ASCO annual meeting update no. 3

Four oral presentations this morning (Sunday) addressed some of the most current data in treatment of hormone refractory prostate cancer, with specific reference to new investigational drug combinations.

Ning et al. reported on a Phase II trial of a combination of thalidomide (Thalomid®), bevacizumab (Avastin®), docetaxel (Taxotere®), and prednosine in chemotherapy-naive patients with metastatic hormone-refractory prostate cancer. The patients also received enoxaparin as a prophylactic agent for prevention of thrombosis (blood clots).

This trial offered potentially interesting results, with 51/60 patients showing PSA declines > 50 percent and 41/60 patients showing PSA declines of ≥ 80 percent. Of patients with measurable disease, 2 has complete responses (CRs), 18 had partial responses (PRs), and 11 had stable disease. The estimated progression-free survival was reported as 18.2 months. Significant adverse reactions included febrile neutropenia (3/60 patients), syncope (5/60 patients), gastrointestinal perforation or fistula (3/60 patients), thrombosis (3/60 patients), and grade 3 bleeding (2/60 patients). All these adverse reactions are to be expected on this combination of agents, and the investigators reported them all to be manageable. The “New” Prostate Cancer InfoLink expects this trial to be followed by a randomized Phase II trial of some type, perhaps comparing this combination to standard therapy with docetaxel and prednisone.

Morris et al. reported on a Phase I trial combining docetaxel with the radiopharmaceutical samarium-153 (Quadramet®). This trial was primarily designed to demonstrate that repetitive dosing with this combination of agents was viable in patients with metastatic hormone-refractory prostate cancer, and indeed this was shown to be the case. Phase II trials with this combination of agents may now be possible.

Saad et al. provided a report on a randomized, Phase II trial of custirsen (OGX-011) + docetaxel + prednisone vs. custirsen + mitoxantrone + prednisone in metastatic hormone-refractory prostate cancer patients who relapsed on or within 6 months of treatment with first-line docetaxel therapy. Both drug combinations appeared to be well tolerated at a median follow-up of >15 months. However, the combination of custirsen + docetaxel + prednisone appeared to have a higher degree of efficacy and a superior safety profile to the combination of custirsen + mitoxantrone + prednisone. A randomized, multicenter Phase III clinical trial of custirsen + docetaxel + prednisone vs. docetaxel + prednisone is now projected as a follow-up trial as second-line treatment in patients failing first-line docetaxel chemotherapy.

Finally, Sartor reveiwed data from the randomized, double-blind, placebo-controlled, multicenter Phase III trial of satraplatin in hormone-refractory prostate cancer (the SPARC trial). It had previously been reported that this trial showed a progression-free survival benefit for satraplatin, but that there was no overall survival benefit. Sartor reported that stratplatin was well tolerated, and reduced the risk of progression in men with hormone-refractory prostate cancer. However, the results of the trial may have been affected by the fact that “progression” was defined by multiple possible criteria, and that a high proportion of patients had other forms of combination chemotherapy following progression on satraplatin or placebo. This made interpretation of the overall survival data impossible from a statistical point of view. Further evaluation of the data from this trial is still being undertaken to see whether there is still potential to demonstrate a survival benefit for satraplatin in a further, better structured clinical trial.

The session co-chair, in commenting on this final paper, noted the importance of seeking out better endpoint definitions and trial structures that might allow us to clearly recognize overall survival benefits of trials of new agents in hormone-refractory prostate cancer patients, possibly including a limited set of “progression” endpoints to allow patients to continue on investigational therapies despite (for example) a rising PSA. A similar problem was encoutered over 5 years ago with the results of the trial of atrasentan vs. placebo in hormone-refractory prostate cancer.

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