Small Steps That Lead to a Giant Leap for Prostate Cancer Patients

It was just 45 years ago that Apollo 11 landed on the lunar surface and Neil Armstrong uttered those famous words, “That’s one small step for man, one giant leap for mankind.” That immortal exclamation was made at a time in prostate cancer therapy when very little was happening. Between then and the present day, many baby steps toward better therapy have been taken-such as weak antiandrogens, LHRH (luteinizing hormone–releasing hormone) agonists, and minimally effective chemotherapy. In the past 5 years, however, we have taken at least 7 steps forward for men with prostate cancer-which hopefully will turn into “one giant leap” in our attempt to convert advanced and castration-resistant prostate cancer (CRPC) into a chronic disease.

What are these steps? The first is an effective LHRH antagonist, degarelix, that addressed the disadvantages of agonists. The drug is now demonstrating other attributes, including flare reduction and reduced follicle-stimulating hormone levels (which result in better cancer control and perhaps fewer cardiovascular events). The second is denosumab, a novel RANK ligand inhibitor. Pivotal clinical trials of denosumab have clearly shown an improvement in skeletal-related events, delayed time to metastasis in M0 CRPC, and prevention of androgen deprivation–induced bone loss.

The third-a real game changer-is abiraterone. Studies of this drug blazed trails in both the post- and prechemotherapy settings, leading to improvements in both quality of life and survival. The drug is being moved even further forward-into use in M0 disease, as studied in the IMAAGEN trial. Another step forward was taken with the introduction of sipuleucel-T. This is a sleeping giant that has not received the attention it deserves. I consider sipuleucel-T a foundational drug that should be given early and then built on. There are data showing that, when it is given to men with metastatic CRPC and a PSA level of less than 20 ng/mL, the survival benefit exceeds a year compared with placebo.

Enzalutamide can be considered the fifth step forward. The drug capitalizes on tight binding to the androgen receptor (AR) binding domain, such that it is not translocated to the nucleus and is not susceptible to mutation stimulation. Like abiraterone, it is being considered for earlier use in M0 CRPC and even androgen-sensitive disease. The sixth step forward came with the approval of radium-223. Who would have thought, given the challenges surrounding the use of strontium -89 and samarium-153, that a radiopharmaceutical would be effective and safe? The ALSYMPCA trial taught us that-and that this drug is not just for men with very advanced disease. It has demonstrated significant clinical advantages both pre- and post-chemotherapy. The last step forward involves a chemotherapy drug called cabazitaxel. Again, who would have predicted that in men in whom the parent compound, docetaxel, has failed, a derivative would improve survival? And yet cabazitaxel has done just that.

Scher and colleagues, in their review on page 693 of this issue of ONCOLOGY, offer a scholarly discussion of some of the agents mentioned above, focusing on those that target the AR signaling pathway, abiraterone and enzalutamide, as well as newer AR-targeted drugs. They provide a glimmer of hope for the possibility of personalized medicine when they discuss possible ways to target disease in men who will not respond because of upregulation of CYP-17 or AR mutations. They also review one study that combines abiraterone and enzalutamide.

So what will be the one giant leap for men with prostate cancer? In the mid-1950s, Emil Frei III proposed combining drugs rather than sequencing them. He was heavily criticized at first, but the cure rates for childhood leukemia went from 0% to near 50% in just a few years after clinicians implemented his approach. In every other cancer we have cured-lymphoma, testis cancer, certain leukemias-it has not been monotherapy, it has not been sequencing one drug after another that has won the day; rather, it has been the combination of drugs. The way to take this giant leap for patients with prostate cancer is to put these agents together, and do so earlier in the disease. Just recently, the CHAARTED trial was reported as showing more than a 1-year survival advantage with the addition of docetaxel to androgen deprivation therapy (ADT). What if we built on that and added sipuleucel-T and radium-223-and if ADT meant degarelix, abiraterone, and enzalutamide? And to protect the bone even more, let’s add denosumab. The first thing investigators would say is that we can’t afford it, there would be too much toxicity, and so on. Really, we could reduce the dose of some of the agents and use them for a limited duration (4 to 6 months). This just might be the giant leap for mankind. I hope it does not take 45 years for it to occur.

Financial Disclosure: Dr. Crawford serves as a consultant or advisor to Bayer, Janssen, Dendreon, and Ferring Pharmaceuticals; he also serves as a lecturer for Bayer, and his wife is employed by Ferring.