Is possible new prostate cancer vaccine really “promising”?

A new article on the Medscape Oncology web site (and again correlated with a media release sent out by the European Association for Urology [EAU] from their annual meeting in Milan, Italy) is headed “Prostate cancer vaccine shows promise.” However, the degree of that “promise” appears to be open to some question.

Of the two opinions leaders contacted by Medscape to seek expert commment on the study data presented by Kimura et al. at the EAU annual meeting, one suggested that the study offered interesting “but limited” information; the other was very clear in stating that, “I would like to see more promising data before I truly believe that prostate cancer vaccines will play a major role in the treatment of this common disease.”

The study by Kimura et al. offered data from 71 men with early stage, castration-resistant prostate cancer (defined by a PSA level of < 10 ng/ml) who were randomized to receive either individualized combinations of peptide vaccines (referred to a “multipeptide” vaccines) and a low dose of dexamethasone (a glucocorticoid) at 1 mg/day or to dummy injections of a placebo and low-dose dexamethasone, with no multipeptide vaccine. (The report does not state this, but we assume that the dummy injections would have been of simple saline.)

Blood samples were drawn from all 71 patients. For the men randomized to receive a multipeptide vaccine + dexamethasone, each of the patients was evaluated for his immunologic reaction to each of 24 peptide candidates. Then, for each patient, up to four different peptides with high rates of immunologic response were combined to form an individualized multipeptide vaccine. The individualized vaccines were then administered to the patients as subcutaneous injections in six doses over a period of 2 weeks — along with the above-mentioned dexamethasone.

According to Dr. Kimura:

Dexamethasone is a glucocorticoid known to have antitumor activity for patients with castration-resistant prostate cancer.  Peptide vaccines are recognized by antigen-presenting cells, such as dendritic cells, which activate peptide-specific cytotoxic T lymphocyte precursors specific for the pre-existing tumor antigens that exist in the circulation of the patients.

The primary endpoint of the study was PSA progression, defined as a PSA level at least 25 percent higher than the patient’s nadir level or or an absolute increase of 2 ng/ml.

Kimura et al. report that:

  • PSA response was not significantly different between the vaccine and non-vaccine groups after the first vaccination.
  • The median time to PSA failure in the vaccine group was longer than in the non-vaccine group.
    • 542 days in the vaccine + dexamethasone group
    • 203 days in the placebo + dexamethasone group
    • This difference was certainly statistically significant (P = 0.0008).
  • With respect to toxicity and safety,
    • No severe adverse events were reported in either study arm.
    • 19 patients in the vaccine + dexamethasone arm experienced injection site reactions.
    • 2 patients in the placebo + dexamthasone arem experienced injection site reactions.
    • 11 patients in the vaccine + dexamethasone arm experienced pruritis.
    • 3 patients in the placebo + dexamethasone arm experienced pruritis.

Kimura is quoted as concluding that “our peptide vaccination therapy in combination with dexamethasone may be a potential tool for chemotherapy-naïve castration-resistant prostate cancer patients.”

That may indeed well be the case, but, like the opinion-leaders with whom Medscape’s reporter discussed this presentation, The “New” Prostate Cancer InfoLink would like to see a good deal more data before we accept this as a real possibility. There are compelling data to suggest that time to PSA failure is probably not the best indicator of the effectiveness of cancer vaccines in the management of late stage prostate cancer. Furthermore, it is highly unlikely that any new vaccine for the treatment of late stage prostate cancer will be approved in the USA without compelling evidence of an overall survival benefit.

It seems to us that Kimura and his colleagues will need to complete at least a small, randomized, Phase II clinical trial in which patients are followed long enough to demonstrate a survival benefit before anyone will invest in a large, randomized, Phase III trial that might lead to the approval of this product for clinical use.

7 Responses

  1. Well, “promising” does not seem to me an extravagant claim.

    Even the dexamethasone + placebo group is claimed to have had a median “203 days” to “PSA failure.” And this is the first I’ve heard of dexamethasone. So I’m not putting up my nose at “multipeptide vaccine.”

  2. Dear Grover:

    Just so that you are aware, dexamethasone is actually a very well studied agent that is routinely used in the management of cancer and other disorders. It is similar to prednisone. Indeed, the early studies of abiraterone acetate were done with low-dose dexamethasone as opposed to prednisone, and one of the leading investigators wanted to do the Phase III trials of abiraterone in combination with low-dose dexamethasone. I agreed with him; others didn’t.


    Thanks for reporting this encouraging research.

    As you note, Sitemaster, PSA response appears to be less than reliable for assessing the success of vaccines as prostate cancer treatments. On the other hand, it would help us greatly if we had some substitute for survival to measure the success of a vaccine, especially to measure success early after vaccine administration to verify whether the patient was responding.

    Regarding end points for assessing the success of vaccines for prostate cancer, I have heard from a doctor directly involved that at least one of the new and much more effective imaging techniques is on the verge of trial use as an assessment tool for an existing vaccine. These techniques are far better than the old techniques for measuring the number and size of metastases in the lymph nodes and bones, and the new levels of effectiveness suggest potential to measure success of vaccines by establishing patient baselines and then checking for changes in the number, locations, and sizes of metastases after vaccine administration.

    Some of the new techniques are the sodium [18F]fluoride PET/CT bone scan (which I’ve had), the Feraheme Ultrasmall Superparamagnetic Iron Oxide contrast agent 3 Tesla MRI scan for lymph node metastasis (which I’ve had), the [11C]choline PET/CT scan being used at the Mayo Clinic in Rochester, MN, by Dr. Kwon and his colleagues, and the [11C]acetate PET scan being used by Dr. Almeida in Phoenix, AZ. (The [11C]choline PET/CT scan and [11C]acetate PET scan were discussed in detail by Drs. Kwon and Almeida respectively at the 2012 Conference on Prostate Cancer at Los Angeles last September. I’m hoping that Dr. Charles Myers will discuss research results with the Feraheme scan at this September’s conference. Informal reports indicate the Feraheme scan, as used by Dr. Stephen Bravo in Florida, can reliably detect lymph node mets as small as 2 mm, and at times as small as 1 mm. I understand that a publication should appear this year.)

    On a personal note, based on results from the Feraheme and sodium [18F]fluoride PET/CT bone scans, I chose to attempt a cure for my challenging case with TomoTherapy including pelvic coverage. I have completed my third week (14 of 39 sessions).

  4. Of course I am pleased that not only is this agent new to me but is in fact “well studied.” I add it among the following: abiraterone acetate (Zytiga), ARN-509, cabazitaxel (Jevtana), cabozantinib, degarelix (Firmagon), dexamethasone, docetaxel, enzalutamide (MDV3100 or Xtandi), finasteride, galeterone, ipilimumab, itraconazole, ketoconazole, “multipeptide” vaccine, orteronel, Prostvac-VF, and sipuleucel-T (Provenge).

    As my 2+ years of hormone therapy draws to an end, I can only hope — but not blindly — that my oncologist’s knowledge of all these and their appropriate sequencing allows (not assures) enough time for me to make it to the next generation of treatments. “Assures” does not seem to be a completely reasonable hope. The “New” Prostate Cancer Infolink is my “promising” source of information to test that he is keeping up.

  5. Dear Jim:

    While it may be possible to use one or more of the imaging tests you refer to as “proof of concept” in Phase II trials, based on prior history I think it is highly unlikely that regulatory agencies are going to accept data on either the number or the size of metastases as proof of efficacy in Phase III (pivotal) trials required for actual product approval. There are now too many cases in which it has been clearly shown that progression-free survival does not correlate with overall survival.

    The FDA has certainly been making it clear that they expect overall survival data as the standard for approval of new agents in the treatment of prostate cancer if at all possible. The exception at this time appears to be quality of life for men who have previously failed multiple available forms of androgen deprivation therapy and at least one form of taxane-based chemotherapy.

  6. Sitemaster’s respone of March 23 at 2:03 pm to my post of 9:51 am about IMAGING AS RESEARCH PROOF (“endpoints”)

    I appreciate and basically concur with your well-taken points.

    However, I’m thinking that new, potentially and apparently much more credible forms of success evidence for prostate cancer may lead the way toward FDA approvals that are not heavily based on either overall survival or quality of life, which is clearly the situation at the FDA and its Oncologic Drug Advisory Committee at present.

    Background that is still relevant was developed during the “FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer,” held June 21-22, 2004, which I was fortunate to attend. The workshop involved many of the heavy hitters in prostate cancer research (and also involved the public, including me as a moderately savvy patient), and, though nearly a decade in the past, many of the issues still resonate. My own bottom line as a patient was there was no clear winner seen at the workshop to replace overall survival, though Dr. D’Amico made a strong impression with his PSA doubling time research (which has since seen its share of follow-up and pro and con comment).

    For those of us who are gluttons for mental punishment, fairly detailed summary information is available online. The URLs for the June 21 morning and afternoon sessions, respectively, can be found here and here.
    (My own audience question is second from the end on page 19. This was fortuitous for me as Dr. Marge Foti, PhD, Executive Director of the American Association for Cancer Research, approached me after the session and suggested I apply for the AACR’s wonderful Scientist-Survivor Program. I’ve served three times.)

    Here is the URL for the second day’s session.

    Page 10, covering part of the morning of the first day, included a talk by Stephen M. Larson, MD, PhD, entitled “Monitoring treatment response of rrostate cancer: bone scan and beyond.” He noted deficiencies of then current technetium-based (still typical) bone scans for assessing progression for patients in trials, but he looked forward to FDG (glucose-based) PET scans as an upcoming improvement. Now, it is recognized that such FDG PET scans are fairly good for well advanced patients but not useful for other prostate cancer patients. However, Dr. Larson also envisioned other metabolic markers with PET imaging, and it looks to me that the Na18F PET/CT scan may satisfy the need, providing cancer-specific findings that fairly rapidly reflect tumor response. Perhaps someone can comment on research about that, and about the potential advantages of the Na18F PET/CT scan over the FDG version for use in assessing progression in clinical trials. I believe I am accurately reflecting the sense of the workshop participants that as of June 2004 bone scans were not the gold standard for clinical trials; indeed, the participants seemed to concur that bone scans with technetium were not all that useful. I’m really curious what the workshop participants would now think of the Na18F PET/CT scan for bone scan evidence of success in clinical trials.

    As for other imaging, which was addressed to some extent during the workshop, for years my impression was that a fusion ProstaScint scan was about the best soft tissue assessor, but that it was not all that accurate, especially regarding false positives. In sharp contrast, we now have the emergence of the feraheme USPIO PET/CT scan, the C11 PET scan, and the C11 acetate scan all appearing to be accurate tools for assessing spread to the lymph nodes (down to 1 to 2 mm), and perhaps other soft tissue. Such apparently reliable technology simply did not exist until the recent past.

    Sitemaster, I recognize your point that “There are now too many cases in which it has been clearly shown that progression-free survival does not correlate with overall survival.” However, my impression is that the indicators of progression were too insensitive to provide clear signals of what was happening. I’m thinking that modern emerging imaging may indeed result in close correlations of progression and survival. Any thoughts?

    I’m hoping studies using these new tools will persuade members of the FDA’s Oncologic Drug Advisory Committee and other relevant advisory committees to appreciate indicators other than overall survival in assessing agents for prostate cancer treatment and monitoring. This is especially important for prostate cancer as overall survival is such an awkward indicator because of the typically long survival for most of us except for quite elderly patients, patients with other serious medical problems, and/or those with very advanced prostate cancer. Moreover, the wonder of a number of new drugs recently or soon to be available for late-stage patients should further lengthen survival, making the “problem” “worse”. Indeed, I think this was somewhat a problem in delaying closing of the key trial leading to approval of Provenge.

    Long survival is not a “problem” with many other cancers. While that is a nice problem to have, I’m optimistic the FDA will in the near future get away from its “one size fits all” criterion for judging success in clinical trials for us prostate cancer patients!

  7. Dear Jim:

    (1) Every one of the newer forms of scan you refer to still have significant false positive and false negative rates.

    (2) I am aware of no good research (as yet) that has correlated the use of these newer scanning methods to actual survival in such a way as to make it even close to clear that these types of scan could be used as accurate surrogate endpoints for overall survival.

    (3) Most of the data showing that the various older means of assessing progression in prostate cancer do not correlate to actual survival came several years after the 2004 worekshop you refer to.

    In my opinion, unless and until someone comes up with a very different type of test to anything we have available today, overall survival will remain the required standard for approval of any new drug for the treatment of advanced prostate cancer.

    The clinical utility of the tests you refer (i.e, their value in managing the care of an individual patient) needs to be carefully differentiated from their utility as ways to accurately assess the therapeutic efficacy of new drugs.

    I would also point out that prostate cancer is now far from being alone in the long period of time from progression to death for many patients. Patients can now live for 20+ years from diagnosis to death with cancers like breast cancer, myeloma, and several others, just as some people diagnsed with prostatge cacner can die within a year of diagnosis. We now know not to think of most organ-defined cancers as coming in only one “flavor.” The Prostate Cancer Foundation currently believes there may be as many as 25 different subtypes of prostate cancer.

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