Lutetium-177 PSMA-617 in Phase III (VISION) trial for treatment of mCRPC

We have just been appraised of a randomized, double-blind, multi-center, Phase III clinical trial of the targeted, radiolabeled agent 177Lu-PSMA-617 (a form of “radioligand” therapy) in the treatment of metastatic, castration-resistant prostate cancer (mCRPC). Details about this trial can be found on the web site. Some basic information for patients is also available on a study-specific web site.

The trial (also known as the VISION study) is nominally being sponsored by Endocyte (the developer of 177Lu-PSMA-617), but Endocyte recently agreed to being acquired by Novartis, and so — to all practical intents and purposes — Novartis is now the effective sponsor of this trial (unless the deal falls through).

The primary endpoint of this study is overall survival (OS) among patients with progressive, PSMA-positive mCRPC randomized to treatment with either

  • 177Lu-PSMA-617 + best supportive/best standard of care or
  • Best supportive/best standard of care alone

Best supportive/best standard of care for each individual patient is as defined by the local investigator at each study center.

The eligibility criteria for enrollment into this study are a little complex but, basically:

  • Patients must have metastatic, castration-resistant prostate cancer.
  • They must have disease that has progressed after
    • An orchiectiomy or treatment with standard androgen deprivation therapy (ADT) and
    • Treatment with at least one drug like enzalutamide (Xtandi) or abiraterone acetate (Zytiga) and
    • Either one or two prior taxane chemotherapy regimens, e.g., docetaxel (Taxotere) and/or cabazitaxel (Jevtana)
  • They must not have received any prior treatment with any other form of radiolabeled therapy, e.g., radium-223 (Xofigo)

Patients will require careful evaluation to ensure that they meet all relevant criteria for inclusion in this trial.

The study protocol indicates that this trial may have been open since late May this year at as many as eight different sites in the US, but this is the first time we have heard about it. The trial expects to enroll a total of 750 patients, and the estimated study completion date is listed as August 2020.

We note that the trial is also said to be an international trial, but no ex-US study sites are currently listed on the web site

15 Responses

  1. Tulane just opened is coordinator

  2. A Patient-Centric Trial!:

    I am very glad this trial is underway, and I like almost all of what I’m seeing in the protocol as summarized at

    I particularly like the allowance of a lot of freedom in the control group, and in the non-intervention part of the intervention group: “Best supportive/best standard of care for each individual patient is as defined by the local investigator at each study center.” That allows flexibility to clinicians managing patients in the trial to adopt advances as emerging research indicates in our dynamic research environment for prostate cancer. It means, for example, that the latest genetic, epigenetic, imaging, etc. advances can be implemented to benefit their patients. To me, this is a trial centered on the patient’s wellbeing, as trials should be in my view, rather than a trial centered on getting the most out of each patient as a data point, with rather restrictive protocols, as some trials unfortunately are structured.

    I will express some concerns later, but, overall, bravo to the trial leaders!

  3. Androgen Level Eligibility Criterion – Loosely High for Testosterone and Omits DHT Entirely

    I want to reiterate that I am very glad this trial is underway, and I like most aspects of it. However, as a now savvy patient and advocate, I hope trialists will consider the following for future trials and for implementation in this trial.

    The level for testosterone: As a 19¾ year survivor who was on intermittent ADT for the first 14 years for a once life-threatening case, I am pretty familiar with best practice regarding monitoring of androgens. The key androgen, of course, is testosterone. Research has indicated that the best level for determining whether ADT is adequate is a level of around 20 ng/dL or lower. Most unfortunately, the overwhelming majority of research trials use a much looser level of &lt ;50 ng/dl or < 1.7 nmol/l, as does this study. What that means is that some progression may be due to inadequate suppression of testosterone rather than true “castrate” level resistance. At least the use of the looser level has the advantage of comparability to the vast body of existing research. However, if I were on a panel reviewing this protocol as a proposal for funding, I would at least make a strongly worded negative comment and downgrade the score a bit on this ground alone, as I have done in the past as a reviewer for the CDMRP’s prostate cancer research program. All this said, doctors who have patients in this trial have the freedom to make sure their patients get their T level down to ~20 ng/dL or lower, and I hope they will do so.

    DHT: The Absence of an Eligibility Criterion for Dihydrotestosterone (DHT): I am no longer surprised that this key antiandrogen is not an eligibility criterion, but it sure should be! It won’t be news here that DHT is a far more potent fuel for prostate cancer cells than is testosterone, from which DHT is made. It may be news that some patients achieve a true castrate level of testosterone, meaning ~20 ng/dl or lower, but still have a high level of DHT, enough to wreck a program attempting androgen blockade. In fact Dr. Charles “Snuffy” Myers, who presented with a case of metastatic prostate cancer way back in 1999, was one such patient himself; my recollection was that his level was 50, while the target level for adequate suppression of this androgen is less than or equal to ~ 5 ng/dl . Possibly the use of Zytiga or Xtandi, or other NAAD (?) ensures such a low level, but I have not seen research on that.

  4. Looking at the criteria for the clinical trial I wonder if a short treatment of Erleada would qualify as a taxane chemotherapy.

  5. Dear Jim:

    I really don’t mean to be rude, but every time you raise these issues on this web site, you are accomplishing nothing. If you want to see change in this area, you need to take these issues up with the Prostate Cancer Working Group and with the Oncology Center of Excellence at the Food and Drug Administration. No one else has the authority to address these issues in ways that might lead to meaningful change (although Howard Soule at the Prostate Cancer Foundation might have some influence).

  6. Dear Donna:

    Sorry, but treatment with apalutamide (Erleada) would not qualify as taxane chemotherapy. That requires treatment with either docetaxel (Taxotere) or cabazitaxel (Jevtana). It would, on the other hand, qualify as treatment with “at least one drug like enzalutamide (Xtandi) or abiraterone acetate (Zytiga)”.

  7. Re your response about level of androgens and trial eligibility/monitoring

    Dear Sitemaster:

    Thank you for your comment and leads; I will try to follow through. I have some hope that trial leaders and “consumer reviewers” might see my comment and find it thought provoking, hopefully leading to action.

    I have never seen good arguments against using the lower level of testosterone (~20 ng/dL to define castrate level) and for monitoring DHT. When I have brought this up as a voting “consumer reviewer” (a.k.a. survivor, patient advocate) in CDMRP Prostate Cancer Research Program proposal reviews, the only answers I’ve had from the dozen or so scientist/physicians on each of these panels is along the lines of “that’s the way we always do it” — no rational, fact and logic-based response.

    Such a change in monitoring would make managing trials somewhat more difficult, but also better for patients — more “patient-centric”, as there would be a higher level of truly achieving adequate androgen suppression, thereby cutting off a greater proportion of fuel for the cancer. Here are two extra demands of using the more stringent approach. First, obviously, it is easier to enroll “castrate-resistant patients” when the higher level is used. Second, and less obviously, when patients are on inadequate testosterone suppression, more is required of the doctor to properly monitor and adjust delivery of the drugs to ensure adequate suppression (such as a shorter dosing schedule, verification of proper targeting such as muscle vs. fat for Lupron, proper storage, proper mixing, proper insertion of coil for Zoladex, etc.), and my impression is that quite a proportion of doctors are likely not up to that, lacking a grasp of the big picture and lacking knowledge of the ins and outs of androgen suppression. So this aspect too would make a trial with the lower T level and DHT monitoring more difficult to manage, especially where more community level care is involved. I believe both of these added demands would not be that hard to satisfy.

  8. Dear Jim:

    Apparently you don’t appreciate that there is a very real reason why 50 ng/dl or less is used as the standard level for serum testosterone (T) in defining a “castrate” prostate cancer patient.

    It is because that was the level of serum T generally measured in men who received an orchiectomy (i.e., in men who were surgically castrated) decades ago. To change that level, we would need to know that most men being treated with an LHRH agonist (or with an LHRH agonist and a standard antiandrogen or some other form of “standard” medical form of androgen deprivation) consistently reached some lower level of serum T. But we don’t know that. What we know is that men whose serum T reaches a level < 30 ng/ml tend to do better over the long term than men whose serum T drops to something between 30 and 50 ng/dl … but then how are you defining "castrate"?

    Measuring serum T levels is actually not difficult at all. Most decent medical laboratories can do that, and it isn't particularly difficult. The much harder question is defining a "standard" measure of serum T that is universally acceptable, and the level reached by men who have had their testes removed is a fairly obvious and meaningful number. Redefining that number to be more like 20 ng/dl when that is not a serum T level reached by a high percentage of men who are truly "castrate" in surgical terms would present all sorts of problems. However, there is no good reason why a particular drug company, in concert with the FDA, shouldn't elect to use a different number (or use both numbers) in a clinical trial. In other words, in conducting a clinical trial the research team could stratify men into subgroups at the start of the trial by agteeing to enroll patients whose level of "castration" at the time of tral entry was either < 50 ng/dl or, say, < 25 ng/dl and then analyzing all trial results based on these two baseline levels.

  9. Continuing the Discussion of the Best Level to Define the Castrate Level of Testosterone

    Dear Sitemaster,

    Thank you so much for responding to my comment in which I advocated for a lower level of ~20 ng/dL to define the castrate level of testosterone. While the following information documents my basis for claiming that lower level as a much superior threshold, based on a key advance in testosterone measurement technology (from the double-isotope-derivative dilution technique to the better radioimmunoassay technique and more recently to the chemiluminescence technique) despite the sluggishness/reluctance of the research community to vary from their traditional level of 50 ng/dl,

    I am most grateful and appreciative that you have taken the time and have had the guts to offer a rebuttal to my position, something no one else has done. This is the way medicine advances, not by passive acceptance of conventional wisdom and ignoring counter arguments based on fact and logic! Bravo to you! (And it’s one of the reasons your site continues to be a key part of my continuing education program as a survivor and advocate!) So this puts the ball back in your court, and I hope the volley continues.

    Here is an abstract of an early paper from 2000. It’s short and makes key points.

    (I really like this research group. They also had a neat paper that showed much longer survival than conventionally described for men with metastases. That paper was a huge boost in my morale when I first saw it years ago!)

    An Italian paper entitled “Impact of Surgical and Medical Castration on Serum Testosterone Level in Prostate Cancer Patients”, published in 2009, gave a review (sse Table 1) of surgical castration results from a number of studies, with results ranging from 15 to 26 ng/dL in all but one study.

    Here is key text from this well-referenced Italian study: “Various levels of testosterone have been reported to define castration [12]. The most commonly used value is 50 ng/dl or less, but values up to 100 ng/dl have been re-ported [13]. The castration testosterone cut-off point of 50 ng/dl or less derives from assay methods developed in the late 1960s and early 1970s [12]. These early methods used the double-isotope-derivative dilution technique, which had 50 ng/dl as the lower detection limit. These methods of measuring serum testosterone have been abandoned for the more rapid and accurate radioimmunoassay technique and, more recently, the chemiluminescence technique. Despite these advances in methodology with more accurate lower limits of detection however, the definition of testosterone levels after bilateral orchiectomy has not been updated.”

    I also found two additional small Japanese studies (see below) that were consistent with this range:

    Japanese research published in 1997: 4 metastatic patients showing post-orchiectomy testosterone ranging from 10 to 17.

    Japanese research published in 2003: small study pre- and post-orchiectomy or ADT: post-orchiectomy value of serum testosterone 0.15 ng/mL, or 15 + 0.05 ng/dL (8 patients); post-ADT 0.14 + 0.07 ng/mL, or 14 ng/dL (9 patients)

    See also a Spanish article from 2007 finding clinical significance in serum testosterone levels well below 50 ng/dL, especially 32 ng/dL, after ADT.

    I do recognize that a level of less than 50 ng/dL will catch the vast majority of patients, but that leaves a few with inadequate androgen suppression, and those few, probably ranging from 5% to 10% based on one study and comments I have heard over the years, have the potential to mess up analysis and interpretation of some studies that have falsely assumed adequate testosterone suppression. If I were in charge, I would want to eliminate that possibility, and that is quite easy to accomplish.

  10. Dear Jim:

    With the greatest respect, I am well aware of these papers. At best they constitute pilot studies (and even that is a stretch). And once again I am going to point out that having this conversation on this web site will accomplish absolutely nothing.

    What is going to be necessary are data on serum T levels after orchiectomy and after standard ADT in several hundred patients according to a single standard laboratory protocol (not a sophisticated research protocol). None of the studies you refer to (including the studies referenced in the Italian review) come close to meeting that set of criteria. One is then going to have to determine not the average level of serum T, but the range. If there is going to be an acceptable new standard for defining a “castrate” level of serum T using this particular way of measuring serum T, the acceptable level would probably need to be the upper 95th percentage level of all of the results as compared to the median.

    Get that study done; then take it to the PCWG and the FDA, and you might have a shot at seeing some change. The current conversation is all speculation and is based on meaningless data from (mostly) very small data sets (many probably compiled retrospectively).

    Please understand that I am not saying you are wrong. What I am saying is that the discussion is pointless without a truly meaningful new set of prospective data that can support your argument, and even then the new “castrate” level will not be the lowest level or the median level or the mean level, but a level that would include something like 95% of all patients.

    I would point out that this would not be a difficult study to do. Thousands of men start on ADT every year and have their serum T levels reduced to nominally castrate levels. One could probably do this study in 6 months with collaboration from half a dozen major prostate cancer centers.

    I am not the person you need to convince (and neither, as far as I am aware, is any other reader of this web site). It took about 150 years before we redefined the “normal” average body temperature among adults down from 98.6 F to 97.7 F (see here). And even then, the new number is not considered to be “right” for all people because some of us simply have biological “engines” that run hotter or colder than the average. Similarly, there is probably not any type of “absolute” castrate serum T level after an orchiectomy. There will be a range.

    An utterly different concept (which is really what you are talking about) is an ideal serum T level after any form of androgen suppression that can be associated with the highest quality of outcome in terms of impact on prostate cancer progression. That we already know. It is probably something like < 20 ng/dl. However, as I said in my prior message, you'd still need to do a prospective study to prove this, and so such study has ever been done.

  11. Thank you for your reply. Also, it is nice to know that I am, in fact, “normal” (“the “normal” average body temperature among adults down from 98.6 F to 97.7 F” – didn’t know that). LOL

  12. As an interested reader, I want to say that I generally appreciate the information that Jim has to offer. But my time for reading these things is limited, so I would implore him to try to make his points in the least wordy way possible. These lengthy discussions seem a bit futile to me.

  13. Tom, thanks for your feedback comment.

    I am aware of the length issue; it’s the main reason I often use a title with the thought that those not interested in a particular aspect will just bypass that comment. It’s also why I typically address only one aspect in a comment. However, I do often see the need to make a credible case, and that requires at least mentioning the key points and indicating at least some supporting information. Otherwise, don’t we get down to just low credibility sound bites? Any suggestions?

  14. As of 11/28/18, four sites in the UK are listed so Sitemaster may wish to amend his last paragraph.

    I also note the contact parties for the Arizona & Nevada sites have been switched; I have notified the trial coordinator.

  15. The lead investigator told me that he expects to have 30 sites eventually.

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