• Dr. Robert A. Nagourney, MD

A “Clinical Trial” Gone Too Far - Hormone Refractory Prostate Cancer

An interesting paper was published in the January 10 NEJM (Abiraterone in Metastatic Prostate Cancer with Previous Chemotherapy, Ryan et al). The study randomized 1,088 hormone refractory prostate cancer patients to receive abiraterone plus prednisone, or placebo plus prednisone.

Abiraterone works by blocking the syntheses of testosterone (the critical survival factor for prostate cancer cells), both in the adrenal glands and within the tumor cells themselves. The drug had previously been approved for patients who had failed hormone therapy, but was only approved for those who had also failed Taxotere chemotherapy.

The results were so strongly positive in favor of the treatment arm, revealing a significant progression-free survival 16.5 versus 8.3 months (p < .001) and overall survival hazard ratio 0.75 (p = .01) that the monitoring committee invoked early stoppage rules. Virtually all of the other markers of disease also strongly favored the treatment arm. All of this speaks for an effective therapy in hormone refractory prostate cancer and we applaud their success.

The question remains: Did we really need to conduct this study?

On a biochemical level, abiraterone represents an effective mechanism for androgen ablation. The drug has been established to work well in patients who have failed prior hormone and Taxotere chemotherapy. In that prior exposure to Taxotere would not be expected to substantively influence abiraterone efficacy, the wisdom of committing 1,088 hormone refractory prostate cancer patients to a “placebo controlled” randomized trial to prove its efficacy in the Taxotere naive population seems questionable.

Prostate cancer generally afflicts older men. While most patients respond to hormonal ablation, hormone refractory prostate cancer develops in virtually all patients over time. A comparatively mild oral therapy like abiraterone represents a demonstrably superior alternative to a comparatively toxic alternative intravenous cytotoxic drug like taxotere. Did we need to marshal a multi-million dollar trial to prove that abiraterone worked in people who had not received Taxotere, when there was absolutely no reason to believe that it wouldn’t?

The reason that this trial was conducted was to meet an increasingly onerous regulatory environment that demands that every use of every drug in every situation be proven with a large and enormously expensive clinical trial.

Registration trials cost between $10,000 and $20,000 per accrued patient. Using these figures, we can guess that this clinical trial cost between $10,000,000 and $20,000,000 to conduct. Those costs must now be recouped from patients and insurers. Thus, the very agency whose purpose is to protect patients and limit the inappropriate use of drugs has created an environment that adds to those expenses and it can be argued, prevents the appropriate use of drugs.

To put this into perspective, let’s examine the female counterpart – breast cancer. Once aromatase inhibitors showed activity in postmenopausal women, they were rapidly incorporated into clinical therapeutics. Dovetailing nicely with the established antiestrogen tamoxifen, these drugs became second line hormonal therapies. While these drugs naturally assumed their roles in hormonal management of breast cancer, no one would ever demand that a breast cancer patient with ER positive cancer first receive chemotherapy before being allowed to use the well-established aromatase inhibitors. Had the FDA demanded that no one could receive anastrozole, letrozole or Aromasin until they had had Adriamycin, there would have been a march on Washington to reverse the policy. It was obvious to all those engaged in the field that these drugs worked and that they would work at different points in hormonal management of the disease.

The physiology of and clinical experience in breast cancer management allowed smart scientists with the approval of the regulatory agencies to “crosswalk” the application of these important agents. It is time for the American public to demand that clinical trials be conducted (and resources allocated) when the questions they address can only be answered through the expenditure of these vast financial and human resources.