Enzalutamide monotherapy in hormone-naive prostate cancer: early data

A currently unanswered question being addressed in clinical trials is whether the oral agent enzalutamide (Xtandi) is effective and safe as monotherapy in the treatment of progressive, hormone-naive prostate cancer (i.e., before the use of other drugs such as the LHRH agonists and other forms of androgen deprivation therapy [ADT]).

We won’t have a clear answer to this question for some years — until we are able to evaluate the outcomes of the EMBARK trial in about 2020. However, we do now have some data from a small, open-label, Phase II study of enzalutamide monotherapy in 67 men with hormone-naive prostate cancer. Tombal et al. have now reported the data from this study in European Urology.

Patients enrolled in this trial were all hormone naive, had a non-castrate testosterone level of at least 230 ng/dl and were treated for up to 2 years with enzalutamide monotherapy (at a dose of 160 mg/day) — until either disease progression or unacceptable levels of toxicity were reached. The primary study endpoint was a decline in the patient’s PSA level of ≥ 80 percent from baseline (at 49 weeks and 97 weeks on study).

Here are the study results:

  • The average (median) age of the patients was 73 years (range, 48 to 86 years).
  • 26/67 patients (39 percent) had metastatic disease at the time of study entry.
  • Of 67 patients initially enrolled
    • 22 (33 percent) had dropped out prior to week 97.
    • 45 (67 percent) remained on enzalutamide at week 97.
  • Among the 45 patients remaining on therapy at week 97, 45 (100 percent) had a PSA level at least 80 percent lower than their baseline level.
  • Among the 26 patients with metastases at baseline,
    • 13 (50 percent) still had a PSA level at least 80 percent below baseline at week 97 on treatment.
    • 4 (15 percent) had had a partial response to enzalutamide.
  • There was overall maintenance of total-body bone mineral density (BMD) and moderate changes in lean and fat body mass at 49 and 97 weeks.
  • The most common adverse events were gynecomastia, nipple pain, fatigue, and hot flushes.

Whether these relatively short-term outcomes will translate into a real clinical benefit that can be demonstrated in the EMBARK trial is obviously impossible to say. They suggest a possibility but it is hard to interpret the current data with a high level of confidence. The other, related but unanswered questions at this time are:

  • Whether men treated with this type of enzalutamide monotherapy will benefit later from second-line or add-on use of LHRH agonist therapy when patients progress on enzalutamide monotherapy?
  • Whether that benefit will be purely palliative or whether there is any possibility of a survival benefit from second-line or add-on use of LHRH agonist therapy, and if so in which specific subsets of patients?

2 Responses

  1. If anyone is interested, the full text of the Tombal paper is available online.

    Table 2 in the paper gives interesting details about the outcomes. In particular, the men who entered with metastatic disease fared even better than stated in the above summary: 19 of these men (73%) remained on treatment at the end of 2 years, and at that time all 19 of them were seeing PSA levels at least 90% below the pre-treatment level.

    Seeing these results, I can’t help but wonder: Is is possible that Xtandi monotherapy is superior, in terms of PSA response, objective tumor response, and side effects, to Lupron monotherapy? The EMBARK trial should answer this question, but 2020 seems a long time to wait.

  2. Dear Tom:

    It is inevitable that the EMBARK trial is going to take a while to show meaningful results. It takes time to enroll 1,860 men like this with high-risk, non-metastatic disease and then monitor them until about half of them show clear signs of metastasis — even if they are only getting treatment with an LHRH agonist.

    I would note that actually the design of this trial has been carefully constructed by Medivation/Astellas to minimize the time it will take to get a result by limiting trial enrollment to men at high risk for progression. I am sure that the companies are as interested as you are in getting the result of this trial as soon as they can — although I am equally sure that they have an additional motivation to the ones that you have! A significant positive result favoring enzalutamide/Xtandi monotherapy would change treatment paradigms for tens of thousands of men with high-risk disease.

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