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Have the days of ADT Monotherapy for Hormone Sensitive Prostate Cancer Come to an End? STAMPEDE in the June #urojc

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The much awaited results of the STAMPEDE study of abiraterone for hormone naive prostate cancer was simultataneously presented at #ASCO17 and published ‘on line ahead of print’ in the NEJM. The formal title of the study was “Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy”.

Briefly, the study randomised 1917 men with locally advanced or metastatic hormone naive prostate cancer  to receive either ADT alone or ADT in combination with abiraterone and prednisolone.  significantly higher rates of overall and failure-free survival than ADT alone.We were privileged to have the lead author Professor Nick James join us for the June #urojc.  He posted the following video which is a lovely summary about STAMPEDE.  All of us could benefit from watching this and it is a useful link for our patients.

The data from the study is clear and it was not surprising that the majority of the discussion surrounding this paper was not going to be a dissection of the methodology or dataset and its analysis but rather how these results might impact upon urological practice.

There was a somewhat provocative start to the discussion with:-

To turn the question around, we saw the following tweet:-

But @urogeek came out swinging

But he was not alone in these thoughts.

But lets be fair, these responses are from urologists immersed in clinical trials experience and highly academic centers.  The following tweet perhaps brought out what many were thinking.

But perhaps the onus is upon us to make that extra effort to learn. As has been mentioned, we manage one of the most toxic agents competently in the form of intravesical BCG for bladder cancer.

Naturally, there was bound to be some discussion about cost of treatment.

For a bit of light hearted banter, there was the following exchange which we hope nobody took too seriously.

The twitter account of the journal Prostate Cancer and Prostatic Diseases posted a poll which was responded to by 117 participants with only 10% choosing the ADT alone option.  Whilst far from scientific, does this represent a significant change in thinking?  It was not long ago where we could have predicted that almost all respondents would have chosen the ADT alone option.

And to finish up, a question answered by Nick James as follows:-

A big thanks to all who participated in the June #urojc discussion. A special thanks to lead author Nick James for his insightful comments that really added to the discussion.  We will be back for another installment of the #urojc in July.  See you then.

Henry Woo (@drhwoo) is the Director of Uro-Oncology and Professor of Robotic Cancer Surgery at the Chris O’Brien Lifehouse in Sydney, Australia. He is also Professor Surgery at the Sydney Adventist Hospital Clinical School of the University of Sydney.

 

Article of the Month: CGa and NSE serum levels as predictors of treatment outcome in patients with mCRPC undergoing abiraterone therapy

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Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Chromogranin A and neurone-specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration-resistant prostate cancer undergoing abiraterone therapy

Matthias M. Heck*, Markus A. Thaler†, Sebastian C. Schmid*, Anna-Katharina Seitz*, Robert Tauber*, Hubert Kubler*, Tobias Maurer*, Mark Thalgott*, Georgios Hatzichristodoulou*, Michael Hoppner*, Roman Nawroth*, Peter B. Luppa†
,Jurgen E. Gschwend* and Margitta Retz*

 

*Department of Urology, and †Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

 

Read the full article

Objective

To determine the impact of elevated neuroendocrine serum markers on treatment outcome in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing treatment with abiraterone in a post-chemotherapy setting.

Patients and Method

Chromogranin A (CGa) and neurone-specific enolase (NSE) were determined in serum drawn before treatment with abiraterone from 45 patients with mCRPC. Outcome measures were overall survival (OS), prostate-specific antigen (PSA) response defined by a PSA level decline of ≥50%, PSA progression-free survival (PSA-PFS), and clinical or radiographic PFS.

jan-2017-aotw1-results

Results

The CGa and NSE serum levels did not correlate (P = 0.6). Patients were stratified in to low- (nine patients), intermediate- (18) or high-risk (18) groups according to elevation of none, one, or both neuroendocrine markers, respectively. The risk groups correlated with decreasing median OS (median OS not reached vs 15.3 vs 6.6 months; P < 0.001), decreasing median clinical or radiographic PFS (8.3 vs 4.4 vs 2.7 months; P = 0.001) and decreasing median PSA-PFS (12.0 vs 3.2 vs 2.7 months; P = 0.012). In multivariate Cox regression analysis the combination of CGa and NSE (≥1 marker positive vs both markers negative) remained significant predictors of OS, clinical or radiographic PFS, and PSA-PFS. We did not observe a correlation with PSA response (63% vs 35% vs 31%; P = 0.2).

Conclusion

Chromogranin A and NSE did not predict PSA response in patients with mCRPC treated with abiraterone. However, we observed a correlation with shorter PSA-PFS, clinical or radiographic PFS, and OS. This might be due to an elevated risk of developing resistance under abiraterone treatment related to neuroendocrine differentiation.

Read more articles of the week

Editorial: Circulating biomarkers of NEPC – an unmet challenge

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Prostate cancer is a global health issue and, although the overwhelming majority (>95%) of metastatic castration-resistant prostate cancers (CRPCs) have adenocarcinoma histology [1], a subset of tumours acquire histopathological and immunohistochemical evidence of neuroendocrine differentiation, with a variety of morphological classifications being reported [1]. Nonetheless, the term ‘neuroendocrine prostate cancer’ (NEPC) should be reserved for tumours with absent or minimal androgen-signalling modulated transcription [2]. NEPC arising in the castration-resistant scenario (treatment-related NEPC or tNEPC) [2] is a disease of unknown prevalence and without an optimum treatment regime. Autopsy studies have shown at least focal neuroendocrine differentiation may be present in up to 33% of patients [3]. The cellular precursor of tNEPC is still debated, but a common clonal origin from adenocarcinoma CRPC (adeno-CRPC) is likely [2]. The assumption of negligible androgen signalling in these tumours implies resistance to agents such as abiraterone and enzalutamide. In this setting, research focused on identifying biomarkers of tNEPC is to be welcomed.

Heck et al. [4] determined the prognostic impact of elevated circulating neuroendocrine biomarkers chromogranin A (CGA) and neuron-specific enolase (NSE) in the serum of patients with CRPC treated with abiraterone in the post-chemotherapy setting. Although CGA and NSE did not predict PSA response, they correlated with clinical and radiographic progression-free survival (PFS), as well as overall survival (OS). The association between these biomarkers and clinical outcomes in metastatic CRPC has been confirmed in retrospective studies [5]. According to the authors, this association, independently of PSA response, underlines the sub-clonality of this disease, and the key role of androgen receptor (AR) signalling, even in advanced disease [4].

The marker NSE is considered to be generic, with high sensitivity but low specificity; CGA is a more specific neuroendocrine tumour biomarker and a common constituent of neuroendocrine tumour secretory granules. Abnormal CGA levels have, however, been significantly associated with intake of proton pump inhibitors in patients treated with abiraterone for metastatic CRPC rather than with duration of treatment [5]. Unfortunately, the use of proton pump inhibitors in that study was not disclosed and may have affected the reported results. Moreover, compared with previous experience, the rate of abnormal NSE was significant higher, probably in keeping with the low specificity of this biomarker.

Interestingly, the authors report an OS and PFS of 12.7 and 3.7 months, respectively [4]. These data are significantly different from the results of the COU-AA 301 study, in which treatment with abiraterone resulted in improved OS (14.8 vs 10.9 months) [6]. Surprisingly, there was no difference in PFS between abiraterone in the study by Heck et al. and the control arm of the COU-AA 301 trial (3.6 months) [6]. This discordance could be attributable to the small sample size of their study rather than the high PSA level at initiation of abiraterone, as claimed by the authors. In support of this alternative possibility, a post hoc analysis of the AFFIRM trial [7] showed consistent benefits in OS and PFS with second-generation hormonal treatments, regardless of baseline disease severity as assessed by PSA level.

Nevertheless, identifying patients with tNEPC is an urgent clinical need; genomic germline and somatic DNA next-generation sequencing as well as transcriptomic analysis of metastatic biopsies should now be considered a key approach to better understanding the heterogeneity of metastatic CRPC and to personalize treatment in order to maximize benefit.

There is substantial genomic overlap between adeno-CRPCs and tNEPC. TMPRSS2-ERG is the most common genomic aberration in prostate cancer and has been reported in NEPC with a similar frequency [2]. Furthermore, both adeno-CRPCs and tNEPCs are enriched for the inactivation of key tumour suppressor genes, such as RB1 and TP53, compared with hormone-sensitive prostate cancer, albeit in different proportions [2]. Although genomic amplification and activating point mutations of the AR in tNEPCs are notably absent, the presence of AR-splicing variants, including ARv7, is still detectable, suggesting that AR signalling is still present in at least a proportion of tNEPCs [2].

Despite a common background of genomic aberrations, tNEPCs have also been reported to have significant overexpression and copy number gains of AURKA and MYCN (40% of NEPC vs 5% of primary prostate cancer tumours), although these findings remain unsubstantiated [3]. As such, these have been postulated to be drivers of this disease phenotype and are under investigation as targets of novel agents.

Genome-wide DNA methylation analysis has, however, also shown that there are marked epigenetic differences between NEPC and adeno-CRPC, suggesting that epigenetic modifiers play a major role in the induction and maintenance of the neuroendocrine status [2].

In conclusion, the identification and definition of NEPC remains challenging. Blood biomarkers such as NSE and CGA cannot be considered to be proven prognostic biomarkers of NEPC as they have only been evaluated in small retrospective studies not adhering to REMARK criteria [8]. Genomic profiling from tissue biopsies or circulating DNA remains a preferable way to identify NEPC and is increasingly feasible, although still not affordable or a standardized procedure for the definition of NEPC.

Read the full article
Pasquale Rescigno*,†, Daniel Nava Rodrigues*,† and Johann S. de Bono*,†

 

*Institute of Cancer Research, London, UK and †Royal Marsden NHS Foundatio n Trust, London, UK

 

References

 

1 Epstein JI, Amin MB, Beltran H et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol 2014; 38: 756–67

 

2 Beltran H, Prandi D, Mosquera JM et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 2016; 22: 298–305

 

3 Mucci NR, Akdas G, Manely S, Rubin MA. Neuroendocrine expression in metastatic prostate cancer: evaluation of high throughput tissue microarrays to detect heterogeneous protein expression. Hum Pathol 2000; 31: 406–14

 

4 Heck MM, Thaler MA, Schmid SC et al. Chromogranin A and neurone- specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration-resistant prostate cancer undergoing abiraterone therapy. BJU Int. 2017; 119: 30–7

 

5 von Hardenberg J, Schwartz M, Werner T et al. Influence of abiraterone acetate on circulating neuromediators in chemotherapy-naıve castration- resistant prostate cancer. Prostate 2016; 76: 613–9

 

6 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

 

7 Saad F, de Bono J, Shore N et al. Efficacy outcomes by baseline prostate- specific antigen quartile in the AFFIRM trial. Eur Urol 2015; 67: 223–30

 

8 McShane LM, Altman DG, Sauerbrei W. REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 2005; 93: 387–91

 

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