New Phase III trial is testing ADT + bicalutamide vs. ADT + TAK-700


It has been brought to our attention that the Southwest Oncology Group (SWOG) has initiated a new, randomized, double-blind, multi-center, Phase III trial designed to compare androgen deprivation therapy (ADT) + bicalutamide (Casodex) to ADT + the investigational drug TAK-700 in men newly diagnosed with metastatic, hormone-sensitive prostate cancer.

The details about this new trial (known as S1216) are available on the ClinicalTrials.gov web site or you can get the quick summary from a recent SWOG Update newsletter. The following key points are worth noting:

  • There are already about 30 patients enrolled in this trial, but the total number of patients projected for the study is nearly 1,500.
  • At this time patients are being enrolled exclusively at two centers in Nevada and Utah, but the study will presumably be expanding to include a lot more centers in the near future.
  • The estimated length of this study for any individual is expected to be about 3 years (and trial results are projected to be available in about 2020).
  • The primary endpoint for the study is overall survival.

Patients will be randomized to one or other of two arms of the trial:

  • Patients randomized to the experimental arm will receive an LHRH agonist (given as approved for androgen deprivation at a dose necessary to maintain castrate levels and equivalent to an intramuscular injection of 22.5 mg of leuprolide every 3 months*) + TAK-700 (300 mg, orally, twice daily).
  • Patients randomized to the comparator arm will receive an LHRH agonist (given as approved for androgen deprivation at a dose necessary to maintain castrate levels and equivalent to an intramuscular injection of 22.5 mg of leuprolide every 3 months*) + bicalutamide (50 mg, orally, once a day).

The goal is to see if using TAK-700 (also known as orteronel) instead of bicalutamide together with an LHRH agonist as a form of continuous, combined ADT can have a signifciant effect on patient survival.

TAK-700 is already in Phase III clinical trials in men with chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC) and in men with post-chemotherapy mCRPC. However, to date we have no data from either of these Phase III trials by which to judge its efficacy.

One important note. This trial is not going to be suitable for any patient who wants to consider using any form of intermittent ADT as a way to manage metastatic prostate cancer. Whichever arm of the trial one is in, continuous therapy will be the required form of androgen deprivation.

*Note: The trial protocol on the ClinicalTrials.gov web site actually states “2.5 mg of leuprolide every 3 months” but we think this must be a typographic error since 22.5 mg is the standard 3-month dose of leuprolide acetate for the treatment of advanced prostate cancer.

9 Responses

  1. OLIGOMETASTATIC DISEASE AND THIS TRIAL OF TAK-700

    Research and treatment are moving so fast in prostate cancer that it must be tough to design trials that make good sense throughout their duration.

    For this trial, one challenge I see is what appears to be the rapid emergence of the concept of oligometastatic prostate cancer, with “oligo” meaning “few” and apparently typically defined as five or fewer bone metastases, or fewer than five metastases in total, or some other fairly small number of bone, lymph node or other tissue metastases. The key idea is that it may be possible to cure a recurring patient by eliminating the few existing metastases (more often apparently with radiation, but also with surgery).

    A quick search of PubMed with the string “oligometastatic prostate cancer” suggests a rapidly emerging approach. out of a total of 7 papers:

    — 1 was published in 2007.
    — 2 were published in 2010.
    — 1 was published in 2012.
    — 3 have already been published in 2013.

    My own recent TomoTherapy for a challenging 14-year case follows testing with Feraheme USPIO for nodes and Na[18F] PET/CT for bones to determine eligibility for such a cure. Unexpectedly, no metastases were found. (Happy face here!) That will probably keep me out of an additional series that should result in initial publication later this year.

    I have read both links above. In this trial, “metastatic” is not operationally defined in a way that eliminates men with oligometastases. I’m thinking that it would be better if appropriate scans were done and such patients excluded from this trial so they could potentially benefit from the new approach, unless it were clear that the metastases were in areas untreatable with current technology. Doesn’t this raise an ethical issue? If oligometastatic treatment becomes the rage within the near future, that development might strongly affect the motivations of the trial participants (many of whom are likely paying rapt attention to developments as I was) and ethical imperatives for the trialists.

  2. Mike you are correct. I am with the principal investigator on this trial today and he confirmed the error at ClinicalTrials.gov. He will submit the change on the site to NCI as soon as possible. 22.5 mg is the dosage of leuprolide acetate that the patient will be prescribed and it’s outlined in the Informed Consent Form.

    Just a couple notes. TAK-700 is a CYP17 pathway inhibitor. This is similar to abiraterone acetate but with an important exception, TAK-700 does not require a steroidal intervention at the 300 mg dosage. Thus many of these men today are commonly being routed to Zytiga as part of their treatment protocol but the steroid adds some less than desirable side effects. Bicalutimde has given us a good ride as an anti-androgen. The question in this trial is to see if TAK-700 is a step up ontologically.

  3. Dear Jim:

    I think you are over-estimating the degree of conviction held by most physicians (let alone patients) in the effectiveness of curative treatment for oligometastatic prostate cancer. At present, the numbers of patients treated are small and the follow-up is short. The available data are basically no more than pilot data, and there has been no study showing that using the combination of radiation therapy (or surgery) and ADT is any more effective than using ADT alone in such patients. I would point out that in your 14-year case, intermittent ADT seems to have been highly effective — indeed, so effective that there is no sign of any metastases that need treatment!

  4. Tony:

    Actually it was Ralph Valle that picked up the error, so that’s where the thanks are due!

    Mike

  5. INVESTIGATIONAL NATURE OF ATTEMPTING TO CURE OLIGOMETASTATIC DISEASE

    Hi Sitemaster,

    I agree with your comments at 3:46 pm: aiming for cure of oligometastatic prostate cancer is clearly investigational at this point and existing results are early, not extensive, and not robust. However, I have a hunch there will soon be a surge in enthusiasm. If that occurs, it could complicate trials like this with fairly long follow-up.

  6. BONE DENSITY PROTECTION NOT ADDRESSED

    While the trial’s inclusion criteria state that a DEXA scan within 2 years is required, there is no mention of use of any drug with supplemental calcium and vitamin D3 to protect bone density while on extended ADT. Here are a couple of thoughts/issues that are prominent to me as a 14th-year veteran of IADT that has included BMD monitoring and protection from the first year through the present.

    Type of BMD scan: My impression is that the DEXA scan is the typical way of assessing bone mineral density (BMD) for those of us on ADT. In fact, I have had only DEXA scans. However, DEXA scans can be thrown off when patients have calcification of arteries, arthritis, and perhaps other conditions. In such cases, the quantitative CT (qCT) scan is apparently much more effective at assessing BMD. One problem is that the patient and his doctors often do not know whether he has calcification or arthritis, including me. I was surprised this year to learn that I had some of both (incidental findings from the scans I mentioned earlier). My next BMD scan will probably be the qCT type, which is not thrown off by calcification or arthritis. I don’t see where the trial would lose any ground by broadening the criterion to include qCT scans as well as DEXA scans. I’m also thinking periodic BMD scans should be required during the trial. Perhaps that is being handled by some informal mechanism.

    Type of BMD protection drug: There are now a number of BMD protection drugs available, ranging from those that are effective but relatively mild to those that are powerful, such as Zometa, and more recently denosumab. My impression, based on published research as well as informal reports that included before- and after-scan evidence, is that the powerful drugs can exert some degree of anti-metastatic activity for some patients, in addition to their BMD role. I realize that research has been mixed regarding the anti-metastatic role. However, as more research is published, it may become clear that one or more of these drugs can play a substantial anti-metastatic role. That may be a potential confounding element if not addressed in the protocol; in other words, some of the results may be due in fact to the BMD drug and not the experimental conditions, but the degree of influence would not be determinable without solid data.

    I always understood that I would switch to a powerful BMD drug if I developed metastases, and I believe most savvy prostate cancer patients with challenging cases share that understanding. (Various evidence suggests I have not had metastatic disease, including a negative initial bone scan [technetium] in 1999 and recently the Na[18F] PET/CT (as well as my response to ADT). Therefore, I have always been comfortable with the milder BMD protection drugs, first and for many years Fosamax; later, for a couple of years, Boniva; and, after a vacation, now Vivelle estradiol transdermal patches during my current cycle of ADT.) Therefore, convinced that some form of BMD drug protection is needed during prolonged ADT for the vast majority of us, including these trial participants, and thinking that the type of drug, if not specified, could be a confounder, I’m thinking the trial should address this issue. At least for trial participants with bone metastases, it makes sense to me, with my layman’s limitations, that the protocol should require treatment with Zometa or denosumab.

  7. CURIOUS ABOUT RATIONALE FOR EXPLORING THIS FORM OF COMBINED ADT — DOUBLING DOWN AGAINST TESTOSTERONE PRODUCTION WHILE VARYING BLOCKING OF ANDROGEN RECEPTOR

    Traditional combined ADT is based on an LHRH receptor agonist to stop testicular production of testosterone plus an antiandrogen (such as Casodex/bicalutamide, flutamide, or nilutmide) to compete with any remaining androgen for fuel docking sites (androgen receptors) at the cancer cell. (In triple ADT, a 5-alpha-reductase inhibitor drug [finasteride or dutasteride/Avodart] is added to prevent the conversion of testosterone that remains to the far more potent prostate cancer fuel DHT.)

    As I understand it, TAK-700 blocks the same pathway as abiraterone, and therefore functions as a very effective agent that shuts down testosterone production — hopefully not just from the testes but from indirect adrenal gland production and from the cancer cells themselves, as abiraterone does. I’m thinking that puts TAK-700 in the role of a super LHRH agonist (though by a different mechanism), in that it aims at testosterone production.

    Therefore, this trial appears to be doubling down on shutting off testosterone production equally in both arms of the study, but testing that in one arm with no attempt to block the androgen receptors and in the other arm with blocking by the traditional drug of choice, bicalutamide.

    I’m a strong believer in empirical evidence, seeing it often trumping well thought out rationales based on our current understanding of mechanisms of action, so I’m thinking this trial should yield some valuable information. But I’m still a bit puzzled by doubling down on the testosterone suppression aspect and varying the blocking aspect of ADT.

    I’m wondering if the trialists considered a design where bicalutamide was used in both arms but an LHRH agonist was used in the control arm versus TAK-700 in the intervention arm. Perhaps TAK-700 is not yet well enough established as a testosterone suppressor that it qualifies ethically as substitute treatment for the LHRH agonist, as abiraterone does.

    Am I missing something here?

  8. Dear Jim:

    Yes … You are missing something.

    No one has ever done a significant trial of any drug in the treatment of metastatic prostate cancer since the 1980s that did not include an LHRH receptor agonist as part of the “standard therapy” arm. Furthermore, as yet there are no data at all to suggest that TAK-700 is either effective or safe in large randomized trials.

    In all honesty, I am mildly surprised that the manufacturer is willing to take the risks it is taking with the current trial. I don’t think it would be ethical at this point in time to try replacing an LHRH receptor agonist with a drug like TAK-700. As far as I am aware, there aren’t even any pilot Phase II data to support such a strategy.

  9. Mike:

    Your point is valid but I believe we’ll be seeing data soon enough that suggests that positive oncological results occurred with TAK-700 in trial that did not occur in the Phase III control arm. I don’t think there would be a good reason to do this trial if data wasn’t compelling enough to do so.

    @ Jim. As far as leaving the bicalutimde component in the active arm of this trial, I asked that question. As stated above, the trial drug is similar to abiraterone acetate in that it shuts down the CYP17,20 pathways and I was told that bicalutimide would be ineffective while the LHRH agonist will still work in the role of shutting down testosterone through the pituitary gland. I have heard the use of the term “super LHRH agonist” before, but I don’t think that accurately describes either TAK-700 or abiraterone acetate. This is evidenced by the abiraterone acetate trials that all have the requirement of serum testosterone below 50 ng/dl. In other words the patient must be physically or medically castrated already, and signs the disease is refractory needed to be present before taking the drug. So it is that this trial, S1014, is attempting to prove that abiraterone acetate is a complement to, rather than a replacement to, an LHRH or GnRH agonist.

    There are other trials, also, looking an LHRH antagonist (degarelix) that are ongoing.

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