Adding a TKI to docetaxel + prednisone for men with mCRPC

One of the great unanswered questions (so far) is whether adding a tyrosine kinase inhibitor (a TKI) to docetaxel + prednisone can improve outcomes for men with metastatic, castration-resistant prostate cancer (mCRPC). The difficulty with trying to answer this question is which of all the available TKIs (there are lots of them) might actually produce such an effect — if any one of them can.

In a report presented today at the IMPaCT meeting in Orlando, Heath et al. presented data from a Phase II, multi-center clinical trial of docetaxel + prednisone + cediranib (aka AZD2171, a vascular endothelial growth factor [VEGF] TKI) compared to docetaxel + prednisone alone in men with mCRPC.

Any patient with mCRPC who has not received prior chemotherapy is eligible for this trial. All patients are given docetaxel at 75 mg/m2 IV q3w + prednisone at 5 mg po bid in 21-day treatment cycles. The patients on the investigational treatment arm were also given cediranib at 30 mg po daily.

The primary objective of the trial is to determine the 6-month progression-free survival (PFS) benefit of adding cediranib to docetaxel + prednisone.

Early stage data from the trial (which is not yet fully enrolled) are as follows:

  • 34 men with mCRPC have been enrolled.
  • 33/34 eligible and enrolled patients have begun treatment.
  • Average (median) patient age is 67 years (range, 52 to 84 years).
  • 27 percent of enrollees are African American.
  • Median PSA levels at time of enrollment was 105 ng/ml (range, 0.12 to 2,284 ng/ml).
  • 66 percent of patients had Gleason grade 8 to 10 disease at diagnosis, and 47 percent had bone and visceral disease at enrollment into the trial.
  • The median nadir PSA levels (to date) have been 11 ng/ml (range, 0.08 to 840 ng/ml) among men receiving cediranib, and 21 ng/ml (range, 0.10 to 1245 ng/ml) in the men receiving docetaxel + prednisone alone.
  • 68 percent of the patients receiving cediranib have needed at least one reduction of their cediranib dose level.
  • Docetaxel dose reductions have also been required in 47 percent of the patients receiving cediranib (but only in 7 percent of the men not receiving cediranib).
  • The most significant toxic side effect to date has been neutropenia (fever)  in 6 patients.
  • Other signifciant side effects have included fatigue, diarrhea, hypertension, and deep vein thrombosis.

The preliminary data from this study have led to a reduction in the daily dose of cediranib from 30 to 20 mg. However, it will be a while before progression-free survival data are available and we can make a sound evaluation of the potential of cediranib combined with docetaxel and prednisone in this patient population.

As yet there have been no truly compelling data to suggest that adding a TKI to docetaxel + prednisone can extend survival or progression-free survival in men with mCRPC. However, there is a slew of new TKIs in development, and it is still possible that one of these very varied types of therapy can demonstrate a significant clinical benefit.

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