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Article of the week: Management of patients with advanced prostate cancer in the Asia Pacific region: ‘real‐world’ consideration of results from the Advanced Prostate Cancer Consensus Conference 2017

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Every week, the Editor-in-Chief selects an Article of the Week 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 editorial written by a prominent member of the urological community. These are 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. There is also a video produced by the authors describing the ‘real-world’ findings.

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

Management of patients with advanced prostate cancer in the Asia Pacific region: ‘real‐world’ consideration of results from the Advanced Prostate Cancer Consensus Conference 2017

Edmund Chionga, Declan G. Murphyb,c, Hideyuki Akazad, Nicholas C. Buchane,f, Byung Ha Chungg, Ravindran Kanesvaranh, Makarand Khochikari, Jason Letranj, Bannakij Lojanapiwatk, Chi-fai Ngl, Teng Ongm, Yeong-Shiau Pun, Marniza Saado, Kathryn Schubachq, Levent Türkeris, Rainy Umbast, Vu Le Chuyenu, Scott Williamsv,r, Ding-Wei Yew, ANZUP Cancer Trials Groupx and Ian D. Davisy,z,r

 

aDepartment of Urology, National University Hospital, National University Health System Singapore, hDivision of Medical Oncology, National Cancer Centre Singapore, Singapore City, Singapore, bDivision of Cancer Surgery, vDivision of Radiation Oncology, Peter MacCallum Cancer Centre Melbourne, yMonash University, zEastern Health, Melbourne, cSir Peter MacCallum Department of Oncology, University Melbourne, Parkville, qAustralian New Zealand Urology Nurses (ANZUNS), Melbourne, VIC, Australia, rANZUP Cancer Trials Group, xLifehouse, Camperdown, Sydney, NSW, Australia, dStrategic Investigation on Comprehensive Cancer Network, The University of Tokyo, Tokyo, Japan, eCanterbury Urology Research Trust, fCanterbury District Health Board, Christchurch, New Zealand, gDepartment of Urology, Yonsei University College of Medicine, Seoul, Korea, iSiddhi Vinayak Ganapati Cancer Hospital, Miraj, India, jSection of Urology, Department of Surgery, University of Santo Tomas, Manila, Philippines, kDivision of Urology, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, lDepartment of Surgery, SH Ho Urology Centre, The Chinese University of Hong Kong, Hong Kong, wDepartment of Urology, Fudan University Shanghai Cancer Center, Shanghai, China, mDivision of Urology, Department of Surgery, oDepartment of Clinical Oncology, Faculty of Medicine, University of Malaya, Kuala Lumpur,Malaysia, nDepartment of Urology, National Taiwan University Hospital, Taipei, Taiwan, sDepartment of Urology, Acibadem University, Istanbul, Turkey, tDepartment of Urology, University of Indonesia, Jakarta, Indonesia, and uDepartment of Urology, Binh dan Hospital, Ho Chi Minh City, Vietnam

 

Abstract

Objective

The Asia Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2018) brought together 20 experts from 15 APAC countries to discuss the real‐world application of consensus statements from the second APCCC held in St Gallen in 2017 (APCCC 2017).

Findings

Differences in genetics, environment, lifestyle, diet and culture are all likely to influence the management of advanced prostate cancer in the APAC region when compared with the rest of the world. When considering the strong APCCC 2017 recommendation for the use of upfront docetaxel in metastatic castration‐naïve prostate cancer, the panel noted possible increased toxicity in Asian men receiving docetaxel, which would affect this recommendation in the APAC region. Although androgen receptor‐targeting agents appear to be well tolerated in Asian men with metastatic castration‐resistant prostate cancer, access to these drugs is very limited for financial reasons across the region. The meeting highlighted that cost and access to contemporary treatments and technologies are key factors influencing therapeutic decision‐making in the APAC region. Whilst lower cost/older treatments and technologies may be an option, issues of culture and patient or physician preference mean, these may not always be acceptable. Although generic products can reduce cost in some countries, costs may still be prohibitive for lower‐income patients or communities. The panellists noted the opportunity for a coordinated approach across the APAC region to address issues of access and cost. Developments in technologies and treatments are presenting new opportunities for the diagnosis and treatment of advanced prostate cancer. Differences in genetics and epidemiology affect the side‐effect profiles of some drugs and influence prescribing.

Box 1: Management of advanced prostate cancer in the APAC region: real‐world challenges in implementing the St Gallen APCCC recommendations.

  1. Differences in toxicity: safety data for docetaxel are not fully established in Asian men and concerns about the toxicity profile and risk of neutropaenia may influence prescribing.
  2. Disparities in access to imaging technology: variable access to imaging technology may limit prescribing according to precise definitions.
  3. Disparities in access and cost of treatment: availability and cost of treatments are the most significant factor influencing prescribing decisions in the region; lower‐cost alternatives are not always culturally acceptable, and informed choice is important.
  4. Variability in MDT approaches: the importance of multidisciplinary input to treatment recommendations is understood but MDTs are a challenge in some APAC countries; virtual MDT participation should be encouraged.
  5. Variability in demographics: genetics and epidemiology in Asian men with prostate cancer may result in different treatment responses; collaborative registry studies and trials in APAC populations are likely to be valuable.

Conclusions

As the field continues to evolve, collaboration across the APAC region will be important to facilitate relevant research and collection and appraisal of data relevant to APAC populations. In the meantime, the APAC APCCC 2018 meeting highlighted the critical importance of a multidisciplinary team‐based approach to treatment planning and care, delivery of best‐practice care by clinicians with appropriate expertise, and the importance of patient information and support for informed patient choice.

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Editorial: The Advanced Prostate Cancer Consensus on a regional level – what can we learn?

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In this issue of BJUI Chiong et al [1] present the results of the Asia Pacific (APAC) Advanced Prostate Cancer Consensus Conference (APCCC) 2018, during which the implications of the APCCC 2017 findings were discussed in the context of the APAC region. For background, it is important to understand the concept of the original APCCC and why it was initiated [1,2,3].

The consensus conference aims to target areas of controversy in the clinical management of advanced prostate cancer where evidence is either limited or lacking or where interpretation of evidence is controversial. The expert consensus aims to complement existing clinical practice guidelines that are mostly based on high‐level evidence. The APCCC’s most prominent aim is knowledge translation, in the sense of improving care of men with advanced prostate cancer worldwide who are treated outside of centres of excellence. During the original APCCC in St Gallen, where 61 prostate cancer experts and scientists were assembled, the majority of the consensus questions were discussed; these had been prepared prior to the conference under the idealistic assumption that all diagnostic procedures and treatments (including expertise in their interpretation and application) mentioned were readily available. These assumptions have been specifically chosen, because availability of systemic treatment options for advanced prostate cancer, access to next‐generation imaging (whole‐body MRI and positron‐emission tomography [PET]) and expertise in molecular techniques and interpretation of results vary widely across the world. The original global APCCC did not generally address regional or country‐specific situations, but APCCC 2017 did have a special session and also voting questions for treatment options in countries with limited resources. Importantly, consensus recommendations may even inform and influence regulatory authorities, for example, if a specific treatment is considered to be the best option by the majority of experts and availability in a certain country is lacking.

The APAC APCCC 2018 consisted of 20 experts (mostly urologists) from 15 countries and discussed the findings and voting results of five of the 10 APCCC 2017 topics. Whether or not Turkey should be considered an APAC country is unclear. The most relevant observations were as set out below:

  • There is huge variation in access to drugs used for treatment of advanced prostate cancer in the APAC region. Australia and Hong Kong have access to almost all treatment options (notably cabazitaxel is not mentioned) compared with countries such as Vietnam or the Philippines, where there is limited availability of many compounds. Regarding imaging technologies (standard CT is not mentioned), there seems to be wide availability of next‐generation imaging such as whole‐body MRI and choline‐ or PSMA‐PET technologies; however, these imaging methods are often not reimbursed.
  • Pharmaco‐ethnic issues have so far not been considered by the original APCCC and the APAC report clearly highlights the need to address such issues. The higher toxicity of docetaxel in Asian men may influence treatment recommendations, especially in situations such as low‐volume metastatic castration‐naïve prostate cancer, where the role of early addition of docetaxel to androgen deprivation therapy is less clear.
  • The authors of the APAC meeting state that ketoconazole and bicalutamide are still widely used despite the proven superiority of enzalutamide vs bicalutamide. A possible reason for this is the lack of reimbursement in some APAC countries.
  • There is an obvious need for clinical trials in the APAC region because of variations in genetics, genomics, epidemiology and pharmaco‐ethnicity. Such trials may answer questions about toxicity/tolerability and also optimal use of resources in the context of economic limitations.

In summary, the APAC APCCC 2018 is an excellent example of how the global APCCC findings should be discussed and integrated on a regional or even country‐specific level. The authors are therefore to be congratulated for their efforts and for writing up the discussions. The next APCCC  (2019; apccc.org) will take up a number of points raised by the APAC meeting, namely, more panel experts from APAC countries and pharmaco‐ethnic topics.

References

  1. Edmund C, Declan GM, Hideyuki A et al. Management of patients with advanced prostate cancer in the Asia Pacific region: ‘real‐world’ consideration of results from the Advanced Prostate Cancer Consensus Conference (APCCC) 2017. BJU Int 2019; 123: 22–34
  2. Gillessen S, Omlin A, Attard G et al. Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015. Ann Oncol 2015; 26: 1589–604
  3. Gillessen S, Attard G, Beer TM et al. Management of patients with advanced prostate cancer: the report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 2018; 73: 178–211

 

 

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

 

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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.

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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.

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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

 

Article of the Month: Is there an anti-androgen withdrawal syndrome with enzalutamide?

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Every week the Editor-in-Chief selects the Article of the Week 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.

Is there an anti-androgen withdrawal syndrome with enzalutamide?

Alejo Rodriguez-Vida1, Diletta Bianchini2, Mieke Van Hemelrijck3, Simon Hughes1, Zafar Malik4, Thomas Powles5, Amit Bahl6, Sarah Rudman1, Heather Payne7, Johann de Bono2 and Simon Chowdhury1,*

1 Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, UK, 2 Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, UK, 3 King’s College London, Division of Cancer Studies, Cancer Epidemiology Group, London, UK, 4 Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, UK, 5 St. Bartholomew’s Hospital NHS Foundation Trust, London, UK, 6 University Hospitals Bristol NHS Foundation Trust, Bristol, UK, 7 University College Hospital, London, UK

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OBJECTIVE

To examine prostate-specific antigen (PSA) levels after enzalutamide discontinuation to assess whether an antiandrogen withdrawal syndrome (AAWS) exists with enzalutamide.

METHODS

We retrospectively identified 30 consecutive patients with metastatic prostate cancer who were treated with enzalutamide after docetaxel. Post-discontinuation PSA results were available for all patients and were determined at 2-weekly intervals until starting further anticancer systemic therapy. PSA withdrawal response was defined as a PSA decline by ≥50% from the last on-treatment PSA, with a confirmed decrease ≥3 weeks later. Patient characteristics were evaluated in relation to the AAWS using univariate logistic regression analysis.

RESULTS

The median (range) patient age was 70.5 (56–86) years and the median (range) follow-up was 9.0 (0.5–16) months. The most common metastatic sites were the bone (86.7%) and lymph nodes (66.7%). Most patients (70%) had previously received abiraterone and 12 patients (40%) had also received cabazitaxel. The median (range) treatment duration with enzalutamide was 3.68 (1.12–21.39) months. PSA levels after enzalutamide withdrawal were monitored for a median (range) time of 35 (10–120) days. Only one patient (3.3%) had a confirmed PSA response ≥50% after enzalutamide discontinuation. One patient (3.3%) had a confirmed PSA response of between 30 and 50% and another patient (3.3%) had an unconfirmed PSA response of between 30 and 50%. The median overall survival was 15.5 months (95% CI 8.1–24.7). None of the factors analysed in the univariate analysis were significant predictors of PSA decline after enzalutamide discontinuation.

CONCLUSIONS

This retrospective study provides the first evidence that enzalutamide may have an AAWS in a minority of patients with metastatic castration-resistant prostate cancer. Further studies are needed to confirm the existence of an enzalutamide AAWS and to assess its relevance in prostate cancer management.

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Editorial: Enzalutamide withdrawal syndrome: is there a rationale?

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Enzalutamide is a second generation non-steroidal antiandrogen (AA), which significantly improved overall  survival (OS) and progression-free survival (PFS) after docetaxel (AFFIRM study), and OS and radiographic PFS before chemotherapy (PREVAIL study) in patients with metastatic castration-resistant prostate cancer (mCRPC) [1].

Being a potent androgen receptor (AR) antagonist, an enzalutamide withdrawal syndrome (EWS) appeared unlikely [2,3]. In contrast with this position, and considering the well-known AR structural alterations in CRPC, very recent preclinical and clinical data support the possibility of the existence of an EWS after the discontinuation of this drug, in a castration-resistant setting.

In patients with mCRPC progressing on androgen-deprivation therapy (ADT), the AAWS, due to the interruption of first generation AAs (flutamide, bicalutamide, nilutamide, cyproterone acetate and megestrol acetate), often pursues as a further hormonal manipulation, although no level one studies supported its efficacy. AAWS leads to a PSA reduction in 15–30% of patients, with concomitant symptomatic relief and radiographic responses in some cases, without impacting on survival [1]. The molecular mechanisms of the AAWS are still unclear. One of the possible mechanisms responsible for the AAWS is the mutation of the AR. In vitro models showed that bicalutamide may switch from antagonist to agonist in LNCaP-cxD cell lines, due to an additional AR mutation in codon 741 during bicalutamide treatment [4]. Similarly, preclinical in vitro and in vivo studies demonstrated that initially enzalutamide exerts its AR antagonist activity, but during the treatment enzalutamide potently induces an AR mutation, leading to the mutant ARF876L, which confers agonism to enzalutamide, and resistance to enzalutamide therapy [1]. In the clinical setting, the first evidence of possible EWS has begun to appear. Phillips [5] observed EWS in one patient, 40 days after enzalutamide discontinuation. Rodriguez-Vida et al. [1] showed EWS in three of 30 (10%) patients with mCRPC after the drug cessation, although none of the 17 factors examined were statistically significant predictors of PSA decline after enzalutamide interruption. Considering the clinical characteristics of the three patients showing EWS, interestingly all of them were aged <70 years, had Gleason score ≥7, had bone and/or lymph node metastases without visceral sites of disease, and had had previous treatments with bicalutamide and docetaxel. In all three patients, EWS seems to have no correlation with: prostate cancer staging at diagnosis (M0 vs M1), PSA value before enzalutamide, PSA decline on enzalutamide treatment, LHRH analogues and enzalutamide therapy duration. Similarly to bicalutamide WS, in all three patients no symptomatic improvement was recorded during EWS.
Focusing on patient 1, interestingly he displayed initially a PSA response during enzalutamide and later a further PSA decline plus radiological response after enzalutamide interruption (i.e. EWS), showing a sensitivity either to initial enzalutamide antagonism and to subsequent agonism, and exhibiting an EWS not preceded by a bicalutamide WS. This supports previous data concerning different AR mutations for the two different AAs, without subsequent clinical correlations between the two different AAWSs. A LHRH analogue duration treatment (5 months) shorter than a subsequent enzalutamide duration therapy (21.4 months) suggests different tumoral cells sensitivity to different ADTs, in different stages (hormone naïve and castration-resistant prostate cancer), likely related to several AR structural alterations collected along the disease. Intriguingly, patient 3 discontinued enzalutamide after only 1.2 months, maybe due to primary resistance [6]; nevertheless, he showed a PSA
response after enzalutamide interruption, suggesting that EWS, characterised by the switch from enzalutamide antagonism to agonism, could occur even in prostate cancer patients primary resistant to this drug. Limitations of the two first clinical reports related to EWS include a restricted sample size, a reduced number of EWS events and a short duration of follow-up after enzalutamide discontinuation. Furthermore, preclinical studies on EWS and published data concerning AAWS described more frequently early stage mCRPC, while the two papers considered heavily pretreated patients with mCRPC, in whom EWS incidence could be reduced due to several previous treatments, which probably produced various AR alterations.

In conclusion, the preclinical models have demonstrated one possible plausible mechanism responsible for EWS and enzalutamide resistance. First clinical reports suggest the possibility of EWS in a minority of patients after enzalutamide discontinuation in mCRPC. Further studies are needed to confirm and detail the EWS, before translating these data into clinical practice.

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Alessandra Mosca
Medical Oncology, ‘Maggiore della Carità’ University Hospital, Novara, Italy

References

1 Rodriguez-Vida A, Bianchini D, Van Hemelrijck M et al. Is there an antiandrogen withdrawal syndrome with enzalutamide? BJU Int 2015; 115: 373–80

2 von Klot CA, Kramer MW, Böker A et al. Is there an anti-androgen withdrawal syndrome for Enzalutamide? World J Urol 2014; 32: 1171–6

3 von Klot CA, Kuczyk MA, Merseburger AS. No androgen withdrawal syndrome for enzalutamide: a report of disease dynamics in the postchemotherapy setting. Eur Urol 2014; 65: 258–9

4 Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 2003; 63: 149–53

5 Phillips R. An enzalutamide antiandrogen withdrawal syndrome. Nat Rev Urol 2014; 11: 366

6 Efstathiou E, Titus M, Wen S et al. Molecular characterization of Enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur Urol 2015; 67: 53–60

 

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