however, my impression is that these doctors are moving to degarelix as the agent to limit testosterone and combining it with other appropriate drugs.

  3. Dear Richard:

    (1) 50 mg/day (not 150 mg/day) is the standard dose of bicalutamide when used in combination with an LHRH agonist. Higher doses of bicalutamide (e.g., 150 mg/day) have been approved in Europe, but not in America, when bicalutamide is used as a single agent. In this trial the drug was not being used as a single agent. So from a scientific point of view, yes, I do beleive that this was a trial in which apples were being compared to apples.

    (2) The cost issue is a whole different matter. The “New” Prostate Cancer InfoLink is not in the business of telling individual people what individual treatments are “worth” to them. On the other hand, we are quite convinced that the increasing costs of health care are unsustainable and that that is something we should all be concerned about.

  4. Dear Jim:

    I am not aware of any data demonstrating that the use of a dose of 150 mg/day of bicalutamide in combination with an LHRH agonist is associated with any type of survival benefit in the management of metastatic prostate cancer. I acknowledge that such a dose level may be helpful in managing the patient’s PSA level, but that is not a clinically significant endpoint.

  5. A Klotz study using 150 mg/day of bicalutamide in combined therapy

    I too am not aware of any published peer reviewed paper of a conclusively proven survival advantage, and strongly suspect there is none. On the other hand, I strongly expect that a solid connection between PSA control and survival for many (not all) metastatic patients will one day be published.

    Regarding research on use of a dose of 150 mg for bicalutamide in combined therapy with an LHRH-agonist, I was not aware of published evidence either, but I just found this 2013 paper. It’s a small Phase II trial by Klotz and colleagues on escalating the dose of bicalutamide from 50 mg to 150 mg for men who had become resistant (CRPC) at the initial dose in a combined therapy (LHRH agonist plus bicalutamide) setting. Here’s the key line from the results section of the abstract: “Among 59 evaluable ITT [intention to treat] patients, 13 (22%) patients had a >50% PSA decline, 5 (8%) had a decline between 10 and 50%, 4 (7%) had stabilization and 37 (63%) had PSA progression. The median duration was 3.7 months (95% confidence interval of 0.92-6.21 months).”

    That’s maybe not a home run, but at least a single or double. One doctor whose name is often mentioned here (and not Dr. Klotz) would likely treat the non-responders or patients who relapsed after initial success with a further boost in dose to 200 or 250, carefully monitoring for response and intolerable toxicity. This doctor is known for special talent including substantial pharmacology experience and research, and such intervention — obviously well beyond approved guidelines — would probably be unwise for less expert physicians.

    I’m hopeful the Klotz team will follow-up with a larger, Phase III type trial, though even better therapies, such as using degarelix instead of an LHRH agonist, may crowd out such research. (What an exciting era for prostate cancer research!)

  6. Dear Jim:

    I think it is extraordinarily unlikely that anyone would even consider a Phase III trial of the type you are suggesting. Managing PSA levels is not a meaningful endpoint in the management of prostate cancer, and the data from the Phase II trial wouldn’t be good enough to justify such a trial. You’d have to have seen more like 90% of the patients in the Phase II trial demonstrate a 50% drop in their PSA level. And in any case, bicalutamide is now generically available, so there is no potential benefit commercially for conducting such a trial.

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