Oral LHRH antagonists for the treatment of prostate cancer: an update

Some time ago we noted that there were three oral (as opposed to injectable) LHRH antagonists in development for the treatment of prostate cancer, i.e., drugs like degarelix (Firmagon) that could be given by mouth as opposed to needing to be injected.

At this time, it appears that one of these drugs (TAK-385 or relugolix) has shown some degree of success in the treatment of prostate cancer. Of the other two agents, elagolix, by contrast, still shows no sign of having been tested in the treatment of prostate cancer, and ASP-1707 has, at best, been tested in a small Phase I trial in patients in prostate cancer.

Data from a Phase II clinical trial of TAK-385 was given by Shore et al. in a presentation at the recent meeting of the European Cancer Congress (see also this article in The ASCO Post).

As a quick reminder, LHRH antagonists (e.g., degarelix) are drugs that can be used to suppress serum testosterone but they differ from LHRH agonists (e.g., leuprolide acetate/Lupron, goserelin acetate/Zoladex) in that they seems to lower serum testosterone levels further and faster than the LHRH agonists. They can also be given without any need for short-term use of an antiandrogen (e.g., bicalutamide/Casodex) to suppress the so-called “flare reaction” associated with the initial use of the LHRH agonists. Thus, at least in theory, an oral LHRH antagonist might be able to work better than the traditional LHRH agonists and could allow the patient to avoid the relatively frequent trips to the urologist’s office for injections of 3-, 4-, or 6-monthly implants of this form of androgen deprivation therapy (or worse still, the monthly implants of degarelix).

TAK-385 is an investigational, oral, non-peptide LHRH antagonist. The data presented below are from an interim analysis of the Phase II trial of this drug at two different dose levels compared to 12-weekly injections of leuprolide acetate.

Patients with a PSA level of > 2 ng/ml and a baseline serum testosterone level of > 150 ng/dl were randomized to receive one of the following three forms of medication for a period of 48 weeks:

  • TAK-385 at a dose of 80 mg taken once daily
  • TAK-385 at a dose of 120 mg taken once daily
  • Leuprolide acetate 22.5 mg injected subcutaneously every 12 weeks

The primary study endpoint was an effective serum testosterone level of < 50 ng/ml from weeks 5 to 24. (And yes, we realize that lower serum T levels appear to be better, but the medical castration level is defined as a serum T level of < 50 ng/ml.)

Here are the study findings:

  • 26 patients were treated with TAK-385 at 80 mg once daily.
  • 24 patients were treated with TAK-385 at 120 mg once daily.
  • 13 patients were treated with leuprolide acatete.
  • Average (median) duration on treatment was
    • 24.7 weeks for men taking TAK-385 (range, 4.6 to 36.7 weeks)
    • 27.1 weeks for men taking leuprolide acetate
  • After 1 week on therapy
    • Serum T levels among the TAK-385 patients had dropped 95 percent from baseline (to a median of 21 ng/dl; range, 6.9 to 474.8 ng/dl).
    • Serum T levels among the leuprolide acetate patients had dropped by 29 percent from baseline (to a median of 282.9 ng/dl; range, 114.1 to 744.7 ng/ml).
  • After 4 weeks  on therapy
    • PSA levels among the TAK-385 patients had dropped 89 percent from baseline (to a median of 0.8 ng/ml; range, 0.1 to 118.6 ng/ml).
    • PSA levels among the leuprolide acetate patients had dropped 79 percent from baseline (to a median of 1.8 ng/ml; range, 0.1 to 16.5 ng/ml).
  • After 12 weeks on therapy
    • Serum T levels among the TAK-385 patients had dropped 98 percent from baseline (to a median of 8.9 ng/dl).
    • Serum T levels among the leuprolide acetate patients had also dropped 98 percent from baseline (to a median of 8.9 ng/dl).
    • PSA levels among the TAK-385 patients had dropped 97 percent from baseline (to a median of 0.1 ng/ml; range, 0.1 to 21.4 ng/ml).
    • PSA levels among the leuprolide acetate patients had dropped 92 percent from baseline (to a median of 0.3 ng/ml; range, 0.1 to 1.8 ng/ml).
  • Over the period from week 5 to week 24, serum T levels of < 50 ng/ml were maintained in
    • 88 percent of patients in the two TAK-385 arms of the study
    • 92 percent of patients in the leuprolide acetate arm of the study
  • The most common adverse events observed were
    • Hot flashes in 50 percent of TAK-385 patients and 54 percent of leuprolide acetate patients
    • Fatigue in 14 percent of TAK-385 patients and 23 percent of leuprolide acetate patients
    • Elevated alanine transferase levels in 10 percent of TAK-385 patients and 8 percent of leuprolide acetate patients.

Shore et al. conclude that

The safety and efficacy profile of TAK-385 was acceptable and consistent with the mechanism of action. TAK-385 rapidly reduced T and maintained levels at < 50 ng/dL over 24 weeks. These data support further investigation of oral TAK-385 as a therapeutic alternative to injectable [LHRH] androgen deprivation therapies.

Based on these data and others still awaited (from a trial in combination with radiation therapy), we expect TAK-385 to move into Phase III clinical trials at some stage in the not too distant future.

16 Responses

  1. I don’t see that these new drugs provide any improvements over DES, and they will certainly be a lot more costly. Did I miss something?

  2. Your comment regarding “medical castration” is very on point and appropriate. The testicles will dissolve.

  3. Dear Fred:

    The only way we could know that would be if someone did a randomized trial of one of these drugs against DES. I can’t make meaningful comment based on no data!

    As for testicles “dissolving” … that’s not a syndrome that I am familiar with. They may shrink since they are not in use to produce spermatazoa … but they also tend to do that with increasing age too, for the same reason. It’s not quite the same as “dissolving”!

  4. I can give you the DES side; and, from what I can see, there is no difference, other than cost. One man’s opinion.

    I suspect the “cure” is only temporary; that is, it works only as long as the drug use continues. There appears to be no “healing” here, only drug addiction. I like the researchers use of PSA as an indicator of success. I have found it to be very reliable.

  5. Who suggested that any known drug could “cure” prostate cancer? I don’t know of any — DES included.

  6. Oral DES causes clinical significant blood clots in ~ 12% of patients. In contrast, the LHRH drugs do not have the same blood clot risk. That is the reason why they replaced DES several decades ago in the affluent world that can afford them.

    If TAK-385 is tasteless, it could become a popular antidote to the date rape drug. While he is trying to slip her roofies, she can be putting TAK-385 in his beer.

    Richard W.

  7. I didn’t suggest any drug could “heal” the cancer, only that the drug being tested would only “cure” the disease temporarily. Thus, it is no improvement over DES and is a waste of time. Don’t get me wrong. I am pleased that research is going on. I just think this bit of research is going down a useless path, especially when the DES is already available and does the same thing; and it’s cheap.

  8. Impressive Phase II Results for Oral TAK-385 Compared to Degarelix/Firmagon as an LHRH-antagonist

    Degarelix (Firmagon) is known for reducing testosterone very rapidly and to a very low level compared to the LHRH agonist alternatives, and these Phase II results indicate that TAK-385 is having similar success.

    Of course the huge advantage is that it is an oral drug rather than an injection; this is a big deal as Firmagon has a reputation for a lot of pain and discomfort at the injection site. Apparently that pain can be greatly reduced by appropriate injection technique (patient flat on back, inject over 2 minutes, sit for 2 minutes, then use ice pack per Dr. Charles Myers, MD), but my impression (based on a handful of patient accounts and two doctors) is that the majority if not vast majority of care delivery personnel do not use good technique, with the result that patients routinely experience injections that are quite painful and uncomfortable. One medical oncologist who presented to our Us TOO group said he did not use Firmagon much because of that pain and discomfort.

    Dr. Myers also emphasized that Firmagon does not pose cardio risk or risk of renal failure (some risk with LHRH agonist drugs), and has a lower side effect burden that the agonist drugs. I’m curious whether the Phase II trial of TAK-385 revealed any data regarding cardio and renal concerns, though with such a small trial and fairly short follow-up, I doubt it. In my own case, Firmagon was an option for my fourth round of ADT3 (in support of hopefully curative radiation), from October 2012 through April 2014; I could have used it instead of Lupron. However, my oncologist did not suggest it, and I did not request it. That was because Lupron had worked well for me as part of ADT3; I knew the countermeasures to reduce and prevent side effects; I tolerated Lupron fairly well; research had not yet so clearly established the advantages of Firmagon; and whatever enthusiasm I had for Firmagon was greatly diminished by the reputation it had for painful injection. If an oral version of Firmagon had been available that was approximately as effective as we now know it to be and with the same advantages for side effects, I’m confident I would have requested the oral LHRH antagonist.

    I hope I don’t have a recurrence of course, but if I do, I hope an oral LHRH antagonist is available as an option. I hope Takeda moves ahead smartly with a Phase III trial!

  9. Would Like to See Explanation for a “Failing” Patient(s) Explained in the Paper We Can Expect on the Phase II Trial

    While TAK-385 achieved impressive success in the trial, it is clear that at least one patient did not enjoy such success. We can see that from the figures for the high end of the range (T of 474.8 ng/dl and PSA at 1 week and a PSA of 1118.6 ng/ml at 4 weeks) as described in the excerpts below from Sitemaster’s article:

    “After 1 week on therapy
    Serum T levels among the TAK-385 patients had dropped 95 percent from baseline (to a median of 21 ng/dl; range, 6.9 to 474.8 ng/dl).”

    “After 4 weeks on therapy
    • PSA levels among the TAK-385 patients had dropped 89 percent from baseline (to a median of 0.8 ng/ml; range, 0.1 to 118.6 ng/ml).“

    It’s possible this was a compliance issue, with the patient just not taking the pills as directed. Perhaps he developed really irritating hot flashes (severe, or long, or frequent, or during sleep, or all of these) and just stopped or skipped pills.

    Alternately, it’s possible that his adrenal glands really kicked in gear when the body signaled a testosterone shortage, and made up a lot of the loss, as happens for a few of us.

    It’s also possible that he regularly produced a lot of DHT and was one of those patients whose DHT does not fall sharply as its source (testosterone) is reduced. (Knocking down DHT conversion from testosterone is a key role of 5-alpha-reductase inhibitor drugs, specifically finasteride and dutasteride; it seems likely that patients in the trial were not on either drug, though they were not addressed in the exclusion criteria.)

    Perhaps there is some other reason. I’m curious what the distribution results were for achieving very deep and rapid PSA supression coupled with discussion of any outliers (i.e., patients not achieving rapid and deep suppression — the patients for whom the drug “failed”). As expected in such preliminary reports, there were no graphics covering this issue.

  10. Regarding DES — Cardio Concerns

    Dear Fred and aloe910,

    Are you aware that DES is no longer used much because it has much more serious cardio risk concerns than the alternatives? Also, DES is known for some other unwanted effects, and apparently there are no longer any US manufacturers of DES.

  11. “Dissolving Testicles” Assertion


    Many of those of us who have been on androgen deprivation therapy (ADT) have experienced reduced size, but on intermittent therapy — where drugs are given on and off — during the off-therapy period, after several months the testicles often recover in size as they again produce testosterone.

    However, a long-time on ADT, being elderly, etc., can lead to locking up of the “machinery” so that testosterone production is quite low, and the testicles may become much smaller. I’m not sure if testosterone replacement therapy, which is sometimes feasible in prostate cancer patients, can reverse this.

    I’m curious whether the faster acting and more effective drug Firmagon has a more profound effect than the LHRH agonist drugs on permanently locking down testosterone production. I did not find the answer with a brief check on http://www.pubmed.gov.

  12. Dear Fred:

    (1) There is no such thing as a “temporary” cure. That effect is known as “remission”.

    (2) DES may work for you, but there are a lot of men who simply cannot take DES at any dose level. The risk for blood clots and other cardiovascular side effects is too high for such men (as noted by others).

  13. I will leave this closing comment to this discussion as a means of comparison, since it appears alternative views are not well received at this site. I take five supplements along with the DES to counter the unfavorable cardiac side effects. I endure the others. My PSA was over 35 when I first discovered the problem. Not long after, say 6 months, it was over 98. Then, I discovered the “poor man’s cure for prostate cancer”, DES. After taking 2 mg per day for 30 days, the PSA was 11. After 30 more days, it was 0.3. I then tapered off with 2 mg for 30 days and 2 mg for 30 more days, and the PSA started to climb. I wind up getting back on DES at least once for the same protocol within every 12 month period. In the meantime, I am experimenting with various options and homeopathic cures; but as of now nothing has worked at all except the DES. I pay $40.00 for a 30-day supply (30 capsules) and am actively managing the cancer. All I ever get from the “experts” is “cut it out”. That is not an option for me. I am trusting this site to continue to provide us with worthwhile information in hopes that a true healing solution will be found. We don’t need any more “cures”. We need a final solution other than death. Thank you for your valuable support in this endeavor, whoever you are.

  14. Dear Fred:

    You seem to be under the misapprehension that people are telling you that DES is no good. That is a misapprehension. Low-dose DES has long been an appropriate management option for many men. It is cheap. It is effective. And for men with minimal risk for cardiac events it is reasonably safe. I am delighted it works well for you. And if your PSA was 35 at diagnosis and rose to 98 within 6 months then the chances that you could have been cured by radical surgery are near to zero.

    However, as I said in my last message, DES is not a safe drug for all men. They need other options to help treat their advanced disease. Of course we would also like a real “solution” … but until we can find such a solution the best hope comes from having a wide variety of options (and an oral formulation of an LHRH antagonist is just that — a potential option. Based on the data available to date, we don’t even know if it could get approved by the FDA. And no one at all has suggested that it is “better” than DES. All we know is that it is different (and, you are correct, it would probably be much more expensive).

    Alternative views are always welcome at this site … but alternative views (like alternative shoes) do not necessarily fit everyone as DES seems to fit for you.

  15. Responding to fred simpson, on December 1, 2015 at 10:39 am:

    Hi again Fred,

    I was and am fortunate to have excellent insurance (though I pitch in a hefty sum for premiums and additional expenses), so I have been able to get triple ADT without too much financial discomfort. Here are a few other tactics you might want to try that could help and will not break the bank. I am a now savvy patient but have had no enrolled medical education at all, so all of this should be at least run by a medical professional. That said, some of the professionals are not well informed about these tactics, and it would help if you could build up your own information base on the drugs, other tactics, and side effects.

    Adding finasteride (Proscar) to your regimen: This drug sharply curtails the conversion of testosterone into DHT (dihydrotestosterone), which is a far more potent fuel for the cancer than testosterone itself. The key fact is that it has been generic for many years now and is reasonably inexpensive, available under prescription. There is a more effective similar drug — Avodart (dutasteride), but that drug is substantially more expensive. The combination of DES and finasteride may yield better results for you.

    Adding bicalutamide (Casodex): This drug competes with the androgens (especially testosterone and DHT) for fuel input and signaling docking sites (known as androgen receptor) on the cancer cells. By blocking the sites, it hinders the cancer from obtaining fuel and sending dangerous signals to the cancer cell’s nucleus. Casodex has been generic for some years as bicalutamide, so its cost has dropped a lot. That said, it is not even now a cheap drug. (A far more potent, similar drug that is much superior at muscling out the androgens at the docking sites is known as enzalutamide [Xtandi]. Unfortunately, it would be available only under an “off label” prescription for someone in your circumstances, which might very well affect a doctor’s willingness to prescribe it or insurance to cover it, and it is very expensive. Of course, in time it will be available as a generic, so if you can gain time, that’s a plus.]

    Quality pomegranate juice or extract capsules: There have been several research studies that document some effectiveness in slowing down the cancer or even stopping or reversing it for some of us. You might have the right genes or genetic environment for it to work well. The juice has the usual amount of sugar for a fruit drink, so that may be a problem for you. The extracts have no sugar. I have been taking a capsule daily for years, and my hunch is that they have helped, such as in preventing metastases. (No proof of effectiveness, but no detectable mets either for a challenging case.) However, for me, unlike many others of us, they had little noticeable effect on my PSA. The juice that has been studied is made by POM Wonderful. The extract capsules I have taken have been made by either Life Extension Foundation or POM Wonderful, and both have been studied with some tentative favorable evidence. The trick is to try them and see what effect they have on your PSA. The capsules can be obtained for a little more than a dollar a day, or perhaps somewhat less.

    A statin drug: If you tolerate a statin well, this could help, as these drugs lower cholesterol, and cholesterol is a building block for testosterone, which fuels the cancer directly and indirectly (DHT). There has been encouraging research on the impact of lowering cholesterol on prostate cancer. Some of these drugs,such as simvastatin (generic Zocor), are dirt cheap.

    Metformin, traditionally a diabetes drug: This dirt cheap drug has recently been documented to have favorable effects on a number of cancers, including prostate cancer. There is a lot of enthusiasm about it, and apparently it has a very low burden of side effects for most of us.

    Lifestyle tactics, such as eliminating excess body fat (especially belly fat), a good diet (such as a Mediterranean diet), exercise (especially aerobic and strength), and stress reduction seem to help both with the cancer and with reducing side effects.

    Thanks for your account about coping with the cancer with DES. I’m glad it is working for you.

    I’ll close by echoing Sitemaster’s comment: I have found that this site is not closed to alternative approaches.

    Good luck!

  16. Thank you for your comments, the time it took you to babysit me, and for all you have done in furtherance of our education on the subject of prostate cancer. It was very dark out here in the beginning. Your website has been a welcome ray of sunshine.

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