The potential of low-dose enzalutamide in intermediate-risk prostate cancer

A case study report in the journal Research and Reports in Urology (which is not exactly a widely read publication) addresses the treatment of an elderly man with low-risk prostate cancer with low-dose enzalutamide as a form of first-line therapy. The full text of this article by Moyad and Sholtz is available on line.

The authors describe the diagnosis and management of a man of 77 years of age who had been diagnosed with intermediate-risk prostate cancer. He is said to be “healthy”, but, like many of us as we age, he did have a history of other disorders, specifically including neuralgia and hypertension. His prostate cancer diagnostic history included:

  • A baseline PSA of 2.9 ng/ml
  • Increases in his PSA to 3.9 and 4.5 ng/ml over an 8-month period
  • An initial, negative 12-core biopsy
  • A further increase in his PSA to 5.1 ng/ml within 12 months
  • Detection of a suspicious lesion on MRI
  • A repeat biopsy, apparently under color Doppler ultrasound guidance, showing three positive biopsy cores of which one included 10 percent cancerous tissue with a Gleason score of 3 + 4 = 7

The patient is described as being “reluctant” to receive either local therapy or active surveillance. As a consequence, he was treated (off label) with a low dose of enzalutamide (at 80 mg/day for 2 weeks and then at 120 mg/day). The outcomes were as follows:

  • Mild hot flashes with minimal insomnia and significant loss of libido,but no breast tenderness; this led to prophylactic treatment with letrozole (2.5 mg every other day).
  • After 2 months on enzlautamide the patient’s PSA was 1.2 ng/ml.
  • After 6 months on enzalutamide,
    • His PSA was undetectable (< 0.1 ng/ml).
    • There was almost complete resolution of the prostate lesion on color Doppler ultrasound and MRI.
  • Enzalutamide and letrozole were stopped after 6 months.
  • At 6 months after cessation of enzalutamide treatment
    • The patient’s PSA was 1.9 ng/ml.
    • His total testosterone was 430 ng/dl.
    • Color Doppler ultrasound images remained the same as during treatment.
    • He reported minimal or no fatigue.
    • No gynecomastia was noted.

The patient now reports less anxiety and fewer concerns about prostate cancer and continues to be monitored every 4 to 6 months.

The authors are very clear to point out that they “in no way advocate the described treatment modality” in the treatment of men with intermediate-risk prostate cancer

However, they do also state that:

We respect the desire of a small number of patients to try a novel and costly therapy despite not being fully aware of the true risk-to-benefit scenario in this specific setting.

They also argue that, based on such data:

a clinical trial to evaluate short-term low-dose treatment using enzalutamide is warranted.

The potential to use a drug like enzalutamide in the treatment of men with low- to intermediate-risk prostate cancer is considerable — particularly for those men who are unwilling or unable to deal with active surveillance or localized, interventional therapies as treatment options. It is not clear (but it is implied) that this patient was able to pay for enzalutamide himself, meaning that the issue of drug cost was not a barrier to treatment in this case.

Whether Medivation and Astellas would be willing to fund a trial of the type proposed by the authors is open to some question. It is by no means clear that the costs of the trial would be covered by the potential return on the investment if payers were to determine (as would certainly be arguable based on the case described) that the patient’s potential long-term survival — with or without treatment of any type — did not actually justify treatment at all.

These are complex questions, and they have major financial implications for all concerned. Most of us couldn’t afford to pay out of our own pockets for about 6 months of treatment with low-dose enzalutamide, at an approximate cost of between $35,000 to $50,000 (depending on the exact dose and the time on treatment), but for those who can afford to do so, this form of treatment certainly appears to provide an option.

3 Responses

  1. Isn’t it interesting that “for those that can afford it” comes into the conversation here? But when it comes to drugs like Provenge that have only been effective at increasing lifespan by 3.5 years, Medicare pays $95 K for it?

  2. Dear Jim:

    (1) Provenge actually increases lifespan by something like 3 months (on average) … not 3.5 years.

    (2) Medicare only covers costs for treatment with Provenge under specific circumstances, just as it only pays for abiraterone and enzalutamide under specific circumstances. CMS is required to make these drugs available to Medicare patients by law according to the FDA approved labeling, and it is unable to negotiate on cost. However, my suspicion is that within the next decade CMS will be able to negotiate with drug companies in the same way that commercial insurers, Tricare, and the VA can (and as NICE can in the UK), and that failure to find appropriate accommodations on cost for specific drugs will mean that these drugs are not going to be available to patients covered under Medicare.


    Thank you Sitemaster! Very timely for me, as I’m preparing a talk on ADT for our group and intend to make some comments on Zytiga and Xtandi.

    I am not surprised that this first report of very early use of enzalutamide (Xtandi) was managed by Dr. Mark Scholz, so well known to many of us ADT veterans for pioneering work on ADT and other drugs, yet also known for his careful scientific approach. (I’m also not suprised that Dr. Mark Moyad has a hand in this; he has done so much to help all of us keep up with the field.) To me and many of us, Dr. Scholz ranks among the foremost experts in ADT, and that gives this report added credibility.

    The Scholz/Strum/Lam and colleagues have also published on the use of traditional ADT drugs for a year as primary therapy, followed by active surveillance, with encouraging results. Their conclusion: “Despite a high prevalence of ≥ 50% core biopsies positive at baseline, AD [Androgen Deprivation, aka ADT aka hormonal therapy] induces durable remissions in most men with low-risk and about half with intermediate-risk PC.” I have the complete paper, and the form of ADT was as follows: “While unconventional, our protocol was standardized to 12 months of therapy with an antiandrogen and LHRH agonist. After completion, a 5-alpha reductase inhibitor [5-ARI] was routinely administered as maintenance.” (This group has also informally reported on use of IADT3 – intermediate triple androgen deprivation therapy with 5-ARI maintenance as both primary and recurrence therapy. My sole therapy, with supporting drugs and lifestyle tactics, was primary IADT3 for my first 13.5 years prior to a shot at curative IMRT last year.)

    As an ADT veteran, I am again impressed with this evidence of the power of Xtandi, which was the sole drug used except for the drug used to counter gynecomastia. I’m impressed that such an encouraging result was seen after just 6 months of treatment. (My impression is there is a consensus of experts that at least 9 months and probably 12 to around 18 months is better for a round of “traditional” IADT3.) I’m a bit curious why the PSA test the team used was not an ultrasensitive test, the kind so often used in the Scholz/Lam practice and in research by this team, including a paper they published demonstrating the value of achieving a nadir of < 0.05 on ADT. The test used for the patient in the subject study apparently had a sensitivity of just < 0.1.

    COST. Regarding cost, there is a much less expensive alternative: a similar approach but with one round of ADT, preferably triple ADT with 5-ARI maintenance, or ADT2 with 5-ARI just as maintenance as described above by the Scholz/Strum/Lam team. I have a hunch the Xtandi approach described in this paper will prove superior, but maybe not that much superior and certainly much more expensive. Dr. Robert Leibowitz has also published formally and informally about such primary ADT3 with finasteride maintenance.

    As for a trial, the former Strum/Scholz team tried to get a trial of ADT3 funded back around 2000 but were unable to find a sponsor. At that time the LHRH-agonist drugs — like Lupron and Zoladex — were quite expensive (more so than now, partly due to price fixing), and so was the antiandrogen of choice, Casodex. Proscar (the 5-ARI drug then available) was not cheap but was much more affordable. I suspect the price of Xtandi may deter sponsorship. I expect that our knowledge of this role for Xtandi will depend on formal and informal papers from special practices like the ones in this paper, which are dedicated solely to a large group of prostate cancer patients, and that our knowledge will not come from definitive Phase III studies after initial Phase I and Phase II work. After the latter course, drug patents often have few years left, and that can discourage sponsor interest.

    I am highly encouraged by this early and successful foray of one of the potent new drugs into the early disease stage scenario! I'm also grateful that the authors chose to make their complete paper freely available online.

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