Sipuleucel-T before or after ADT in men with biochemically recurrent disease?


A paper to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago is entitled, “A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): immune results.”

This paper, to be presented by Antonarakis et al., addresses whether, in a man with biochemically recurrent disease after first- or second-line therapy for localized disease who is considered to be at high risk for metastasis, it is better to do one or other of the following:

  • Treat the patient with sipuleucel-T first, and then add ADT or
  • Start the patient on ADT and then, after a short “run-in” periodof ADT, add treatment with sipuleucel-T while maintaining the ADT.

Although sipuleucel-T (Provenge®) is currently approved only for the treatment of asymptomatic and minimally symptomatic, metastatic, castration-resistant prostate cancer (mCRPC), the question addressed in this study is of importance because it looks at the key question of just how early patients with progressive disease may benefit from treatment with sipuleucel-T.

This Phase II study, the co-called STAND trial, randomized 68 eligible patients (i.e., men with biochemically recurrent prostate cancer and a PSA doubling time of ≤ 12 months) to one or other of the following forms of treatment:

  • Sipuleucel-T followed by 12 months of ADT — starting 2 weeks after the third infusion or sipuleucel-T (Arm 1, given to 34 men) or 
  • 3 months of ADT (i.e., a 3-month lead-in period) followed by sipuleucel-T and an additional 9 months of ADT (Arm 2, also given to 34 men)

All 68 patients had three infusions of sipuleucel-T and 12 months of ADT in total (45 mg leuprolide s.q. at 6-month intervals). The primary endpoint of the study is cellular immune response to treatment. Secondary endpoints are humoral and cytokine responses, product parameters, and safety.

Here are the preliminary study findings:

  • Higher levels of serum cytokines were observed in men in Arm 2 as compared to Arm 1.
  • The pattern of these serum cytokines suggests a mixed TH1/TH2 cellular immune response.
  • Elevations were observed in  the TH1 (IFNγ, IL-12), TH2 (IL-4, IL-5, IL-10, IL-13) and TH17 (IL-17) subsets (all P < 0.05).
  • The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT immune responses 2 weeks after the third sipuleucel-T infusion in Arm 2 vs. Arm 1 (40.5 vs. 12.8 spots; P = 0.086).
  • Antigen-specific humoral responses were induced in both arms of the trial with no differences yet observed between the arms.

Antonarakis et al. conclude that these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation.”

The authors further note that, while these data will require further confirmation, “they are consistent with preclinical studies showing that ADT enhances T-cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity.”

What these data do not tell us, however, is the following:

  • Whether augmented immune responses in men receiving ADT before sipuleucel-T will correlate with future clinical data (such as the onset of PSA recurrence)
  • Whether using sipuleucel-T alone in men with high-risk disease before the onset of biochemical recurrence may be able to significantly delay biochemical recurrence altogether.

We would emphasize again that the data presented in this paper are preliminary and can not yet be used to justify the clinical use of sipuleucel-T before or after initiation of ADT in men with biochemical recurrence and a PSA doubling time of ≤ 12 months. At present they are no more than suggestive of the possibility of a superior clinical effect if ADT is started in such men prior to administration of sipuleucel-T.

2 Responses

  1. As a patient who may someday be faced with the question addressed in this study, I’m glad the study was done.

    However, as a 14th year veteran of IADT3 for a challenging case, I have some concerns.

    I looked up this study at http://www.clinicaltrials.gov, and was a bit surprised to learn that the ADT consisted only of an LHRH-agonist, Eligard, instead of at least combined (with an antiandrogen) or triple therapy (also adding a 5-alpha reductase inhibitor: finasteride or Avodart. These men had at least a couple of higher risk case characteristics in that they had failed prior therapy and had PSA doubling times of 12 months or less. If it were me, I think I would not have accepted single ADT therapy, but it might have been tempting if the Provenge were given free.

    I am concerned that no bone density protection was included in the protocol for either arm of the trial. I consider that a significant fault that has likely endangered the bone mineral density of some of the participants after a year on ADT.

    As a practical matter, cost is a concern. At $92,000 a pop for the course of Provenge treatment, at least at present, I'm wondering if it is a wise investment to try Provenge when well-done ADT probably can be done for many years at much lower cost.

    However, all that said, I'm glad Dendreon took on this study. At the outset, it was possible the study could have resulted in a grand slam home run. It will be worthwhile to see how these patients fare in coming years.

  2. I’ve been rethinking my initial impression of the study regarding the riskiness of these recurrences. These patients would fit in the Freedland study at Johns Hopkins for men with PSA doubling times from 9.0 to 14.9 months or faster. That group is not the most favorable PSA doubling time group (i.e., those with a PSA doubling time of 15 months or more), for whom prostate cancer-specific survival tended to be extremely high even with unfavorable Gleason and speed of recurrence, but that group is still in a broad range where the preponderance of recurrences could have been fairly mild.

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