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Optimal management of metastatic castration-resistant prostate cancer: Highlights from a European Expert Consensus Panel

European Journal of Cancer, 9, 50, pages 1617 - 1627

Abstract

The exponential growth of novel therapies for the treatment of metastatic castration-resistant prostate cancer (mCRPC) over the last decade has created an acute need for education and guidance of clinicians regarding optimal strategies for patient management. A multidisciplinary panel of 21 European experts in mCRPC assembled for comprehensive discussion and consensus development, seeking to move the field forward and provide guidance and perspectives on optimal selection and sequencing of therapeutic agents and monitoring of response to treatment and disease progression. A total of 110 clinically-relevant questions were addressed and a modified Delphi method was utilised to obtain a consensus. The panel reached a consensus on several important issues, providing recommendations on appropriate phase III clinical trial end-points and optimal strategies for imaging and monitoring of bone metastases. Guidance regarding selection and sequencing of therapy in patients with newly diagnosed or progressive mCRPC is emphasised, including the use of novel bone-targeted agents, chemotherapy, androgen receptor pathway-targeted agents and immunotherapy. The impact of drug resistance and prostate-specific antigen flare on treatment decisions was also addressed. Ultimately, individualised therapy for patients with mCRPC is dependent on continued refinement of clinical decision-making based on patient and disease characteristics. This consensus statement offers clinicians expert guidance on the implementation of recent advances to improve patient outcome, focusing on the future of prostate cancer care.

Keywords: Metastatic castration-resistant prostate cancer, Consensus, Radium 223 dichloride, Abiraterone, Enzalutamide, Docetaxel, Circulating tumour cells, Sipuleucel-T, Cabazitaxel, Denosumab.

1. Introduction

Despite continued advances, prostate cancer claims the lives of over 70,000 men in the European Union (EU) each year [1] . Although docetaxel has been established as the standard of care for progressing patients with metastatic castration-resistant prostate cancer (mCRPC) who are able to tolerate this agent, it is now clear that this agent could not be universally used[2], [3], and [4]. Intense research and a better understanding of the pathophysiology of the disease have resulted in the development of new drugs that are now making their way into the clinic.

Since 2004, we have learned that the androgen receptor (AR) could be further manipulated by novel hormone therapy (i.e. abiraterone acetate and enzalutamide), that the patient immune system could be enlisted to fight the cancer (sipuleucel-T), that novel chemotherapy active against docetaxel-resistant cells could be used (cabazitaxel), and that the bone microenvironment could more effectively be targeted to delay skeletal complications (i.e. denosumab) or even increase overall survival (OS) (223RaCl2— radium 223 dichloride [Ra223])[5], [6], [7], [8], [9], [10], [11], [12], and [13]. Clinical trials have compared these new drugs either to placebo or outdated comparators and there is no head-to-head comparison between these agents. As a result, the need for individualised therapy is widely recognised and treating physicians are left with difficult choices and few available solid determinants.

Against the backdrop of these novel therapeutic developments, a panel of European experts convened with the following objectives:

  • 1. To examine appropriate end-points for current and future clinical trials in mCRPC.
  • 2. To assess the role of imaging in diagnosing metastases and monitoring response to therapy.
  • 3. To discuss the importance of patient phenotype in therapeutic decision-making.
  • 4. To review the role of novel bone-targeted radiopharmaceuticals, chemotherapy, immunotherapy and AR pathway-targeted agents.
  • 5. To evaluate current opinion regarding the most appropriate sequencing of available therapies for mCRPC.

2. Methodology

The European Consensus Panel was held on 7th September 2013 in Nice, France, and consisted of 21 experts with extensive experience in the field of prostate cancer ( Appendix A ). The format of the consensus conference was modelled after that of the very successful St. Gallen Early Breast Cancer Consensus Conference organised biannually by Professors H.-J. Senn and A. Goldhirsch [14] . A modified Delphi method was used to obtain a consensus and a consensus threshold of 70% was agreed upon. Participants considered a series of 110 questions, completing a baseline questionnaire prior to any discussion. The experts then shared their assessment of topics by answering specific questions during the conference. Guided by the moderator, the panel debated any conflicting viewpoints, followed by another opportunity to vote on the same question. The process continued until the consensus threshold was met, or until it became apparent that a consensus was lacking ( Table 1 ). Not all questions resulted in a consensus and some experts chose to abstain due to perceived lack of information or expertise regarding the topic. To better quantify the results of this conference, we have used the following nomenclature throughout this manuscript: strong consensus (⩾80% agreement on a choice, with ⩽5% abstaining), consensus (⩾70% agreement on a choice, with ⩽20% abstaining) and no consensus (<70% agreement or >20% abstaining).

Table 1 European Consensus Panel voting results. Bolded values indicate the consensus.

  Yes No Abstain Consensus level
Definition of CRPC
In patients with castrate serum testosterone levels, CRPC can be defined as
 Confirmed PSA progression 81% 19% 0% Strong consensus
 Confirmed PSA progression having received combined androgen blockade and after anti-androgen withdrawal for ⩾4 weeks 57% 38% 5% No consensus
 Confirmed PSA progression after ⩾2 prior hormonal therapies 10% 81% 10% Consensus
 
End - points for Phase III Clinical Trials
Appropriate primary end-points for phase III clinical trials
 OS 100% 0% 0% Strong consensus
 Radiographic progression-free survival 71% 10% 19% Consensus
 Clinical progression-free survival 29% 71% 0% Consensus
 PSA progression 11% 89% 0% Strong consensus
 Skeletal-related events 29% 71% 0% Consensus
 Pain/pain deterioration 10% 90% 0% Strong consensus
 Quality of life deterioration 14% 81% 5% Strong consensus
Should phase III trial end-points differ depending on the line of therapy? 71% 29% 0% Consensus
Are coprimary end-points appropriate for phase III clinical trials in mCRPC? 76% 24% 0% Consensus
Can CTC count serve as a surrogate for OS in phase III clinical trials of systemic therapy for mCRPC? 10% 86% 5% Strong consensus
Are there other reliable surrogates for OS? 10% 81% 10% Consensus
 
Imaging
In the absence of bone pain, is an unequivocally positive or negative bone scan adequate to assess presence or absence of bone metastases? 38% 62% 0% No consensus
If bone scan is equivocal or negative despite bone pain, which of the following is reasonable and appropriate for diagnostic imaging?        
 Plain x-rays of areas of concern 70% 30% 0% Consensus
 Axial skeleton MRI scan 85% 10% 5% Strong consensus
 Whole body MRI scan 29% 71% 0% Consensus
 FDG-PET/CT 5% 86% 10% Consensus
 Fluoride PET/CT 53% 47% 0% No consensus
 Choline PET/CT 60% 40% 0% No consensus
Which of the following imaging studies is most useful for assessment of response of bone metastases to therapy?
 Tc-99 bone scan 29% 71% 0% Consensus
 Whole body MRI 24% 71% 5% Consensus
 Axial skeleton MRI 75% 25% 0% Consensus
 PET/CT 21% 68% 11% No consensus
Should early imaging be performed to detect primary resistance to novel agents targeting the AR pathway? 81% 19% 0% Strong consensus
 
Therapeutic Implications of Patient Phenotype
Prostate cancer exhibits histological/genomic heterogeneity
 Within the same patient 100% 0% 0% Strong consensus
 Between patients 100% 0% 0% Strong consensus
Should biopsy of a metastatic site be performed for selected patients with CRPC and accessible lesions? 71% 19% 10% Consensus
Which of the following are reasons for rebiopsy?        
 To confirm that histology is consistent with prostatic origin 71% 29% 0% Consensus
 To reassess differentiation or proliferation 71% 29% 0% Consensus
 To assess potential tumour heterogeneity 84% 11% 5% Strong consensus
How would you define primary resistance to AR pathway-targeted agents?
 Lack of PSA decrease of ⩾50% during therapy 5% 84% 11% Consensus
 Lack of PSA decrease of ⩾30% during therapy 5% 90% 5% Strong consensus
 PSA progression within 3 months of therapy initiation 19% 76% 5% Consensus
 Radiological progression within 3 months of therapy initiation 76% 14% 10% Consensus
 <1 year duration of response to first hormonal therapy 5% 90% 5% Strong consensus
Indicators of increased risk for primary resistance to AR pathway-targeted agents include
 High Gleason score grade of primary tumour 53% 42% 5% No consensus
 Short duration of response to first-line ADT 86% 14% 0% Strong consensus
 Presence of visceral metastases 10% 90% 0% Strong consensus
 Rapid PSA doubling time 15% 80% 5% Strong consensus
 Testosterone level 0% 100% 0% Strong consensus
 Anaemia 0% 95% 5% Strong consensus
 High LDH 10% 90% 0% Strong consensus
 Alkaline phosphatase 0% 100% 0% Strong consensus
 Degree of bone pain 5% 95% 0% Strong consensus
 Decreased performance status 5% 95% 0% Strong consensus
Preferred first-line therapy for a patient with an increased risk for primary resistance to AR-targeted therapy
 Taxane 70% 15% 15% Consensus
 AR-targeted therapy prior to chemotherapy 10% 81% 10% Consensus
 
Bone-targeted Therapy
Should every patient with mCRPC and bone metastases (and no contraindications) receive bone-modifying agents? 24% 76% 0% Consensus
When might radium-223 be used for mCRPC with symptomatic bone metastases?        
 Postdocetaxel as monotherapy 75% 20% 5% Consensus
 Predocetaxel as monotherapy 80% 20% 5% Strong consensus
 Concomitantly with other pre- or post-docetaxel therapies 33% 48% 19% No consensus
Is there a role for radium-223 in asymptomatic mCRPC? 52% 33% 14% No consensus
Assuming EMA approval of radium-223, is there a role for continued use of beta-emitting radiopharmaceuticals? 48% 38% 14% No consensus
 
Cross-resistance Between AR Pathway Inhibitors
Is there cross-resistance between approved AR-targeted agents? 90% 5% 5% Strong consensus
For a patient with disease progression on abiraterone, when could enzalutamide be considered?        
 If any clinical and/or biochemical response to abiraterone has occurred 29% 67% 5% No consensus
 Only if a ‘durable’ response to abiraterone has occurred 24% 76% 0% Consensus
 Independent of response to abiraterone 40% 60% 0% No consensus
 Should not be considered due to cross-resistance 10% 85% 5% Strong consensus
For a patient with disease progression on enzalutamide, when could abiraterone be considered?
 If any clinical and/or biochemical response to enzalutamide has occurred 24% 76% 0% Consensus
 Only if a ‘durable’ response to enzalutamide has occurred 24% 76% 0% Consensus
 Independent of response to enzalutamide 48% 52% 0% No consensus
 Should not be considered due to cross-resistance 10% 86% 5% Strong consensus
 
Immunotherapy
Is sipuleucel-T a reasonable option for asymptomatic or minimally symptomatic mCRPC? 71% 29% 0% Consensus
How should sipuleucel-T be positioned relative to other approved therapies?        
 Before docetaxel 81% 5% 14% Consensus
 After docetaxel 10% 65% 25% No consensus
 Before abiraterone and/or enzalutamide 70% 10% 20% Consensus
After abiraterone and/or enzalutamide, regardless of whether docetaxel is given 10% 67% 24% No consensus
 
Managing Disease Progression and Sequencing Therapy
mCRPC disease progression can be defined as
 Confirmed PSA progression 80% 20% 0% Strong consensus
 Radiologic progression 90% 10% 0% Strong consensus
 Clinical progression 71% 29% 0% Consensus
 Pain progression only 10% 90% 0% Strong consensus
 Decreased quality of life 15% 85% 0% Strong consensus
Which of the following warrants a switch in therapy?
 Confirmed PSA progression 14% 81% 5% Strong consensus
 Radiologic progression 81% 14% 5% Strong consensus
 Clinical progression 75% 20% 5% Consensus
Does the sequence of taxane versus AR pathway-targeted therapy first change the efficacy of subsequent therapy? 62% 10% 29% No consensus
Which of the following should be used following disease progression during docetaxel therapy?
 AR pathway-targeted agent only 0% 100% 0% Strong consensus
 Cabazitaxel only 10% 90% 0% Strong consensus
 Both an AR pathway-targeted agent and cabazitaxel are reasonable 86% 10% 5% Strong consensus
 Some other approach 5% 35% 60% No consensus
Is there a clinically relevant difference between primary and acquired resistance to docetaxel? 76% 19% 5% Consensus
For a patient with a partial response to docetaxel and disease progression ⩽6 months following docetaxel discontinuation, the next line of therapy should be
 An AR pathway-targeted agent 95% 5% 0% Strong consensus
 Rechallenge with docetaxel 33% 62% 5% No consensus
 Cabazitaxel 100% 0% 0% Strong consensus
 All three options are reasonable 52% 48% 0% No consensus
 Some other approach 75% 20% 5% Consensus
For a patient with a partial response to docetaxel and disease progression >6 months following docetaxel discontinuation, the next line of therapy should be
 An AR pathway-targeted agent 100% 0% 0% Strong consensus
 Rechallenge with docetaxel 76% 24% 0% Consensus
 Cabazitaxel 100% 0% 0% Strong consensus
 All three options are reasonable 90% 10% 0% Strong consensus
 Some other approach 86% 10% 5% Strong consensus
When prescribing an AR pathway-targeted agent, which one would you use first?
 Abiraterone first 10% 85% 5% Strong consensus
 Enzalutamide first 29% 65% 6% No consensus
 It does not matter 71% 19% 10% Consensus
Should ongoing LHRH agonist or antagonist therapy be continued when a patient is starting on abiraterone or enzalutamide? 95% 0% 5% Strong consensus
In a patient receiving LHRH agonist or antagonist at the time of disease progression on either abiraterone or enzalutamide, should abiraterone or enzalutamide be discontinued? 85% 0% 15% Strong consensus
Do you agree that initial PSA rise during docetaxel or cabazitaxel therapy should be ignored? 95% 5% 0% Strong consensus
Is the occurrence of PSA flare during taxane therapy associated with a similar response compared to primary responders? 71% 0% 29% No consensus
Is the occurrence of bone flare associated with an inferior response to therapy compared to a primary responder without a flare? 0% 76% 24% No consensus

Abbreviations:ADT, androgen deprivation therapy; AR, androgen receptor; CRPC, castration-resistant prostate cancer; CTC, circulating tumour cell; EMA, European Medicines Agency; LDH, lactate dehydrogenase; LHRH, luteinizing hormone-releasing hormone; mCRPC, metastatic CRPC; MRI, magnetic resonance imaging; OS, overall survival; PET/CT, positron emission tomography/computed tomography; PSA, prostate specific antigen.

3. Consensus development and panel discussion

3.1. Clinical trial end-points

Clinical trials and appropriate primary end-points are critical for moving the field of prostate cancer forward. The panel consensus was that OS and radiologic progression-free survival (rPFS) were appropriate primary end-points for phase III clinical trials investigating cancer-specific therapeutic agents for mCRPC. In contrast, the panel felt that clinical PFS (based on physical exam and/or pain and/or deterioration of performance status [PS]), prostate specific antigen (PSA) progression, occurrence of symptomatic skeletal-related events (SREs), occurrence of pain and quality of life were not appropriate primary end-points for phase III trials, but could serve as important secondary end-points. Panelists emphasised that primary end-points will most likely evolve with the continued emergence of novel therapeutic agents. For bone-targeted therapies, OS is not required, but the occurrence of SREs may be a sufficient end-point in clinical trials.

Circulating tumour cell (CTC) count is a predictor of OS in patients with CRPC receiving either chemotherapy or abiraterone[15], [16], and [17]. However, the technology for detection of CTCs requires further fine-tuning to ensure accuracy [15] . Furthermore, preclinical data suggest that the interaction of CTCs with platelets may promote evasion of immune surveillance and current CTC detection methods, suggesting CTC enumeration may not reflect a patient’s true risk for metastatic disease [18] . Based on currently available data, 86% of the panel agreed that CTCs are not ready for use as a surrogate OS marker in clinical trials of CRPC. They also emphasised that there are currently no other reliable surrogates for OS in prostate cancer, including PFS.

3.2. Monitoring progression and response

Despite advances in mCRPC, disease diagnosis and monitoring of progression and response in bone still rely on99mTc-polyphosphonate bone scintigraphy and standard x-rays or computed tomography (CT), even with a proven poor sensitivity and specificity. The limitations of bone scanning were reiterated by the panel, emphasising that a negative bone scan is not sufficient to exclude the presence of bone metastases, particularly in patients with bone pain or rapidly rising PSA levels.

The use of advanced imaging modalities, such as positron emission tomography (PET)/CT and magnetic resonance imaging (MRI), has important implications in treatment decision-making [19] . For patients with bone pain and equivocal or negative bone scans, the panel strongly agreed that axial skeleton MRI was a reasonable and appropriate diagnostic imaging study [20] . Despite initial disagreement regarding the role of plain x-rays, discussion led to a consensus that x-rays also have diagnostic value in patients with bone pain and an equivocal or negative bone scan. Consensus was reached that [18F]-fluorodeoxyglucose (FDG)–PET/CT and whole-body MRI are not appropriate in this clinical setting. The panel identified axial skeleton MRI as the most useful imaging tool for assessing response of bone metastases to therapy over bone scan, whole body MRI and FDG–PET/CT [21] . The panel stressed that advanced imaging modalities are not readily accessible in all areas of the world [19] . Future efforts should focus on validating newer imaging technologies and making them affordable and available to all patients.

The panel was initially divided on whether early imaging was appropriate to detect primary resistance to novel agents targeting the AR pathway. While early response assessment gives the opportunity to discontinue ineffective therapies, accuracy is highly dependent on the sensitivity of the imaging method utilised. Following discussion, 81% of the panel members agreed that early imaging should be performed during therapy for mCRPC to detect resistance to novel agents targeting the AR pathway and 3 months was recommended as the appropriate minimum time point based on the imaging modalities currently available. Imaging prior to 3 months may detect bone flare and should be avoided.

3.3. Therapeutic implications of patient phenotype

The panel agreed unanimously that prostate cancer demonstrates significant heterogeneity between individuals and even within the same patient. In order to better understand prostate cancer heterogeneity and move the field forward with regard to personalised treatment decisions, the panel reached a consensus that, when possible, biopsy of metastatic lesions should be considered. Biopsy of accessible metastatic lesions provides the opportunity to reassess differentiation and proliferation characteristics, confirm that the histology is consistent with the primary tumour and assess potential tumour heterogeneity. Discussion amongst the panelists emphasised that re-biopsy of metastatic sites is important, provided that the results can influence treatment decisions. At this point in time, however, it is not standard of care since this will require predictive biomarkers to allow individualised treatment selection [15] .

Resistance to treatment is unfortunately common in mCRPC. The panel consensus was that primary resistance to AR pathway-targeted agents can be defined as radiologic progression within 3 months following therapy initiation. Panel members agreed that primary resistance cannot be sufficiently defined by a lack of PSA decrease or PSA progression within 3 months of therapy initiation. While short response to initial hormonal therapy seems to be associated with poor response to subsequent hormonal therapies, this is not always an indicator of absolute androgen independence and does not exclude potential benefit from novel AR-targeting strategies, such as abiraterone or enzalutamide.

The panel agreed that short duration of response (<1 year) to first-line androgen deprivation therapy (ADT) could potentially be used to identify patients with an increased risk for primary resistance to AR pathway-targeted agents [22] . The panel felt there is not sufficient evidence to use high Gleason score, the presence of visceral metastases, rapid PSA doubling time, testosterone level, anaemia, high lactate dehydrogenase, alkaline phosphatase, degree of bone pain and decreased PS as indicators of resistance. While all of these factors may influence resistance, none alone would be sufficient to select first-line chemotherapy over AR-targeted therapy. Data from the post-docetaxel era are currently limited regarding the benefit of abiraterone or enzalutamide in patients with a high risk for primary resistance. Thus, clinicians should consider all patient and disease characteristics when choosing between chemotherapy and AR-targeted therapies. Given these caveats, the panel agreed that the preferred first-line therapy for patients with mCRPC and awell-definedrisk of primary resistance to AR-targeted therapies would be a taxane rather than an AR-targeted agent.

3.4. Bone-targeted therapies

Denosumab and zoledronic acid are commonly used to delay and prevent SREs in patients with CRPC and bone metastases. Despite the significant published data supporting the value of these agents, the panel felt that the use of bone-targeted therapy should remain an individualised treatment decision based on evaluation of the benefit/risk ratio[11], [12], and [23]. When asked ifeverypatient with mCRPC and bone metastases should be treated with a bone-modifying agent, the panel consensus was ‘no’.

There is renewed interest in bone-targeted radiopharmaceuticals for mCRPC based on recent data demonstrating an OS advantage for the alpha-emitting agent Ra223 over placebo in patients with mCRPC and bone metastases [13] . Consistent with the patient population from this trial, the panel agreed that Ra223 can be considered as pre-docetaxel or post-docetaxel therapy in patients with mCRPC and symptomatic bone metastases. The panel did not feel there was sufficient data to support its use in patients with asymptomatic bone metastases. Given the excellent safety profile of Ra223, there is interest in combination regimens with therapies such as abiraterone and enzalutamide. However, further studies are needed before these combinations can be routinely recommended in clinical practice.

3.5. Cross-resistance between AR pathway inhibitors

Regulatory approval of both abiraterone and enzalutamide raises questions regarding potential cross-resistance and optimal sequencing of AR-targeted therapy [24] . The panel strongly agreed that at least partial cross-resistance does exist between approved AR-targeted agents. Small retrospective studies evaluating patients with progressive CRPC following docetaxel and enzalutamide demonstrated that subsequent abiraterone produced few responses of brief duration[25] and [26]. Similarly, two retrospective analyses of patients who received enzalutamide for CRPC progressing after docetaxel and abiraterone showed a modest response rate and evidence of cross-resistance[27] and [28].

However, cross-resistance was not inevitable and responses to secondary AR-targeted therapy were observed[25], [26], [27], and [28]. Abiraterone and enzalutamide inhibit persistent AR signalling through different mechanisms, suggesting that patients with resistance to one agent may still benefit from the other agent. Based on insufficient data to exclude the possibility of crossover responses, the panel agreed that abiraterone or enzalutamide could be considered for patients who experienced disease progression while receiving the other AR-targeted agent. However, no consensus was reached regarding precisely which patients should receive a second AR-targeted therapy following progression. Until conclusive data are available, clinicians need to carefully consider both patient and disease characteristics when sequencing these therapies.

3.6. Immunotherapy

Based on current phase III data demonstrating good tolerability and an OS benefit for sipuleucel-T [9] , the panel agreed it is a reasonable option for patients with asymptomatic or minimally symptomatic mCRPC. Importantly, they felt that sipuleucel-T should be considered prior to docetaxel, abiraterone and enzalutamide, not following these agents. This is in agreement with the recent EU regulatory approval, which specified eligibility only in patients for whom chemotherapy was not yet clinically indicated [29] . Sipuleucel-T provides a new treatment option during the time period between development of castration-resistant disease and becoming a candidate for chemotherapy. Further studies will be necessary to determine the efficacy, safety and cost-effectiveness of sipuleucel-T in patients who have already received abiraterone and/or enzalutamide.

3.7. Managing disease progression and sequencing therapy

Clear guidelines regarding when to switch therapy and how to sequence therapy for mCRPC are currently lacking. It is important to avoid premature treatment discontinuation and allow adequate time for systemic therapies to be effective [30] . The panel agreed that radiologic progression and clinical progression would warrant a switch in therapy. Importantly, 81% agreed that it was inappropriate to switch therapy based solely on confirmed PSA progression. Careful assessment of all response parameters must be weighed against the specific agent’s mode of action in order to determine whether treatment should be continued or switched [30] .

Sequencing therapy is complicated by the potential for cross-resistance between AR pathway-targeted agents and taxanes [24] . Preclinical studies suggest that the mechanisms of action for AR-targeted agents and taxanes overlap regarding interference with AR nuclear translocation, raising concerns that the action of one of these agents on AR signalling as first-line therapy may impair the ability of a second-line agent to subsequently inhibit this pathway[31] and [32]. This is supported by a retrospective analysis of 35 patients with abiraterone-pretreated CRPC who subsequently received docetaxel at progression [33] . Only four patients achieved a partial radiologic response and the median OS was 12.5 months, compared to a median OS of 18.9 months for docetaxel administered in a different setting but using the same schedule in patients without prior abiraterone in the phase III TAX327 trial[2] and [33]. In a similar retrospective study of cabazitaxel in patients with progressive mCRPC following abiraterone and docetaxel, 56% of patients had a PSA decline of ⩾50% and 15% had a partial response (PR) [34] .

While this suggests prior AR pathway-targeted therapy could compromise the efficacy of subsequent taxane therapy, it is unclear whether the reverse is true. Overall survival data from the phase III COU-AA-301 and AFFIRM trials demonstrated sensitivity to abiraterone and enzalutamide in docetaxel-pretreated mCRPC[6] and [8]. However, retrospective studies have shown poor response to abiraterone and enzalutamide in patients with disease progression following docetaxel therapy[22], [23], [24], [25], and [35]. Given the lack of prospective data, the panel failed to reach a consensus regarding whether the sequence in which agents are administered changes the efficacy of subsequent taxane or AR pathway-targeted therapy, although a majority did feel that drug sequence may affect response to subsequent therapies.

The panelists also agreed that there is a clinically relevant difference between primary and acquired resistance to docetaxel. The panel reached a strong consensus that both AR pathway-targeted agents and cabazitaxel are reasonable second-line options for patients experiencing disease progression during docetaxel therapy and for those with a PR to docetaxel who progress ⩽6 months after discontinuing therapy. There was no consensus on the role for docetaxel rechallenge in patients who progressed within 6 months following completion of initial docetaxel. Conversely, for patients with disease progression >6 months following a PR to docetaxel, 90% of the panel felt that all three options (AR pathway-targeted agents, cabazitaxel and docetaxel rechallenge) were reasonable. Panel commentary emphasised that while approximately 50% of patients will respond to docetaxel rechallenge, there are currently no data to support an OS benefit[36] and [37]. This should be taken into consideration given the OS advantage associated with abiraterone, enzalutamide and cabazitaxel in patients with docetaxel-pretreated mCRPC[6], [8], and [10]. The panel also agreed that regardless of the duration of response to docetaxel, other approaches such as Ra223 or enrolment on a clinical trial could be considered following docetaxel.

When considering an AR pathway-targeted agent for a patient with disease progression following docetaxel, the panel agreed that either abiraterone or enzalutamide could be given first as they have not been compared head-to-head in a clinical trial. There was also a strong consensus that patients with mCRPC receiving either a luteinising hormone-releasing hormone (LHRH) agonist or antagonist should continue on these agents, or have orchidectomy, when initiating abiraterone or enzalutamide. This is consistent with the current EAU and European Society for Medical Oncology (ESMO) treatment guidelines[38], [39], and [40]. Interestingly, 85% of the panel agreed that patients receiving LHRH agonists or antagonists with either abiraterone or enzalutamide should discontinue abiraterone or enzalutamide at the time of disease progression. It was felt that current clinical data are not sufficient to support continuation of these AR pathway-targeted therapies beyond disease progression, although ongoing clinical trials will address this issue.

Patients receiving taxanes can exhibit an immediate, transient rise in PSA levels at therapy initiation[41] and [42]. This flare phenomenon precedes actual response to treatment and can be misinterpreted as therapeutic failure, leading to premature discontinuation of potentially effective agents. While treatment discontinuation should be considered for patients with clear signs of rapid disease progression, 95% of the panel agreed that initial PSA rise during the first 12 weeks of taxane therapy should be ignored. Current data also suggest that PSA flare has no impact on disease outcome and survival for patients receiving docetaxel or cabazitaxel [41] . While the majority of panelists (71%) agreed that a PSA flare during taxane therapy is associated with similar response compared to patients who respond with no PSA flare, 29% abstained, preventing a consensus.

4. Conclusions

This consensus statement provides valuable guidance for clinicians regarding the optimal management of mCRPC given the current lack of definitive data and seeks to move the field forward towards more personalised patient care. The treatment of mCRPC is not only complicated by the sheer number of available therapies, but the prevalence of resistance to these agents and the lack of validated predictive markers. The panel identified considerations for diagnosing and monitoring metastatic disease, risk factors for drug resistance, indicators that warrant a switch in therapy and strategies for treatment selection and sequencing to maximise the potential for response. Importantly, there was a clear consensus that novel bone-targeted agents, immunotherapy, chemotherapy and AR pathway-targeted agents all play an important role across the mCRPC disease continuum. The difficulty lies in selecting the right therapy, at the right time and for the right patient. While this consensus statement provides guidance for making these difficult treatment decisions, evaluation of all the factors that contribute to treatment selection is critical in providing truly personalised care.

Conflict of interest statement

John M. Fitzpatrick has received consulting fees from Astellas, GlaxoSmithKline, Janssen, Millennium, Sanofi and Takeda. Joaquim Bellmunt has received consulting fees from Astellas, Janssen and Sanofi. Karim Fizazi has received consulting fees from Astellas, Bayer, Dendreon, Janssen and Sanofi. Axel Heidenreich has received consulting fees from Amgen, Astellas, Ferring, Ipsen, Sanofi and Takeda. He has performed contracted research for Astellas and Sanofi. Additionally, he has received fees for non-CME services (e.g. speakers’ bureaus) from Amgen, Astellas, Bayer, Ferring, Ipsen, Sanofi and Takeda. Cora N. Sternberg has received consulting fees from Astellas, Bayer and Janssen. Bertrand Tombal has received consulting fees and fees for non-CME services (e.g. speakers’ bureaus) from and performed contracted research for Amgen, Astellas, Bayer, Dendreon, Ferring, Medivation and Sanofi. Antonio Alcaraz has received consulting fees from GlaxoSmithKline and Janssen. Amit Bahl has received consulting fees from Amgen, Astellas, Janssen, Roche and Sanofi. Sergio Bracarda has received consulting fees from Bayer and Janssen. Giuseppe Di Lorenzo has no relevant relationships to report. Eleni Efstathiou has received consulting fees from Janssen and Sanofi. She has performed contracted research for Janssen, Millennium and Sanofi. Additionally, she has received fees for non-CME services (e.g. speakers’ bureaus) from Astellas and Janssen. Stephen P. Finn has no relevant relationships to report. Sophie Fosså has no relevant relationships to report. Silke Gillessen has been a member of advisory boards for Astellas, Bayer, CellSearch, Curevac, Janssen Cilag, Millennium, Novartis, Pfizer, ProteomediX and Sanofi Aventis. Pirkko-Liisa Kellokumpu-Lehtinen has received consulting fees from Pfizer and Roche. She has performed contracted research for Pfizer, Roche and Sanofi. Frédéric E. Lecouvet has no relevant relationships to report. Stephane Oudard has received consulting fees from Astellas, Bayer, Janssen, Sanofi and Takeda. Theo M. de Reijke has received consulting fees from Amgen, Bayer, Ferring and Teva. Craig N. Robson has no relevant relationships to report. Maria De Santis has received consulting fees from Amgen, Astellas, Bayer, Dendreon, Genex, GlaxoSmithKline, Ipse, Janssen, Novartis, Pfizer, Sanofi. She has also performed contracted research for Pierre Fabre, Pfizer, Shionogi and Roche. Bostjan Seruga has received consulting fees from Janssen and Sanofi Aventis. Ronald de Wit has received consulting fees from and performed contracted research for Sanofi.

Acknowledgements

The authors would like to thank Julian Lee Lokey, MD, and Sanneke Koekkoek, BSN, for assistance with data collection; Tristin Abair, PhD, and Julian Lee Lokey, MD, for their assistance in drafting this manuscript; and Trudy Grenon Stoddert, ELS, for editorial assistance and assistance preparing the manuscript for submission. All were compensated by prIME Oncology. Financial support was provided by an educational grant from Sanofi Oncology.

Appendix A. European Consensus Panel Members

A.1. Panel chair

John M. Fitzpatrick, MD, Irish Cancer Society and University College, Dublin, Ireland.

A.2. Scientific committee

 

  • Joaquim Bellmunt, MD, PhD, University Hospital del Mar, Barcelona, Spain.
  • Karim Fizazi, MD, PhD, Institut Gustave Roussy, Villejuif, France.
  • Axel Heidenreich, MD, University Hospital Aachen, Aachen, Germany.
  • Cora N. Sternberg, MD, FACP, San Camillo and Forlanini Hospital, Rome, Italy.
  • Bertrand Tombal, MD, PhD, Centre du Cancer et Institut de Recherche Expérimental et Clinique (IREC); Cliniques Universitaires Saint Luc, Brussels, Belgium.

A.3. Panel members

 

  • Antonio Alcaraz, MD, PhD, Hospital Clinic de Barcelona, Barcelona, Spain.
  • Amit Bahl, MD, University Hospitals Bristol, Bristol, United Kingdom.
  • Sergio Bracarda, MD, Ospedale San Donato, Istituto Toscano Tumori (ITT), Arezzo, Italy.
  • Eleni Efstathiou, MD, PhD, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States.
  • Stephen P. Finn, MB, PhD, St. James’s Hospital and Trinity College, Dublin, Ireland.
  • Sophie Fosså, MD, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
  • Silke Gillessen, MD, Kantonsspital St. Gallen, St. Gallen, Switzerland.
  • Giuseppe Di Lorenzo, MD, PhD, University Federico II, Napoli, Italy.
  • Pirkko-Liisa Kellokumpu-Lehtinen, MD, PhD, Tampere University Hospital, Tampere, Finland.
  • Frédéric E. Lecouvet, MD, PhD, Centre du Cancer et Institut de Recherche Expérimental et Clinique (IREC); Cliniques Universitaires Saint Luc, Brussels, Belgium.
  • Stephane Oudard, MD, PhD, Georges Pompidou European Hospital, Paris, France.
  • Theo M. de Reijke, MD, PhD, Department of Urology, Academic Medical Center, Amsterdam, the Netherlands.
  • Craig N. Robson, PhD, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Maria De Santis, MD, Ludwig Boltzmann Institute for Applied Cancer Research, Kaiser Franz Josef-Spital, Vienna, Austria.
  • Bostjan Seruga, MD, PhD, Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
  • Ronald de Wit, MD, PhD, Erasmus University Medical Center, Rotterdam, the Netherlands.

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Footnotes

a Irish Cancer Society and University College, Dublin, Ireland

b University Hospital del Mar, Barcelona, Spain

c Institut Gustave Roussy, University of Paris Sud, Villejuif, France

d University Hospital Aachen, Aachen, Germany

e San Camillo and Forlanini Hospital, Rome, Italy

f Centre du Cancer et Institut de Recherche Expérimental et Clinique (IREC), Cliniques Universitaires Saint Luc, Brussels, Belgium

g Hospital Clinic de Barcelona, Barcelona, Spain

h University Hospitals Bristol, Bristol, United Kingdom

i Ospedale San Donato, Istituto Toscano Tumori (ITT), Arezzo, Italy

j University Federico II, Napoli, Italy

k University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States

l St. James’s Hospital and Trinity College, Dublin, Ireland

m Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

n Kantonsspital St. Gallen, St. Gallen, Switzerland

o Tampere University Hospital, Tampere, Finland

p Georges Pompidou European Hospital, Paris, France

q Department of Urology, Academic Medical Center, Amsterdam, The Netherlands

r Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom

s Ludwig Boltzmann Institute for Applied Cancer Research, Kaiser Franz Josef-Spital, Vienna, Austria

t Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia

u Erasmus University Medical Center, Rotterdam, The Netherlands

lowast Corresponding author: Address: Centre du Cancer et Institut de Recherche Expérimental et Clinique (IREC), Cliniques Universitaires Saint Luc, Brussels, Belgium.

Financial support was provided by an educational grant from Sanofi Oncology.