Can the new hormone therapies actually replace the older ones?

Here is a question that is on the minds of many physicians and patients on Planet Prostate Cancer today: Can treatment with abiraterone acetate or similar agents replace the continuous and/or the intermittent first-line use of LHRH-agonist–induced medical castration in patients with high-risk and advanced forms of prostate cancer?

A question like this was just addressed by Dr. Matthew Smith of  in an educational program for specialists in the management of prostate cancer. (Dr. Smith is the Director of The Claire & John Bertucci Center for Genitourinary Cancers at Massachusetts General Hospital in Boston and an Associated Professor at Harvard Medical School. He is a well-respected authority on the management of advanced forms of prostate cancer.)

The best way to characterize Dr. Smith’s response to the question is probably, “We think this may well be possible. … We don’t have the data yet to confirm this … but we are working on it.”

From a mechanistic point of view, what Dr. Smith is careful to point out is that abiraterone works by inhibiting an enzyme called CYP-17. Specific inhibition of this enzyme blocks the products of all androgens in all areas where we know they can be manufactured —  in the testicles, in the adrenal glands, and in prostate cancer tumors.  As a consequence, to quote Dr. Smith, “It is possible that, if more complete androgen deprivation is achieved earlier, fewer cases of CRPC will develop.”

The problem with all the LHRH agonists (leuprolide acetate, goserelin acetate, and others) — and with the only available LHRH antagonist (degarelix) — is that in addition to suppressing the production of testosterone by the testes, they have a whole spectrum of other less than wonderful side effects (of varying intensity in differing patients). Some of these side effects (like the initial flare reaction to LHRH therapy) can be moderated by the first- and second-generation antiandrogens (e.g., flutamide and bicalutamide). Other side effects … gynecomastia, weight gain, effects on cognitive function, are more problematic … especially for men on long-term androgen deprivation.

At the present, there appear to be at least two new candidate therapies that have shown effectiveness in the treatment of men with metastatic, castration-resistant prostate cancer (mCRPC) who have progressive disease after docetaxel-based chemotherapy and that might be usable much earlier in the development of progressive disease. One is abiraterone acetate; the other is enzalutamide (MDV3100).

We already know that abiraterone acetate + prednisone is effective in delaying the progression of prostate cancer in men with mCRPC who are chemotherapy naive; we suspect that enzalutamide will also have a similar effect. However, in trials to date, these drugs have been tested in men who continue to receive LHRH agonist therapy in addition to the new drugs. If we are to know whether the new drugs can actually replace long-term LHRH agonist therapy, here is a list of the questions that will need to be answered:

  • Can abiraterone acetate be used earlier without the need for long-term, adjuvant prednisone therapy?
  • Can abiraterone acetate (with or without prednisone) or enzalutamide be used effectively and safely as first-line hormone therapy in men who are in biochemical failure after standard care (e.g., initial surgery and salvage radiation therapy)?
  • Can abiraterone acetate (with or without prednisone) or enzalutamide be used effectively and safely as first-line hormone therapy in men initially diagnosed with evident, metastatic prostate cancer?
  • Are the side effects associated with first-line use of abiraterone acetate (with or without prednisone) or enzalutamide less problematic that those caused by LHRH agonist and LHRH antagonist therapy? (Remember that many of these side effects are actually a consequence of the massive decrease in the levels of serum testosterone, which is a necessary effect of the treatment if it is to prevent progression of prostate cancer.)

Getting good (as opposed to preliminary) answers to these questions is going to take time — which of course patients with higher-risk disease don’t feel that they have.

However, there are also other questions that would help us to act without complete answers to the first list:

  • Can LHRH agonist therapy act effectively as a second-line form of ADT when patients progress after treatment with abiraterone acetate (with or without prednisone) or enzalutamide?
  • Can enzalutamide and abiraterone acetate (with or without prednisone) be used sequentially or even in combination prior to LHRH agonist therapy?
  • What effect do the older, first- and second-generation antiandrogens (flutamide and bicalutimide) have if given at some point after enzalutamide? (Remember that one way to look at enzalutamide is as a “third-generation” antiandrogen.)

On top of this, there are additional questions around the potential of other development-stage agents like TAK-700 (orteronel), which may also have significant clinical effects in the management of prostate cancer patients traditionally treated with an LHRH agonist after a course of antiandrogen therapy to prevent the well-understood flare reaction to LHRH therapy. We also have minimal data on the potential of immunotherapeutic agents when used any earlier than in men with good performance and limited mCRPC (whether or not these men have received docetaxel-based chemotherapy).

However much we want quick answers to all these questions, we are going to need to accept that it will take time to resolve the questions about what works and what works best. It seems likely that by 2020 there may be a whole new paradigm for the treatment of men with progressive forms of prostate cancer — before and after the onset of castration resistance. It would, of course, be helpful if we could get all these answers faster. Whether that is realistic, only time will be able to tell.

8 Responses

  1. Mike:

    I am seeking a clarification. The post states: “Specific inhibition of this enzyme blocks the products of all androgens in all areas where we know they can be manufactured ….”

    Did it intend “products” or “production”? Since I believe abiraterone inhibits circulating levels of testosterone, then it may in fact be “production”.

    I ask because if abiraterone treatment reduces testosterone, then are not the side effects likely to be exactly the same as LHRH drugs where most systemic side effects are attributable to androgen deprivation?

    One possible exception … Snuffy Meyers has pointed out that LHRH drugs may also lower estrogen levels and that may have resulting side effects — I’m not sure that is the case with abiraterone.


  2. Rick:

    Regardless of whether “products” or “production” is the correct term (and yes, arguably it should have been “production”), abiraterone does affect testosterone levels. However, it does this in a very different way to the LHRH agonists and antagonists. As far as I know, we do not (as yet) have well-documented data on the pharmacotherapeutic or the clinical effects of abiraterone acetate alone or in combination with prednisone in hormone therapy-naive men with micrometastatic or metastatic prostate cancer.

    Within the post above, we did, indeed, carefully point out that many of the side effects of standard forms of ADT (e.g., loss of libido) are a direct consequence of the reduction in levels of testosterone. So, if abiraterone acetate can lower testosterone levels in ADT-naive men to the same levels as standard forms of ADT, at least some of these same side effects will be evident. However, there are all sorts of reasons to believe that some of the side effects of LHRH agonists might not be exhibited because LHRH agonist therapy is acting on the pituitary gland, not on androgen production. Injection of LHRH agonists and antagonists are designed to block the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). It is the consequent lack of these hormones that result in the decline in testosterone. However, the lack of FSH and LH almost certainly is having all sorts of other consequences about which we have minimal understanding, so who knows what the real consequences are in terms of exactly what is causing some of the known side effects of LHRH agonist and antagonist treatment.

  3. Thanks for the clarification; as you know, HT side effects are a pet subject for me. While I recognize the side effects are likely comparable between LHRH agonists and abiraterone, parsing the T. is helpful in my understanding.

    On May 7 we have our annual Prostate Cancer Research Day at UCSF; as a Patient Advocate, I get invited — and this year it will be hosted at AT&T (Giants) Stadium rather than on the neighboring Mission Bay Campus as in past years! Since I will have access to all the boffins (Ryan, Fong, Hsei, Small, etc.), it will be an opportunity to feel out the “cutting edge” on whether in fact A. is thought to have lesser side effects.

  4. I have no doubt that abiraterone could replace LHRH agonists as a first-line hormonal therapy, and it would work better at achieving total androgen blockade. However, I think first line therapy considerations are based mainly on cost and so cheaper options such as LHRH therapy or Casodex will be used in preference.

    For early stage prostate cancer, long-term safety issues are important, which is why salvestrols are the safest first-line therapeutic option, and are safe to take long-term with no side effects.

  5. Dear Dr. Potter:

    The key question here is going to be whether abiraterone could be given without prednisone under such circumstances. The cost issue will go awayt fast enough once abiraterone is available as a generic product.

    With respect to salvestrols, I understand your personal passion, but without supporting and compelling data they are never going to be widely recommended.

  6. Abiraterone was tested as a single agent at a dose ranging from 250 to 2000 mg daily in the first Phase I clinical trial of dose escalation studies. This was safely tolerated as a single agent without prednisone. The prednisone was incorporated as a precautionary measure against possible side effects in Phase 2 trials, but prednisone carries with it its own side effects, so the use of abiraterone as a single agent is worthy of further investigation. Lower dosage strategies such as dosing after food to increase absorption is being investigated in current clinical trials at the University of Chicago. The results from this could see the cost fall to less than $1,000 per month, which may make this more acceptable for earlier prostate cancer therapy.

    My personal passion for salvestrols as an effective therapy option for all stages of prostate cancer is based on my experiences of many men with prostate cancer that have benefited from this treatment option and long-term use of salvestrols is common, in some cases for over 8 years and still being alive and disease free, with none of the long-term side effects that you would get from long-term hormonal therapy.

  7. I am a prostate cancer patient interested in volunteering for an “early” clinical trial on abiraterone. These are my stats up to April 16, 2012:

    I have a Gleason 8 cancer diagnosed in January 2008 with a PSA of 7.9 ng/ml. Mortality on the John Hopkins scale is estimated at about 5 years from this date (2013). A radical prostatectomy was done on February 28, 2008; PSA was 2.6 after 2 months. A first cycle of hormone therapy was started in April 2008, ending in November 2008 (6 months). Radiotherapy was used to treat the prostate bed in Octber and November 2008. I was biochemical recurrence-free (PSA < 0.01) for 20 months until April 2010. A second cycle of hormone therapy was started in April 2010 (when my PSA was 2.0), ending on January 12, 2012 (9 months); my PSA was then < 0.01. The biochemical recurrence-free period lasted only 2 months after this second cycle of hormone therapy. As of April 16th, 2012, my serum testosterone is still at an all time low of 0.5, while my PSA has bumped back up to 0.07 in just 3 months — about 10 times faster than after the first cycle. This looks like the very beginning of CRPC.

    If abiraterone can stop all testosterone, including that produced by the tumor, I would like to find out if an early dose of it will kill all the cancer (at least for a longer time than Casodex) rather than waiting until my cancer is super-aggressive and spreading to all parts of the body and much harder to do anything much about it.

    I am also interested in a tumor vaccine, one of the two or both but whichever, to do it early.

  8. Dear Barrie:

    There is nothing that we can do to facilitate “early” use of abiraterone for you. However, abiraterone may well be approved for the treatment of men like you some time later this year or early next year based on data already released by Johnson & Johnson, so you should be able to get this sort of treatment some time in the next 12 months or so.

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