BAT + enzalutamide: data from the RESTORE study

Just over a year ago we wrote up a commentary on this web site entitled, “Can bipolar cycling of testosterone really cure prostate cancer?” It dealt with what is known as “bipolar androgen therapy” or BAT and referred to a Phase II clinical trial known as the RESTORE study.

This week, a new paper by Teply et al. in The Lancet Oncology has reported results from one cohort of patients in the RESTORE trial: the 30-patient cohort with metastatic,  castration-resistant prostate cancer (nCRPC) who had progressed on standard androgen deprivation therapy + enzalutamide (Xtandi) who were first treated with BAT and then re-treated with enzalutamide.

The RESTORE trial is not a randomized or a blinded trial. It is a straightforward, so-called “open label” trial, and all of the patients are being enrolled at the Johns Hopkins medical center here in the USA. And it has three different patient cohorts: the one in which patients are progressing after standard ADT + enzalutamide; a second in which patients are progressing after abiraterone acetate (Zytiga) + prednisone; and a third in which the patients are progressing after standard ADT alone. This report deals exclusively with the 30 men in the first of these three cohorts of the study.

The 30 patients in thia cohort all had to have met the following criteria:

  • They had to have mCRPC.
  • They had to be asymptomatic.
  • They had to have had progressive disease after treatment with no more than two forms of standard ADT (e.g., an LHRH agonist and then a standard antiandrogen like bicalutamide).
  • They also had to have had progressive disease after treatment with continued standard ADT and enzalutamide.
  • They had to have a rising PSA after discontinuation of the enzalutamide.
  • They had to have a serum T level that was in the castrate range (i.e., < 50 ng/dl).

Patients who met these (and some other) criteria were then treated as follows:

  • They were maintained on their LHRH therapy (unless they had had an orchiectomy, in which case no other form of standard ADT was administered).
  • They were treated with intramuscular injections of testosterone cipionate (400 mg every 28 days) until disease progression.
  • At the time of disease progression, the injections of testosterone were stopped,  and the patients were re-treated with enzalutamide (160 mg daily).
 The trial had two co-primary endpoints. These were:
  • A 50 percent decrease in PSA concentration (PSA50) from baseline for BAT (for all patients who received at least one dose of testosterone)
  • A 50 percent decrease in PSA concentration (PSA50) from baseline for the enzalutamide rechallenge (based on intention-to-treat analysis)

Here are the major study findings:

  • The 30 patients were all enrolled between August 28, 2014, and May 18, 2016.
  • All 30 patients had at least one dose of testosterone therapy.
  • 9/30 patients (30 percent) demonstrated a PSA50 to BAT.
  • 29/30 patients completed the BAT component of the trial.
  • 21 patients went on to be re-treated with enzalutamide.
  • 15/21 patients (71 percent; or 52 percent of the 29 patients who had completed BAT) achieved a PSA50 response to the enzalutamide re-treatment.
  • 3/30 patients had grade 3 or grade 4 hypertension during the BAT phase of the study.
  • 5/30 patients had one other grade 4 or grade 4 adverse event during the BAT phase of the study.
  • No grade 3 or grade 4 adverse events occurred in more than one patient during the enzalutamide re-treatment phase of the study.
  • There were no treatment-related deaths observed during the BAT or the enzalutamide re-treatment phases of the study.

The authors interpret these results to mean the following:

BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge.

They also go on to state that additional studies will be needed to better define the potential clinical role for BAT in management of mCRPC.

The other two cohorts of the RESTORE trial are still being studied. Once the data from those two other cohorts are also available, it may be possible to better define an optimal strategy for sequencing of therapies between androgen and antiandrogen therapies in men with mCRPC.

What the RESTORE trial has not told us anything about, however, is whether there is any potential for the early use of BAT in men with high-risk, progressive, hormone-sensitive prostate cancer or in men with non-metastatic CRPC.

We should also note that the data in the abstract of this paper tell us nothing about the survival times of these 30 patients except that no treatment-related deaths occurred. However, this does not necessarily mean that no patients died during the course of the study. Some men could have died from causes that had nothing to do with their treatment at all.

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