One of the major unanswered questions at this time is whether immunotherapy of some type, if given early to patients with prostate cancer, can help to lower risk of progression of the disease.
Sipuleucel-T (also known as Provenge) was approved several years ago now for the treatment of men with asymptomatic or minimally symptomatic, metastatic, castration-resistant prostate cancer, i.e., men with metastatic disease who were starting to progress after treatment with androgen deprivation therapy (ADT). However, from the time of its original development, a key question has been, “What if you could give sipuleucel-T and similar drugs much earlier?”
The so-called STAND trial (NCT01431391) was initiated in 2011 and was designed to start to tell us whether, in men with biochemically recurrent prostate cancer after initial treatment with surgery and/or radiotherapy, the addition of treatment with sipuleucel-T to treatment with ADT seemed to make any potential difference to the outcomes of these patients and to see if the order in which these drugs was given made any meaningful difference.
It is important to note that the men who were enrolled in this trial also had to have (a) no sign of metastatic disease and (b) a PSA doubling time of 12 months or less at the time of their enrollment into the trial. In other words, these were men at relatively high risk for metastasis and also for prostate cancer-specific death over time.
The full text of the final results of the STAND trial have now been published by Antonarakis et al. in Clinical Cancer Research. But this was a relatively small, Phase II clinical trial, and so interpretation of the results has to be done with some care. Here are the basics.
The trial enrolled a total of 68 patents who were randomized to treatment in one of two different ways:
- Initial treatment with sipuleucel-T immunotherapy followed, 2 weeks after the immunotherapy was completed, with initiation of continuous ADT for the next 12 months (Group A, n = 34) or
- Initial treatment with ADT followed, 12 weeks later, with initiation of sipuleucel-T immunotherapy, while the ADT was continued for 12 months in total (Group B, n = 34)
The researchers used a highly specialized test called the ELISPOT test to see if there was any differences in the levels of T cells among the men over time. The ELISPOT test is used to measure a specific type of T cell response to treatment.
Here are the trial results:
- The ELISPOT results were pretty much the same in both groups of patients over time, except at 6 weeks after initiation of ADT.
- At 6 weeks after initiation of ADT the ELISPOT results were higher (i.e., better) in Group A than in Group B.
- When averaged over time, the specific T cell response levels were about twice as high in Group A as opposed to in Group B.
- Compared to baseline levels
- The specific T cell responses increased and were maintained for 24 months in Group A and in Group B.
- Prostatic acid phosphatase (PAP)-specific responses were also higher and were also maintained for 24 months in Group A and in Group B.
- PSA recurrence occurred during the follow-up period in
- 5/34 men (15 percent) in Group A
- 11/34 men (32 percent) in Group B
- The average time to PSA recurrence after the first injection of ADT was similar in Group A (21.8 months) and in Group B (22.6 months).
- There was a correlation between the development of the specific T cell response and prolonged time to PSA progression (hazard ratio [HR] = 0.22, P = 0.007).
- There were no differences between Group A and Group B with respect to
- Time-to-testosterone recovery (≥175 ng/dl) after stopping ADT
- Time to the next anti-cancer intervention
- Rate of metastatic progression
- Treatment with the combination of sipuleucel-T and ADT was generally well-tolerated.
Now what we really don’t know from this trial is whether adding the sipuleucel-T to treatment with ADT made any difference to the time to PSA progression for these patients (because we had no arm of the trial with patients who were given ADT alone).
Antonarakis et al. conclude that the patients in Group A seemed to show “greater antitumor immune responses” than the patients in Group B. They then state that:
These results warrant further investigation to determine if this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation.
The bottom line appears to be that:
- We can certainly give patients with progressive prostate cancer treatment with the combination of sipuleucel-T + ADT.
- It may or may not make any real clinical difference whether we start the sipuleucel-T first or the ADT first, but starting the sipuleucel-T first seems to have benefits in terms of immunological responses.
- We really have no idea — as yet — whether this type of therapy makes any difference to the long-term outcomes of ADT-sensitive patients who would historically have been starting ADT after biochemical progression.
It seems highly unlikely that these data would make any insurance company willing to pay for the early use of sipuleucel-T in combination with ADT. That would require data from a much larger trial, and that trial would probably need to show one or more of the following:
- A meaningful difference in overall survival of men treated with sipuleucel-T + ADT compared to similar men treated with ADT alone
- A meaningful difference in time to onset of evident metastatic disease among men treated with sipuleucel-T + ADT compared to similar men treated with ADT alone
Whether such a trial will ever actually get done is impossible to predict.
Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: "high risk", ADT, immunotherapy, metastasis, outcome, progression, sipuleucel-T, survival |
THE "NEW" PROSTATE CANCER INFOLINK 
Based on that test, why would my urologist want to do Provenge on me with innumerable bone metastases?
Dear Sitemaster,
Once again, I’m baffled by the seemingly obvious design flaws in clinical trials designed by very smart people. It is difficult to understand why they did not include an arm in this trial for men who would receive only ADT. This flaw provides the insurance companies with a perfectly legitimate reason, as you have noted, not to cover sipuleucel-T use in high-risk, hormone-sensitive patients, despite the fact that we hear nearly all oncologists espousing the use of immunotherapies earlier in the disease process. This trial tells us what we already knew (that sipuleucel-T would increase T cell counts), but it does nothing to advance patient treatment for the foreseeable future.
The CDMRP research funding process values the input of consumer reviewers to help evaluate the potential impact of research proposals on the prostate cancer patient population. Maybe academic researchers and pharmaceutical companies need to establish a similar model before going ahead with their research projects. In my opinion, this trial was a lost opportunity to advance patient care.
Dear Len:
This trial was first implemented relatively soon after sipuleucel-T was approved by the FDA. I suspect that the manufacturer (which was funding the trial) had no interest in discovering that if you gave sipuleucel-T earlier, in combination with ADT, to hormone-sensitive patients, that either there was no clinically significant effect on patients’ outcomes.
Dear Stu:
I am not sure why any physician would want to be giving sipuleucel-T to any patient with extensive or “innumerable” bone metastases. There are no data to suggest that it is beneficial in the treatment of such patients.
My thought also, but I get tired explaining things to him.
Larry Fong, the Provenge PI, conducted a relevant trial supporting the relevance of early use of sipileucel-T; results were published in 2014.
In this Phase 2 trial, Provenge was given to men with localized disease prior to RP. Analysis of the post-op pathology showed T-cells ringing the tumor.
If this is the physiological response for men with early disease, why can’t we assume it happens in later stages. The unanswered question is its empirical effect on disease progression.
Dear Rick:
An immunological response like this in early-stage, high-risk patients is intellectually and scientifically interesting, but without long-term follow-up in comparison to men with similar pre-treatment biology who had an RP but no Provenge, there is no way to tell whether it has any clinical value. And you need to remember that the process of extracting the cells for processing is not exactly benign.