No sign of evident clinical benefit in the Phase IV PLATO trial

According to a recent media release, there was no significant benefit for the investigational combination of enzalutamide (Xtandi) + abiraterone acetate (Zytiga) + prednisone in treatment of men with chemotherapy-naive, metastatic, castration-resistant prostate cancer (cnmCRPC).

The multicenter Phase IV PLATO trial had enrolled 509 patients who all had cnmCRPC and who either were on standard androgen deprivation therapy (ADT) or had had a bilateral orchiectomy. Initially, all 509 men were treated with enzalutamide in an “open-label” portion of the study. When patients showed signs of progression (a rising PSA) on enzalutamide alone, they were then randomized to either

  • Staying on enzalutamide (at 160 mg/d) and adding abiraterone acetate (at 1,000 mg/d) and prednisone (5 mg twice daily) or
  • Receiving a placebo instead of the enzalutamide and being treated with the same doses of abiraterone acetate and prednisone

The trial was “double -blind”, i.e., neither the patients nor their physicians knew who was or wasn’t getting the continued enzalutamide. And the primary endpoint for the PLATO trial was progression-free survival, as measured by any one of the following:

  • Radiographic disease progression
  • Unequivocal clinical progression
  • Death of the patient during the study

According to the recent joint media release from Pfizer and Astellas, there was no significant difference in terms of progression-free survival between the patients who did or did not stay on the enzalutamide in addition to being treated with the abiraterone acetate + prednisone.

Obviously this result is a disappointment for the developers of enzalutamide and for some patients. However, it has to be said that it is, in some ways, also a relief for clinicians and other patients. It is already hard enough to know how best to treat men with progressive mCRPC, and the costs associated with combination therapy with both enzalutamide and abiraterone acetate would probably approach $200,000 for each year a patient was on therapy (and that would be the drug-related costs alone). Most payers here in the USA would require patients to cover a significant portion of that cost, and in other nations the national health systems would only have been willing to consider covering such costs if there had been major impact on survival and/or quality of life.

The other issue that is now relevant (but which was not known when this trial was originally started) is that at least some of these cnmCRPC patients — and certainly those with evident signs of significant metastatic disease — should, in any case, probably be receiving early chemotherapy in combination with their ADT, based on the results of the CHAARTED and the STAMPEDE trials, before they become castration resistant at all.

One Response

  1. Just to be clear, this trial did not show that the combination of Xtandi and Zytiga had no benefit over Zytiga alone. It showed that after resistance to Xtandi set in, adding Zytiga to it conferred no benefit. It may well be the case that if the two were started together, resistance to them and progression might be delayed. They (and castration) work in complementary manners. I am hopeful that apalutamide might work longer.

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