Unexpected and perhaps intriguing data from the STAMPEDE trial

In a poster presentation to be given at the upcoming Genitourinary Cancers Symposium in San Francisco later this week, data from the STAMPEDE trial in the UK appear to have demonstrated a result that few people seem to have expected.

James et al. (abstract no. 192; “Celecoxib with or without zoledronic acid for hormone-naïve prostate cancer: survival results from STAMPEDE”) are scheduled to report that, compared to the “standard of care” or SOC alone, the combination of SOC + celecoxib (Celebrex) + zoledronic acid (Zometa) has shown a small survival benefit in treatment of men diagnosed with metastatic prostate cancer who were starting hormone therapy for the first time.

The STAMPEDE trial is a very large, complex, randomized, controlled trial that is based on an innovative, multi-arm, multi-stage design. For the original discussion of this trial on The “New” Prostate Cancer InfoLink, please see here. Information about the STAMPEDE trial design is also available on the ClinicalTrials.gov web site; it continues to evolve and recruit patients today.

Basically, STAMPEDE is designed to recruit patients with high-risk, locally advanced or metastatic prostate cancer who are starting on long-term androgen deprivation therapy (given by either orchiectomy [surgical castration] or an LHRH agonist [medical castration]) for the very first time. Thus, one arm of the STAMPEDE trial is this form of “standard of care” or SOC for a period of at least 2 years. SOC also encouraged the use of pelvic radiation therapy for any patients who have TxNxM0 disease (i.e., no evident sites of metastasis to bone or other soft tissue on a bone scan or CT scan).

In other arms of the trial, patients are then given additional forms of therapy to see if these can improve overall survival, prostate cancer-specific survival, and metastasis-free survival compared to SOC.

With respect to the data to be presented by James et al. at the Genitourinary Cancers Symposium, we are focused on patients randomized to three arms of the trial:

  • The SOC or “control” arm (Arm A)
  • The SOC + celecoxib arm (Arm D), in which patients also received celecoxib (400 mg) twice daily for the first year
  • The SOC + celecoxib + zoledronic acid arm (Arm F), in which patients also received both celecoxib (400 mg) twice daily for the first year and zoledronic acid (4 mg) for six 3-weekly cycles and then 4-weekly he first 2 years.

Two patients were randomized to Arm A for each patient randomized to Arm D and Arm F (a so-called 2:1:1 randomization design). The primary outcome measure was death from any cause.

So here are the basic results to be reported by James and his colleagues:

  • A total of 1,245 patients were randomized to the three study arms between October 2005 and April 2011.
  • The average (median) PSA level of the patients was 66 ng/ml at time of study entry.
  • The average (median) age of the patients was 65 years and the patients were well balanced across the three arms, with
    • 61 percent having metastatic (TxNxM1) disease
    • 14 percent having either TxN+M0 or TxNxM0 disease
    • 25 percent having TxN0M0 disease
  • 94 percent of the patients were newly diagnosed.
  • Average (median) follow-up was 62 months (i.e., just over 5 years).
  • Clinically serious (Grade 3, 4, and 5) adverse events occurred in about a third of the patients in all three study arms.
    • In 35 percent of men in the SOC arm (Arm A)
    • In 32 percent of men in the SOC + celecoxib arm (Arm D)
    • In 32 percent of men in the SOC + celecoxib + zoledronic acid arm (Arm F).
  • In the SOC arm, during the follow-up period,
    • 295 patients died for all causes.
    • 242 of those deaths (82 percent) were prostate cancer-specific.
    • Average (median) overall survival was 68 months.
  • Compared to the data from patients in the SOC arm,
    • For patients in the SOC + celecoxib arm (Arm D), the adjusted hazard ratio (aHR) = 1.00 (p = 0.99) and the median overall survival was 69 months.
    • For patients in the  SOC + celecoxib + zoledronic acid arm (Arm F), aHR = 0.86 (p = 0.16) and the median overall survival was 74 months.
  • Compared to the data for patients with metastatic disease in the SOC arm,
    • For patients with  metastatic disease in the SOC + celecoxib +zoledronic acid arm (Arm F), HR = 0.78.

James et al. conclude that their data

show no survival advantage for the addition of celecoxib alone for men starting long-term [ADT]. However, the addition of celecoxib combined with [zoledronic acid] demonstrated a survival advantage for men with metastatic disease, in a pre-planned analysis.

Now the survival benefit reported here doesn’t reach anything approaching the survival benefit previously shown by the STAMPEDE trial from immediate treatment of the same group of men with SOC + docetaxel-based chemotherapy. The question that this result does raise, however, is whether men with metastatic prostate cancer who are starting on ADT for the first time would benefit more from initial treatment with SOC + docetaxel-based chemotherapy + a COX-2 inhibitor like celecoxib + zoledronic acid as opposed to the simpler SOC + docetaxel-based chemotherapy.

As James et al. also note, this finding is probably going to require further investigation. There is no immediate reason to be able to see why the reported outcome would occur. From this report we can see that adding celecoxib alone to SOC had no impact on overall survival, and from previous reports we know that adding zoledronic acid alone to SOC had no impact on survival in the same categories of patient.

4 Responses

  1. The biochemical basis for testing these substances in the STAMPEDE trial was that the bone microenvironment might be rendered less conducive to the growth of metastases. We’ve seen the association with progression in many studies with inflammation, and it seems to be both cause and effect. Some studies showed that ADT makes the bone microenvironment more hospitable to metastasis development (an effect vastly overpowered by its blocking of androgen-receptor mediated growth), but Zometa or Xgeva prevents that effect if used at the start of ADT. There have been conflicting findings.

    In the TROG 03.04 RADAR study they found that Zometa delayed progression only in men with Gleason scores of 8 to 10. I suspect that there is a certain phenotype that is more susceptible to the combined treatment.

    Zometa, Prolia, or Xgeva is often prescribed anyway at the start of ADT to prevent bone loss and skeletal events, so adding Celebrex (or aspirin) seems to be a minor addition that may have some good effect.

  2. Curious About the Patients Not on Zometa

    This strikes me as an interesting result.

    As a long-time veteran of ADT, protection of bone mineral density while on therapy seems essential. Were the men not given Zometa on some other type of protection, such as a bisphosphonate, denosumab, or estrogen skin patches? I hope so.

    (I was also on Celebrex at different dose levels at times. At one point it appeared to slow PSA doubling, but not dramatically or for long for me. Still, as the ads asserted, I felt good while on the drug — definitely knocked the old arthritis back.)

  3. No. … This was a trial which included an arm in which SOC + zoledronic acid was specifically included to test whether it provided a survival benefit. It didn’t.

  4. Then I’m sure glad I wasn’t in the placebo arm of this trial!

    After about 9 months on Lupron (and other drugs) after diagnosis, my first DEXA scan for bone density registered average density in the osteopenia range, including two lumbar vertebrae in the osteoporosis range. Of course, I may have had some decreased density before starting treatment. To me, long-term ADT without protecting bone mineral density is nuts!

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: