Novel drug reduced tumors, bone pain in advanced prostate cancer

Exploring alternative targets to the androgen receptor (AR) signaling pathway in castration-resistant prostate cancer (CRPC) remains crucial to further improve the outcome of this cohort of patients. Despite the significant growth in the treatment pipeline for CRPC, we continue to fall short of achieving complete and durable responses. Some of the recent FDA-approved therapies don’t come without side effects, and the price tag is quite significant. Perhaps what is more concerning is the lack of understanding about patient selection, appropriate timing of treatment and correct sequence of therapy, as all patients over time will go on to develop some form of resistance to these novel compounds.

The cabozantinib (Cometriq, Exelixis) data published by Smith and colleagues is quite significant. First, this is the first “non-hormonal” agent in CRPC with clinical activity. Second, the type of responses observed in some of the patients in the study are not commonly seen in routine clinical practice. The chosen study design was not only appropriate, but the clinical endpoints utilized reflect the changes in practice with the understanding that prostate-specific antigen — in the setting of CRPC — should not be used to make major treatment decisions, as its decline does not appear to be a solid surrogate for outcome (at least with biologic agents).

Although limited by its sample size, the incorporation of bone markers provided some hint as to the true mechanism of action of the agent. The differences between the RECIST-define response and some of the impressive changes in bone scan findings observed in this study are difficult to understand, although they do point toward the bone microenvironment and the potential role of c-MET in the vicious cycle between prostate cancer-osteoblast-osteoclast activities within the bone microenvironment. Similarly, understanding PFS in the context of a randomized discontinuation phase 2 study is challenging. Clearly therapy with this c-Met inhibitor appears to be better than placebo; however, the true impact of this agent in OS remains unknown.

A disconnect between PFS and OS could be identified in the phase 3 trial of abiraterone acetate (Zytiga, Janssen Biotech) in the pre-chemotherapy setting. Although the initial analysis suggested that OS was likely to be improved with abiraterone therapy, at the end, only PFS was significant. This suggests that although we have active treatments, the timing of their use might not be that relevant as long as our patients get exposed to it. Although the phase 3 development program of cabozantinib with COMET-1 and COMET-2 might help us define its true activity in CRPC, it will not address other important questions, such the true mechanism of action (no biologic samples obtained), timing and appropriate sequence of treatment.

The cabozantinib trial demonstrates that we can attack prostate cancer in a non-AR/testosterone dependent manner. Clearly, trials evaluating the combination of agents capable of targeting AR and non-AR dependent pathways and the inclusion of blood and tissue correlates should take priority in the next years to come.

Smith and colleagues present the results of a well-designed, prospective, international, multicenter, randomized discontinuation trial of the receptor tyrosine kinase inhibitor cabozantinib in 171 men with castration-resistant prostate cancer (CRPC). These are exciting results, as they indicate substantial activity of this agent, with a toxicity profile that suggests it may be safely combined with other active agents in prostate cancer (eg, docetaxel, abiraterone, enzalutamide). It is also exciting that cabozantinib may be the first active RTK inhibitor in prostate cancer.

However, as Smith and colleagues point out: “True benefit will only be determined from randomized trials, and phase 3 studies [COMET 1 and COMET 2] have been initiated to evaluate the effect of cabozantinib on morbidity and mortality in patients with CRPC with bone metastases.”

The COMET 1 trial is a double-blind, placebo-controlled phase 3 study that will enroll 960 patients with metastatic CRPC and bone metastases in whom docetaxel and abiraterone acetate and/or enzalutamide have proven ineffective. Patients are randomly assigned in a 2:1 design to cabozantinib or prednisone. COMET 2 is a randomized trial that will compare cabozantinib to mitoxantrone in men with metastatic CRPC.

While these are important trials and will lead to FDA approval of cabozantinib more quickly than other designs, it is my prediction — based on results of many other studies in many other types of cancer — that the greatest impact of this new agent will be if activity can be established in patients earlier in the course of disease (eg, androgen deprivation plus cabozantinib, docetaxel plus cabozantinib, etc).

Nonetheless, the prospects are good for the addition of yet another new agent to our list of agents helpful in men with advanced prostate cancer.