I have read multiple overviews of the current management of castration-resistant prostate cancer (CRPC). These articles have very adeptly summarized the key trials leading to a multitude of US Food and Drug Administration (FDA) approvals of new agents for men with CRPC. They have also outlined numerous therapeutic options that have become available for advanced prostate cancer management since 2010, as well as promising trial data on pending new treatments. In their article in this issue of ONCOLOGY, Drs. Hurwitz and Petrylak also have successfully highlighted both pivotal trials and noteworthy emerging information in this disease setting. More importantly, the authors clearly identify several critical unmet trial needs, and with clarity and brevity, they outline requirements for optimal clinical decision making based upon current knowledge, published and anecdotal. The latter feature is somewhat unique to this article, and should certainly assist busy and dedicated medical, urologic, and radiation oncologists who oversee the care of men with CRPC. Moreover, the authors very clearly describe their current CRPC therapeutic paradigm, which can be supported by evidence-based data. Importantly, they review uncertainties, challenges, and therapeutic considerations essential to optimizing CRPC drug development and patient management.
In their article, Drs. Hurwitz and Petrylak note that “unfortunately, useful correlative biomarkers in prostate cancer are lacking to help select treatment,” and reflect later that “at some point, analysis of tumors by sequencing, immunohistochemistry, or FISH [fluorescence in situ histochemistry] might be used to determine whether any of these mechanisms were at work and if so, whether they might change management [sequencing decisions].” New antigen-antibody panels, additional gene signatures, and possibly new proteomic/molecular markers of mutations will certainly assist and strengthen this unmet need, thereby improving clinical efficacy and, it is hoped, minimizing future costs. Presumably, this will allow for enhanced clinician identification of responders and of transition points of therapeutic resistance, information that could assist with decisions concerning whether to alter existing antineoplastic therapy. The question of whether to continue or stop abiraterone and/or enzalutamide when prostate-specific antigen (PSA) kinetics escalate, or even if new radiographic progression occurs, is still an unresolved clinical decision point.
Regarding the ongoing acronym designation changes for patients transitioning from the androgen-sensitive to the castration-resistant phenotype (from hormone-refractory prostate cancer [HRPC], to androgen-independent prostate cancer [AIPC], to castrate-resistant prostate cancer [CRPC]), the authors aptly state, “With the likely use of these drugs earlier in the course of disease, the term CRPC will either become outdated or eventually will refer to an entirely different set of clinical circumstances.”
Drs. Hurwitz and Petrylak also review the impact of steroid exposure with respect to the phase III enzalutamide postchemotherapy trial, as well as unpublished experience regarding the use of abiraterone without steroids. When planning treatment regimens for patients with CRPC, is the use of steroids detrimental, beneficial, or both? What is the optimal timing of steroid initiation in terms of concomitant or sequential immunotherapeutics—for example, sipuleucel-T? Ongoing and contemplated IIS trials should provide these answers in the near term.
Notably, the authors emphasize the importance of checking serum testosterone levels, and discuss what the ideal “low T level” is for the CRPC patient, while recognizing that inter-laboratory variability can occur, depending upon the assay technology employed. It is important to bear in mind that there is still a lack of consensus on the optimal T suppression level for the androgen-sensitive patient, based upon the early 1980s FDA endpoint for LHRH agonist pharmacologic approval, which required T suppression to less than 50 ng/dL. Clearly, AR signaling is active throughout the entire disease milieu, significantly impacted by endocrine, paracrine, and autocrine sources. Ultimately, receptor mutations and aberrant pathways intercede, affecting the efficacy of today’s approved agents and providing a fertile field for continuing research and future clinical trials.
The authors discuss ketoconazole and early-generation “lutamide” options, also known as the historic second-line hormonal manipulations, and suggest that their use should be limited to the M0 CRPC population, or when clinical trials are not available, or when cost precludes use of the newly approved oral oncolytics. As additional androgen biosynthesis inhibitors and androgen receptor signaling inhibitors gain regulatory approval—with approval, it is hoped, not as “me-too” agents, but rather as treatment options with enhanced safety profiles and improved efficacy—it is conceivable that the historic second-line hormonal therapies may be relegated to anachronism status, bearing in mind the earlier stated caveat of financial feasibility and accessibility for the newer and more efficacious oral therapies. It is interesting to consider whether these more potent oral oncolytics will have a beneficial role in newly diagnosed high-risk patients (as adjuvants coupled to primary interventional therapies) who are still androgen-sensitive, or even conceivably a role in disease modification for low-risk patients during an active surveillance (monitoring) protocol.
Finally, the authors accurately reflect that given the lack of randomized trial data to guide rational or biologically based sequencing of therapies, treatment in asymptomatic or minimally symptomatic patients is selected based upon rapidity of disease progression and toxicity of treatment, an approach that was very nicely codified and published by the American Urological Association CRPC Guidelines Committee in May 2013. The authors review the important concern of drug resistance in the setting of post-docetaxel therapy and the paucity of significant data to guide the sequencing of therapy. Of course, this dilemma is encountered for sequencing and combination strategies throughout the CRPC management continuum, as these novel newer therapies have been approved in rapid succession. Thus, future protocol designs must consider the challenges raised by patients readily crossing over to recently approved CRPC therapies, and subsequently, the statistical impact on both radiographic progression and survival data interpretations.
Two pressing issues pose a challenge to new drug development in the CRPC space. The first is trial contamination of the many new approved therapies, requiring larger trial cohorts for statistical validation. This leads to the second challenge, that of identifying quality trial sites and accruing appropriate patients who meet the required inclusion/exclusion criteria. The latter issue will continue to drive trial accrual outside of the United States, a disappointing consequence of our recent scientific success.
In summary, the authors succinctly review the evidence-based literature, and their discussion and analysis accurately reflect our unmet needs regarding diagnostics, sequencing of therapy, and combinatorial strategies in the management of CRPC. In addition, they offer their expertise and recommendations for therapeutic selections in the setting of CRPC based upon today’s state-of-the-art information.
Dr. Shore receives consulting fees from Algeta, Amgen, Astellas, Bayer, Dendreon, Janssen, Medivation, Millennium, Pfizer, and Sanofi-Aventis.
1. Hurwitz M, Petrylak DP: Sequencing of agents for castration-resistant prostate cancer. Oncology (Williston Park). 2013;27:1144-61.