What is “bipolar” androgen deprivation therapy?


A report just published in Science Translational Medicine describes a new mode of treatment for men with metastatic, castration-resistant prostate cancer (mCRPC) which the authors have called “bipolar” androgen deprivation therapy (BAT). The research is also discussed in relatively non-technical terms in articles on the Bloomberg and the HealthDay web sites.

The vast majority of readers of this site will already understand that, in time, all men with advanced prostate cancer (unless they die of other causes first) will become refractory to  primary and secondary forms of androgen deprivation therapy (ADT) — including orchiectomy, LHRH agonists and antagonists, and antiandrogens — and to the newer, targeted drugs like abiraterone and enzalutamide.

Schweizer et al. have now reported very early, pilot data from a 16-patient study suggesting a very different way to treat at least some of these men.

Basically, what they report is that — by cycling men rapidly on and off high levels of testosterone — they were able to induce significant responses in about half the patients they treated.

The way this was done was as follows:

  • They selected 16 patients who were showing no symptoms of advanced prostate cancer (i.e., no pain, etc.) but who, in fact, had metastatic, castration-resistant disease (with a low to moderate level of metastasis).
  • They initiated treatment of these men by stopping their ADT and treating them with both intramuscular injections of testosterone (testosterone cypionate 400 mg i.m., on day 1 of a 28-day cycle) and oral etopside, a form of chemotherapy (100 mg/day; on days 1 to 14 of the 28-day cycle).
  • Patients were maintained on this form of therapy for three cycles.
  • After three cycles, the men with a declining PSA level continued on intermittent testosterone monotherapy, but …
  • They were re-started on standard castrating therapy (ADT) to suppress endogenous testosterone production.

The consequence was that men were being cycled rapidly from being on very high (“supraphysiologic”) to very low (near to castrate) levels of testosterone, and it is this that the authors describe as “biopolar” ADT or BAT.

The paper lists the following results:

  • BAT was relatively well tolerated (but see below).
  • 7/14 evaluable patients exhibited significant PSA reponses.
  • 5/10 evaluable patients exhibited significant radiographic responses.
    • Radiographic evidence of metastasis disappeared in 1/10 patients.
  • 10/10 eligible patients exhibited PSA reductions when treated with androgen-ablative therapies after BAT (suggesting that BAT may also restore sensitivity to ADT).
  • All patients eventually exhibited PSA progression, but 4/16 men remained on BAT for ≥ 1 year.
  • 3/16 patients have died since the study was started in 2010.

Now there are evident risks associated with this treatment:

  • One patient died from pneumonia associated with the etopside chemotherapy.
  • A second patient withdrew from the trial after a prolonged erection that may have been a consequence of supraphysiologic levels of  testosterone.

And there are other things that we must be clear about:

  • This type of treatment is absolutely not curative.
  • It has not been shown to extend survival.
  • It is not ready for “prime time”; additional studies need to be carried out before patients should be offered such treatment outside of a clinical trial.
  • It is not currently viewed as an appropriate form of treatment for men who are not both metastatic and castration-resistant.

On the other hand, one of the study authors is quoted as follows in the HealthDay report:

For the most part, men said they felt great. Most of the men felt like they had more energy. Men on hormone treatment who couldn’t have sex could have sex again, so they were very happy about that.

In other words, many of the patients did feel that there was a very real impact on their quality of life.

A second study of BAT in mCRPC is currently ongoing and enrolling 60 patients at Johns Hopkins; another, larger, nationwide trial is in planning stages. It is hoped that this larger study will start to enroll about 180 patients relatively early in 2015.

11 Responses

  1. A good read, but should be old news to the informed reader. Morgenthaler reported on this effect more than 5 years ago. He called it Intermittent ADT.

    https://prostatecancerinfolink.net/2009/02/06/testosterone-therapy-for-men-with-prostate-cancer-is-it-good-science-and-good-medicine/

  2. Dear Thomas:

    With all due respect, Morgenthaler reported an effect seen in some men (and not, largely, in men with mCRPC). This is about trials to prove whether a very specific form of testosterone cycling really has benefits in progressive, late stage prostate cancer, and “intermittent ADT” is a very different animal.

  3. I am mCRPC and am definitely interested.

  4. “BECOMING REFRACTORY IN TIME” MAY WELL TAKE A VERY LONG TIME

    Just clarifying here that primary ADT in advanced patients often works for many, many years. This piece states above that “… in time, all men with advanced prostate cancer (unless they die of other causes first) will become refractory to primary and secondary forms of androgen deprivation therapy (ADT) — including orchiectomy, LHRH agonists and antagonists, and antiandrogens — and to the newer, targeted drugs like abiraterone and enzalutamide.” As a long-time patient with advanced prostate cancer on intermittent triple ADT, I have followed this issue closely. My own belief is that single-agent ADT (including orchiectomy) does not work for very long, that combined control of testosterone and blocking of the androgen receptor (with an antiandrogen) works much better, and that triple ADT (adding either finasteride or Avodart in the 5-alpha reductase inhibitor role) is substantially superior to two agent (combined ADT). There is some research, mainly by Dr. Mark Scholz, MD, and colleagues, that supports this view. My own experience, despite a challenging start with prostate cancer, was that ADT was still working at the 14-year point. Dr. David Crawford has found that for a small percentage of advanced patients ADT worked for more than 20 years, and I believe that was combined, not triple, ADT.

  5. Though we would hope that further and larger trials support the conclusions of this paper, I see it important to pay attention to these remarks noted in this paper:

    “Moreover, the long-term effects or dangers of the therapy aren’t yet known, he said. Only longer, larger trials will help uncover any risks associated with the treatment.”

    And one expert worries that alternating testosterone levels could actually shorten men’s lives.

    “A cancer cell could escape and grow, as happened in breast cancer when this method was tried with estrogen, causing early death,” said Dr. Anthony D’Amico, chief of radiation oncology at Brigham and Women’s Hospital in Boston.

    D’Amico agreed with the study authors that bipolar androgen therapyis not ready to be used in clinical practice and doctors should wait for the results of ongoing trials before offering it to men.

  6. Dear Jim:

    We know that there are at least 25 genetically different subtypes of prostate cancer. We know that there is vast individual variation in patients’ responses to ADT (of all types). My strong sense is that the responsiveness of prostate cancer (in general) to different types of ADT may well be a function of the prostate cancer subtype and the immunogenic function of the individual patient. We know very little about this as yet. However, I am certainly also aware of patients who (like you) have had very good long-term responses to nearly every known type of ADT. The issue of whether single, combined, or triple ADT is necessarily “better” for all subtypes of prostate cancer is utterly unknown at this time. Is there an argument that triple ADT may be more helpful for some patients? Absolutely there is. Are there data to suggest that triple ADT is necessarily “better” for all patients? If there are such data, I haven’t seen them.

  7. Excellent post and good follow-up discussions. The issue of genetic subtypes of prostate (and other) cancers is crucial. Hopefully progress, albeit slowly, will continue to aid in “customized” selection of appropriate treatments.

    As an 8-year prostate cancer patient active in following research on our disease, I am puzzled about the marked reluctance of urologists and oncologists in the West to incorporate Avodart or Proscar in their therapies. Dr. Sholz’s group is a minority exception. Clearly there needs to be more published research in the urology and oncology society journals on the benefits of 5-AR inhibitors to convince the Western community oncologists and urologists to use these agents. The role of dihydrotestosterone in our disease apparently is not being taught in Western medical schools. …

  8. Interestingly, this is a practice encouraged by Dr. Bob Leibowitz in Century City in Los Angeles. And that is to boost a man’s T levels to 2100+ with testosterone supplementation while fighting metastatic prostate cancer. And he is very serious about it. He sent me the video and it was an interesting watch. But it sure lacks paper support.

  9. The Internet and newspapers are now ablaze with headlines like this: “His disease has disappeared: Man ‘cured’ of advanced prostate cancer with shock doses of testosterone.”

    Was something different reported in this new 47 patient study that either supplements, compares, explains, or confirms what you had reported in 2015 for the 14 patient study above? And now that we are further down the road, is there any available update on the men in the 2015 study? Thank you.

    Richard

  10. Richard:

    I shall comment on this as soon as I can this morning in a new commentary

  11. Richard:

    The data in the media are actually data from the first of the two trials mentioned at the very end of the commentary above. See the new commentary just published (top of home page). I know of no updates to information about the patients in the earlier, pilot study.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: