It has been 20 years since Crawford and colleagues published the first large randomized trial related to combined androgen blockade (CAB) in 1989.1 I was a urologic oncology fellow at the time, and my professional career has been marked by “the CAB debate.” Although I suspect that academic debate surrounds most common and uncommon diseases in medicine, debates around the diagnosis, staging, and management of prostate cancer seem to be more controversial, intense, and long-lasting. Those in and outside of the field attribute this to the lack of randomized controlled trials (RCTs) addressing many of the important issues. Although this may be true for many prostate debates, it is not true for the CAB issue. In fact, we have had more RCTs and even multiple meta-analyses to try to address this debate; yet, after 20 years, we are still at it! Despite all these evidence-based, high-level data, we still are in a quandary regarding prescribing CAB for our patients.
In this issue of Cancer, Akaza and colleagues present a well written and very important follow-up of CAB using bicalutamide (80 mg daily) versus lutenizing hormone-releasing hormone (LH-RH) monotherapy in Japanese men with locally advanced and metastatic prostate cancer.2 At a median follow-up of 5.2 years, there was an overall survival advantage for the men who received CAB. A nonprotocol-specified subgroup analysis by stage revealed that the survival benefit for CAB was observed only in the men who had stage C/D1 disease. However, that finding as well as the cause-specific survival data must be interpreted with caution because of small patient numbers/inadequate power. The authors also analyzed CAB versus LH-RH alone by prostate-specific antigen (PSA) nadir groupings and demonstrated that the men who received CAB had a much better chance of achieving PSA <1.0 ng/mL. Furthermore, this robust PSA nadir also was associated with improved overall survival for men in both arms. Finally, the authors reported that the safety and tolerability of CAB with bicalutamide did not differ significantly from those of LH-RH alone.
For those who favor CAB and who are CAB advocates, this article by Akaza et al will be further proof to support its continued or expanded use in their patients. Supporters of CAB will point to this article to confirm the results of Klotz et al, who suggested that bicalutamide (50 mg daily) as part of CAB was associated with a 20% survival benefit over LH-RH or orchiectomy alone.3 Supporters of CAB also will use the article by Akaza et al to justify using CAB in men who have locally advanced or pelvic lymph node-positive only (stage D1) disease. In this case, if a clinician followed the doctrine offered by Messing et al of early hormone therapy for stage D1 disease after radical prostatectomy,4 then he or she would use CAB rather than LH-RH alone. Even more intriguing is the extrapolation of the findings of Akaza et al to those who support early hormone therapy for PSA recurrence. For example, Moul et al demonstrated that early hormone therapy was beneficial for high-risk PSA recurrence in patients who had Gleason scores of 8 to 10 or PSA doubling times <12 months.5 If a clinician believes that these patients with high-risk PSA recurrence are similar to patients with stage C/D1 disease, then he or she would contend that CAB with bicalutamide is superior to LH-RH alone. For the patient with traditional stage D2 disease, supporters of CAB will ignore the article by Akaza et al based on small patient numbers and still will rely on the Prostate Cancer Trialists' Collaborative Group meta-analysis6 and the latest American Society of Clinical Oncology (ASCO) guidelines7 to support the use of CAB.
However, for those who are not or never were fans of CAB, this latest article may not quell their skepticism. Probably, their primary arguments will be that the study is too small, the follow-up still is too short, the benefit of CAB was not observed in D2 disease, the results may not apply to patients in other countries. and no disease-specific survival benefit was observed. Furthermore, the dose of bicalutamide (80 mg daily) used by Akaza et al differed from what is used and approved in most countries (50 mg daily). Despite the small numbers, detractors of CAB will use the article, which demonstrated no survival benefit for D2 disease. to justify LH-RH monotherapy.
We must put the latest findings for CAB from this article in the context of the current prostate cancer milieu in many countries where widespread screening has now resulted in stage migration. For example, in the United States, <5% of men with newly diagnosed prostate cancer have metastases at first presentation.8 Compared with the start of the CAB era in 1989, this is a drastic difference. Back in the day, between 20% and 25% of newly diagnosed men had D2 disease at presentation, and CAB versus castration or LH-RH alone was a commonplace decision for physicians and patients. Now, a “new D2” patient walking through the door is an “interesting teaching case” for my residents and junior faculty colleagues, and some may not even be up to date with the basics of hormone therapy management, much less the intricacies of the CAB debate! Furthermore, intermittent hormone therapy, peripheral androgen blockade, and the hormone therapy side-effect debate were not even on the radar screen in 1989 when CAB first was introduced.9 Where CAB stands in relation to the application in intermittent hormone therapy or compared with peripheral androgen blockade is not addressed in the study by Akaza et al or in any of the CAB literature.
Finally, where do we place the CAB debate in the context of pure LH-RH antagonist medications? Although abarelix was the first pure LH-RH antagonist to be developed and studied, it was withdrawn from the market because of concerns regarding anaphylaxis.10 At the end of 2008, the US Food and Drug Administration approved degarelix as the latest generation, pure LH-RH antagonist.11 One of the key arguments for using LH-RH antagonists is their lack of testosterone surge or flare in the first few weeks of administration. Proponents of these agents will contend that oral antiandrogens are unnecessary to block the flare, and the implication is that a pure LH-RH antagonist eliminates the need for CAB. Whether this is true remains to be studied. A pure LH-RH antagonist proponent probably would say that the only benefit of bicalutamide in the study (or in any other CAB trial) is because of the LH-RH agonist flare protection. In particular, Azaka et al used monthly LH-RH agonist agents, which may be associated with more frequent flare, resulting in a magnified benefit of bicalutamide. Again, whether this is true or not is unknown. However, if degarelix becomes a popular hormone therapy agent, it will be interesting to see how many clinicians still use CAB with it versus a monotherapy pathway.
Several other issues of context for this latest article are in order. In January 2006, the US government, through the Medicare Modernization Act of 2005, began to reimburse for oral antiandrogens through Medicare Part D. Bicalutamide use, at least in 1 large US healthcare system, increased after that time, when the cost of drugs was less of a consideration for many patients.12 Conversely, bicalutamide lost US patent protection in March 2009 and became available as a generic. Thus, no pure “branded” nonsteroidal antiandrogen will remain available, and the pharmaceutical marketing of this class of drugs will stop. It will be interesting to continue to track the market volumes in this class of drugs in this new light. Ironically, between this article, the data reported by Klotz et al,3 and the relatively new ASCO guidelines,7 the support for CAB (and for bicalutamide in particular) is stronger than ever. However, the lack of antiandrogen marketing as well as the advent of safe LH-RH antagonists may render the CAB debate a somewhat moot point.
In summary, Akaza and colleagues are to be congratulated for presenting a clear and concise long-term follow-up RCT favoring CAB with bicalutamide in men with advanced prostate cancer. The 20-year debate continues!