Where do we stand with predictive biomarkers in mCRPC?

20 March 2015 Dr. Robert J. van Soest

Treatment options for men with metastatic castrationresistant prostate cancer (mCRPC) have expanded with the introduction of several new approved agents including abiraterone, enzalutamide, cabazitaxel and radium-2231-6.

With evidence that both abiraterone acetate and enzalutamide are effective agents when administered to men with mCRPC either before or after chemotherapy2-4,6, treatment selection and sequencing for an individual patient has become more challenging.

Therefore, predictive biomarkers for response to the various drugs approved for treatment of mCRPC are needed to guide clinical practice and trial design. Since prospective studies of established predictive biomarkers facilitating treatment decisions are still lacking, we herewith provide an overview of potential predictive factors to the currently available treatment options in mCRPC.

ARv7 expression

The androgen receptor (AR) is a key driver of mCRPC, which is targeted by the novel hormonal agents abiraterone and enzalutamide. The AR-isoform encoded by splice variant 7 lacks the ligand-binding domain, and remains constitutively active in the absence of ligand. ARv7 expression develops in the course of disease progression, and is more likely to occur in patients with more advance disease, and after previous treatment with abiraterone or enzalutamide.

A well-designed, prospective study by Antonarakis et al. showed that men expressing ARv7 in circulatingtumor cells did not respond to treatment with either abiraterone or enzalutamide. Also, clinical/ radiographic progression-free survival (PFS) and overall survival (OS) were inferior in men expressing ARv7. Although these findings require large-scale validation, it is a promising first step towards a more personalized treatment approach in mCRPC, where ARv7 expression in circulating-tumor cells might be used to facilitate treatment decisions.

In the absence of other predictive biomarkers, another challenge is to define subgroups of patients who potentially derive more benefit from novel AR-targeted therapy, or chemotherapy. In this light, several retrospective, hypothesis-generating efforts have been conducted.

Duration of response to prior ADT

An interesting retrospective study of 108 mCRPC patients enrolled in clinical trials demonstrated that patients with a short response to prior androgen deprivation therapy (ADT) (<16 months) had poor PSA responses and PFS when treated with subsequent hormonal agents including abiraterone7.

These findings suggest that patients, who progress rapidly to castration-resistant disease, with short responses to prior ADT, might do worse on consecutive hormonal treatments. In contrast, post-hoc analyses of two large phase III trials of patients with mCRPC receiving docetaxel showed the treatment benefit was irrespective of duration of initial ADT8.

Likewise, a post-hoc analysis of the TROPIC trial of cabazitaxel versus mitoxantrone demonstrated that cabazitaxel improved OS as compared with mitoxantrone regardless of the duration of prior ADT9. Prospective validation of these findings for the various drugs approved for the treatment of mCRPC should define whether duration of response to prior ADT could be a good parameter for further personalizing treatment.

Predictive-biomarkers

Gleason score

Another patient factor of interest is the Gleason score at initial diagnosis. A post-hoc analysis of the TAX327 study showed that the OS benefit obtained by docetaxel was most pronounced in men with high Gleason score tumors, with an OS benefit of 4.4 months in this patient subgroup10.

At the same time, a high Gleason score (8–10) at the time of diagnosis had been reported to be an independent risk factor for poor response to abiraterone11.

These findings suggested a potential predictive role of Gleason score. However, although the OS benefit in the COU-AA-302 study of abiraterone prechemotherapy was less pronounced in patients with high Gleason score tumors (7-10), the clinical benefit as assessed by radiographic PFS demonstrated to be irrespective of Gleason score12. Similarly, a post-hoc analysis of the TROPIC trial has shown that cabazitaxel also provided clinical benefit regardless of the tumor grading at initial diagnosis9.

Thus, Gleason score could be useful in identifying patients who derive the most benefit from docetaxel chemotherapy, but might be of less value to predict benefit from other treatments.

Neutrophil-to-lymphocyte ratio

An emerging biomarker across different tumor types and disease settings is the neutrophil to lymphocyte ratio (NLR). An elevated NLR, a marker for host inflammation, was found to be an independent marker of adverse outcomes for several solid tumors including mCRPC13. In men with mCRPC treated with abiraterone, NLR ≥5 was associated with lower PSA response rates and shorter survival14.

Although associated with worse prognosis, docetaxel provided a robust OS benefit of 4.3 months and ≥50% PSA declines in 53-67% in two randomized phase III trials including patients receiving first-line chemotherapy8. Unfortunately, there is no data to confirm whether NLR is a marker of better response to AR-targeted agents or chemotherapy.

Taken together, with a rapid evolvement of the treatment landscape for mCRPC, predictive biomarkers for the current treatment options are urgently needed. Biomarker-driven studies are key in identifying mechanisms of resistance to new drugs, and developing strategies to overcome resistance. Such translational efforts are necessary to change the current one-size-fits-all approach into a more personalized treatment strategy for mCRPC.

At this time, ARv7 expression in circulating-tumor cells is the most promising biomarker for future treatment selection. Other potential patient factors that might facilitate treatment decisions are derived from retrospective analyses and should therefore be interpreted with care. However, in the absence of prospectively derived biomarkers, duration of response to previous hormonal therapy and NLR are clinical parameters that are readily available, and might have potential to guide future treatment selection.

References

1. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-54.

2. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-48.

3. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. N Engl J Med. 2012;367:1187-97.

4. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.

5. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-23.

6. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N Engl J Med. 2014;371:424-33.

7. Loriot Y, Massard C, Albiges L, et al. Personalizing treatment in patients with castrate-resistant prostate cancer: A study of predictive factors for secondary endocrine therapies activity. J Clin Oncol 30, 2012 (suppl 5; abstr 213).

8. van Soest RJ, Templeton AJ, Vera-Badillo FE, et al. Neutrophil to lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials. Ann Oncol 2014. In press. doi: 10.1093/annonc/mdu569.

9. Oudard S, de Bono JS, Ozguroglu M, et al. Impact of cabazitaxel + prednisone on overall survival at 2 years and in patients with aggressive disease: post-hoc analyses of TROPIC trial. Ann Oncol. 2012;23 Suppl 9; abstr 933.

10. van Soest RJ, de Morree ES, Shen L, et al. Initial Biopsy Gleason Score as a Predictive Marker for Survival Benefit in Patients with Castration-resistant Prostate Cancer Treated with Docetaxel: Data from the TAX327 Study. Eur Urol. 2014;66:330-6.

11. Azria D, Massard C, Tosi D, et al. An ambispective observational study in the safety and efficacy of abiraterone acetate in the French temporary authorizations for use (ATU): Predictive parameters of response. J Clin Oncol 2012;30 (suppl 5; abstr 149).

12. Fizazi K, Flaig TW, Ohlmann CH, et al. Does Gleason score (GS) predict efficacy of abiraterone acetate (AA) therapy in patients (pts) with metastatic castrationresistant prostate cancer (mCRPC)? An analysis of AA phase 3 trials. J Clin Oncol 32, 2014 (suppl 4; abstr 20).

13. Templeton AJ, McNamara MG, Seruga B, et al. Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Solid Tumors: A Systematic Review and Meta-Analysis. J Natl Cancer Inst. 2014;106:dju124.

14. Leibowitz-Amit R, Templeton AJ, Omlin A, et al. Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2014;25:657-62.

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