Endpoints prostate cancer trials

To this end, recent work by a number of authors suggests that several parameters may potentially be considered to assess immune response to a particular drug. These include B-lymphocyte and T-lymphocyte profiling, assessment of absolute lymphocyte count ALC , absolute and relative eosinophil counts pre and post treatment, expression of antigen and antigen ligand, and MDSCs.

Multiple clinical trials in melanoma have highlighted the clinical value of ipilimumab and, for the first time, demonstrated an immune impact through a variety of different parameters.

Many of these parameters fulfill a role as surrogate markers in that they are associated with a biological change in the disease as well as survival. More recently, the anti-PD-1 monoclonal antibody entered the clinical arena and was found to have unexpected efficacy. Unexpectedly, it was observed that overexpression of the PD-1 ligand could correlate with treatment response. In addition, this was the first time that concurrent clinical testing of antibodies blocking an immune regulatory receptor and one of its cognate ligands has been reported.

The availability of clinical material from patients enrolled in several clinical trials using ipilimumab alone and in combination with chemotherapy and biologics in melanoma has enriched efforts toward immunologic biomarker discovery and profiling compared with other solid tumors.

Recent data reported by Schindler et al 41 suggest that pretreatment levels of absolute and relative eosinophil counts are associated with improved overall survival in patients with metastatic melanoma treated with ipilimumab. Although retrospective, relative eosinophil counts also seemed to have similar benefits, suggesting the potential of these values as an immune-mediated response biomarker.

Another preliminary report by Ku et al, 42 detailed a single-institution experience with ipilimumab used as a compassionate drug for patients with advanced melanoma. These observations served as the foundation for further studies by Postow et al 43 who evaluated data from six studies of ipilimumab with or without dacarbazine, a standard chemotherapy used in melanoma.

ALC was measured at baseline, prior to each dose during induction at the established times of weeks one, 4, 7, and 10, and at the end of induction at week In all studies, the ALC increased significantly over time in patients who received ipilimumab irrespective of whether they were being treated with or without chemotherapy. A positive association between rate of ALC increase and overall survival was seen after two treatment doses. However, the increase in ALC was not specifically predictive of an overall survival benefit from ipilimumab based on analysis of the original ipilimumab trial with treatment arms using single-agent ipilimumab versus combination with the glycoprotein vaccine.

Therefore, these data suggest that ALC cannot be regarded as a reliable biomarker in disease management at this time. Recent data presented by Wolchok et al 44 have demonstrated improved efficacy using nivolumab anti-PD-1 in combination with ipilimumab compared with using either drug alone, with a manageable safety profile. An analysis of single versus combined use of these agents was done by Callahan et al, 45 who investigated the question of whether previously identified putative biomarkers for ipilimumab or nivolumab monotherapy are relevant in the combination setting.

Interestingly, objective responses were seen in patients who were negative and positive for PD-L1 by immunohistochemistry. Of note, another potential biomarker, MDSC levels, which were considered to be at a lower frequency before treatment, were associated with an improved overall response when compared with patients showing high MDSC levels. Reference was made earlier to evaluation of MDSCs in a recent analysis of trials in melanoma.

It is known that these cells can increase in both tumor tissue and blood in cancer patients, and that they correlate with a poor clinical outcome. There are pitfalls to using these cells, including their phenotypic and functional heterogeneity within the myeloid compartment. Each is different with respect to its mechanism of suppression. This effect appeared to be independent of pretreatment or week 7 ALC. A general trend of increasing MDSC numbers by week 24 compared with pretreatment baseline seemed to be associated with patients who did not appear to achieve clinical benefit.

The authors concluded that there may be some predictive benefit of MDSCs as a biomarker, but this issue will need further retrospective and prospective validation.

Recent work by Reichenbach and Finn 47 suggests that a better understanding of immune responsiveness to therapy involves potential instances of crosstalk, whereby context and cell type in signaling pathways are activated in an attempt to predict later effects on the immune response. Immune biomarkers may need to be custom-tailored not only to the disease but also to its treatment. There is a need to develop rapid throughput for immune correlates such that real-time immune analyses can be performed.

Despite the plethora of data presented in numerous clinical trials using melanoma as the most interesting immunologic model, there is still a need for better trial design that incorporates viable immunologic endpoints able to demonstrate that there is an impact on tumor biology as well as a correlation between disease improvement and changes in immune criteria.

It is essential that all future trials incorporate acquisition of clinical specimens to address these questions. National Center for Biotechnology Information , U. Journal List Immunotargets Ther v. Immunotargets Ther. Published online Dec Susan F Slovin. Author information Copyright and License information Disclaimer. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

This article has been cited by other articles in PMC. Abstract The rapidly emerging field of immunotherapy and the development of novel immunologic agents that have been approved in melanoma and successfully studied in lung cancer, kidney cancer, and prostate cancer have mandated that there be uniformity in clinical trial analysis beyond conventional survival endpoints and imaging.

Keywords: sipuleucel-T, prostate-specific antigen, prostate cancer, biomarkers, monoclonal antibodies, vaccines, cellular therapy. Introduction The clinical continuum of prostate cancer progression has successfully been interrupted by the advent of several newly approved agents, all of which have shown survival benefit and have unique mechanisms of action to modulate or diminish growth of prostate cancer.

Biomarker assessment within the tissue environment The neoadjuvant setting can provide a direct way of interrogating the tumor and normal tissue microenvironment Table 1. Table 1 Milieux for immunologic interrogation. Open in a separate window. Can drugs influence potential identification of a biomarker? Ipilimumab and anti-PD-1 as foundations for establishment of immunologic response criteria Multiple clinical trials in melanoma have highlighted the clinical value of ipilimumab and, for the first time, demonstrated an immune impact through a variety of different parameters.

Conclusion Immune biomarkers may need to be custom-tailored not only to the disease but also to its treatment. Footnotes Disclosure The author reports no conflicts of interest in this work. References 1. Increased survival with enzalutamide in prostate cancer after chemotherapy.

N Engl J Med. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA randomised, double-blind, placebo-controlled phase 3 study.

Lancet Oncol. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Prostate cancer is an extraordinarily heterogeneous disease with a variety of prognostic factors influential in determining ultimate patient outcomes. However, the vast majority of men harboring pathologic evidence of prostate cancer are not clinically diagnosed with this disease.

Selected patients, particularly those with low clinical stage and low Gleason scores, may have extremely prolonged time until disease progression and cancer-specific death. Because of the potential for a prolonged natural history, factors, such as age and comorbidities, are often critical in evaluating clinical trial outcomes.

Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen PSA , imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales.

Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.