Seeing and not believing: oligometastases and the future of metastatic prostate cancer.

In this month’s issue of European Urology, Ost and colleagues [1] review existing data on the treatment of low-volume metastases in patients with recurrent prostate cancer. The debate over this issue is reminiscent of older debates on the management of renal cell carcinoma, for which similar data exist suggesting that patients who undergo resection of a solitary metastasis have long disease-free intervals. Although it is tempting to believe that such interventions help, for most patients the reality is that metastatic disease burden is more likely just a surrogate for the state of evolution of disease biology, so that lower disease burdens represent less aggressive cancer, or at least cancer that grows more slowly. It is well to remember that in the absence of an untreated control arm or alternative intervention as a comparator, it is only possible to judge the tolerability and toxicity of surgery or radiation in these patients, and not their therapeutic efficacy. In this context, and based on the limitations of the evidence cited by Ost et al, I agree with the authors that metastasis-directed therapy as currently practiced is of no proven benefit (whether measured by delaying the ‘‘need’’ for androgen deprivation or prolonging survival) and we must not confuse our ability to treat such disease safely with an actual benefit in doing so. Furthermore, I believe that the paradigm of treating oligometastatic disease is limited by the inherent limitations of current imaging modalities. For example, imaging agents that are optimal for revealing bone lesions may underestimate the presence and extent of visceral metastases, which rapid autopsy series have suggested occur far more frequently than previously thought [2]. It is also unlikely that any imaging agent is capable of seeing all metastatic deposits, and therefore equally unlikely that treating only visible lesions with an exptirpative approach such as radiation or surgery will have a meaningful impact on overall disease progression. Having said that, I do believe that the field is on the threshold of a revolution in the treatment of metastatic disease on the basis of an emerging understanding of the genomic events that drive prostate cancer to castrate resistance, and the development of targeted therapies. A comprehensive, integrated model of the genetic events that underlie the genesis and progression of prostate cancer from germline susceptibility to castrate-resistant disease is now emerging [3]. It is already possible to have a tumor biopsy from any site analyzed in real time for identification of potential driver mutations and potential targeted agents that act systemically against all tumor deposits, whether or not they can be imaged, and there are anecdotal reports of patients with advanced disease who have achieved significant disease-free intervals and perhaps cure using this approach [4]. Recent data also suggest an ability to perform serial biologic monitoring in patients with progressive prostate cancer, allowing a switch to other active agents when new driver mutations emerge [5]. The development of agents such as abiraterone and enzalutamide, and other new androgen receptor–directed therapies [6], combined with an understanding of the molecular mechanisms that underlie resistance to these agents, holds promise for the development of a precision medicine approach to managing metastatic disease that is likely to supplant our urge to treat only what we can see.