Second-line therapy for progressive, high-risk prostate cancer: time for a STAMPEDE-like trial?

Let’s say you are 58 years of age, in apparently excellent health for your age, when you get diagnosed with high-risk prostate cancer, based on a Gleason score of 4 + 4 = 8, a PSA level of 3.7, and a clinical stage of T1c, with 4/12 biopsy cores positive for cancer.

It doesn’t take you long to work out that men with Gleason 8 disease are reasonably likely to already have extracapsular and possibly micrometastatic disease that may not be curable with any standard form of first-line therapy. (The Kattan pre-treatment nomogram actually projects that such a patient has a 14 percent chance of biochemical progression within 10 years if he is treated surgically.) You also quickly grasp the fact that you can’t just monitor Gleason 8 disease.

So (unhappy though you are about it), you bite the bullet and you go in for surgery (knowing that adjuvant or salvage radiation therapy then remain an option, if necessary). The cancer seems to be limited to your prostate (pathological stage pT2b and still Gleason 4 + 4 = 8). There are no signs of extracapsular disease or positive seminal vesicles or positive lymph nodes, and there are no positive surgical margins. Your PSA drops into the undetectable range and stays there … for 9 months. Then it starts to go up, with a PSA doubling time of 7 months. What are you going to do now?

Historically, when we think we know where the recurrence is (and sometimes when we don’t), we have usually treated men like this with either salvage radiation therapy or with a combination of salvage radiation therapy + androgen deprivation (ADT). But have we actually been selling them short? Many such men go on to have metastatic disease.

There is an increasing amount of data to suggest that early chemotherapy (or other forms of therapy still in development) may be appropriate in patients like this … along with the radiation and the ADT. This would especially be an arguable premise among younger men with a life expectancy of 15+ years. If you want to cure prostate cancer in a man like this, why would you not “throw the book” at the cancer? We know that we can’t actually cure the vast majority of men with evident metastatic disease.

The CHAARTED trial has clearly shown a major benefit to the early use of the combination of ADT + docetaxel chemotherapy in men with metastatic, hormone-sensitive prostate cancer (and especially in men with a high load of hormone-sensitive disease). A new study by Zielinski et al., in Canada, has shown that men who get docetaxel-based chemotherapy (addmittedly, very late in their disease course) do better in general than men who don’t get chemotherapy. However, conversely, the GETUG-AFU 15 trial, carried out some years ago in France and Belgium, did not show any significant benefit associated with early use of docetaxel-based chemotherapy in high-risk, androgen-sensitive patients with metastatic prostate cancer. But men in this trial were only required to have a life expectancy of 3 months. Could too many men in this trial have been too far along in either their life or their cancer to have a strong chance of benefit?

The “New” Prostate Cancer InfoLink thinks that maybe it is time to initiate a STAMPEDE-like trial of second-line therapies for progressive but non-metastatic, high-risk prostate cancer post-surgery. There are plenty of possible therapeutic regimens available that could be tested in such a study:

  • Salvage external beam radiation therapy alone
  • Salvage external beam radiation therapy  + ADT
  • Salvage external beam radiation therapy  + ADT + adjuvant sipuleucel-T
  • Salvage external beam radiation therapy  + ADT + docetaxel chemotherapy
  • Salvage external beam radiation therapy  + ADT + abiraterone acetate
  • Salvage external beam radiation therapy  + ADT + enzalutamide

and that’s without even thinking about the options too hard.

Patients would need to be appropriately stratified prior to randomization, based on their ages and their risk levels, and there should probably be a minimum life expectancy of 3 years for entry into the trial. The primary trial endpoint is an easy one — evident onset of metastatic prostate cancer on a bone or CT scan.

The STAMPEDE model could be easily adapted to conduct a trial of this type. All we need is the will and the … Oh, that’s right, the funding to support the study! Let’s be optimistic, maybe America’s politicians will all come back to their senses after November 2 and actually decide to think about how to fund the NIH at a meaningfully reasonable level again!

6 Responses

  1. Mike

    Totally agree. We need better and more powerful options implemented sooner for men like those you described in your write up.


  2. I would think about not throwing the book at the patient described specifically because there is no proof that such effort has reward. Also, side effects.

  3. Dear Tarhoosier:

    I very carefully wrote, “If you want to cure prostate cancer in a man like this, why would you not “throw the book” at the cancer?”. Of course there is a risk for side effects, but we also know that if you don’t cure such a patient before his cancer metastasizes, we have a very low chance of curing it later (although there are rare exceptions).

    And the fact that “there is no proof that such effort has reward” is exactly the point. There is also no proof that it doesn’t. However, I am aware of many younger men who took this course outside of clinical trials who did very well indeed. Is a trial like this appropriate for relatively frail 75-year-olds? Probably not. But for significantly younger men with a life expectancy of another 25+ years if they can be put into long-term remission or actually cured, I would consider the situation to be very different.

    Interestingly, 17 years ago, when I helped to form the National Prostate Cancer Coalition, a leading breast cancer advocate who had been invited as a speaker asked the attendees at the meeting then, “Why are you men, particularly the young ones, so unwilling to seek really aggressive chemotherapy for high-risk prostate cancer? It works for high-risk breast cancer!” She’s still alive and holding down an important job in Washington, DC today. Apparently the same question may need to be asked again.

  4. There was a Phase 2 trial (RTOG 0621) that was similar to the study of docetaxel + aRT you’re advocating. Their setting was slightly different from your model patient — the patients either never reached an undetectable nadir and were Gleason ≥ 7 post-prostatectomy, or they were Gleason ≥ 8 and reached a nadir ≤ 0.2 but were found to be ≥ pT3. They found that the 3-year freedom from progression was 71% vs about 50% from historical models without docetaxel. It certainly seems worth a Phase 3 trial. Sadly, with cuts in NIH funding and no incentive for Big Pharma in this trial, it may not get funded.

  5. Excellent commentary Mike – just wondering what generated it now … or is it something that has been on yours and many of our minds for some time?

  6. Can’t remember … I wrote it days ago … And I never wonder why I wrote things later! :O)

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