Implementing newer agents for the management of castrate-resistant prostate cancer: what is known and what is needed? Nicolas Mottet, Noel Clarke*, Maria De Santis†, Filiberto Zattoni‡, Juan Morote§ and Steven Joniau¶ University Hospital, Saint Etienne, France, *The Christie and Salford Royal Hospitals, Manchester, UK, †LBI-ACR & ACR-ITR Vienna, Kaiser Franz Josef-Spital, Vienna, Austria, ‡University of Padua, Padua, Italy, §Vall d'Hebron Hospital, Barcelona, Spain, and ¶University Hospitals Leuven, Leuven, Belgium

Men receiving androgen-deprivation therapy will in time develop metastatic castrate-resistant prostate cancer (mCRPC). Whilst effective treatment options for mCRPC have traditionally been limited, new agents are becoming available. Since 2010, the number and class of agents available to treat mCRPC has increased dramatically. As such, there is a need for clear guidance on the optimum treatment and sequence of treatments for mCRPC before and after chemotherapy. This evidence-based statement, reflecting the views of the authors,

Introduction Men with prostate cancer receiving androgen-deprivation therapy (ADT) will, in time, develop metastatic castrate-resistant prostate cancer (mCRPC). The widely accepted definition of CRPC from the European Association of Urology (EAU) is the maintenance of castrate serum levels of testosterone (2 ng/mL (excluding rises due to anti-androgen withdrawal, defined as cessation of ≥4 weeks for flutamide and ≥6 weeks for bicalutamide). Further indicators of CRPC include clinical progression based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria or appearance of ≥2 new bone lesions on bone scan [1]. Until recently, patients with mCRPC had few treatment options and effective treatment of mCRPC has been challenging [2]. It is generally agreed that conventional ADT should be maintained indefinitely, even when the disease becomes castrate resistant. Although this approach is not supported by Level 1 evidence, it is based upon the finding that some tumour cells retain androgen sensitivity even in CRPC [3] and from historical series showing that continued androgen suppression is associated with longer survival [4].

BJU Int 2015; 115: 364–372 wileyonlinelibrary.com

provides suggestions on the continued relevance of conventional approaches to first- and second-line treatment in mCRPC, the potential role of novel treatments, and factors that may influence the choice of hormonal agents and/or chemotherapy.

Keywords castrate-resistant prostate cancer, individualised management, new agents, evidence-based best practice

New hormonal agents are becoming available: when used in combination with ongoing ADT they may extend life after chemotherapy and when used before chemotherapy they may delay chemotherapy initiation. In the last 10 years, six new drugs have been tested in large trials in CRPC. They have been shown to have benefits for overall survival (OS) and/or radiographic progression-free survival (rPFS) and health-related quality of life (HRQL). They have also been shown to reduce the incidence of clinical complications associated with progressive CRPC [5–11]. The optimum treatment and sequence of treatments for mCRPC before and after chemotherapy is currently unknown. Guidance for clinicians is required in this area of clinical practice. An expert meeting of the authors of this paper was held in Paris in April 2013 to discuss the potential use of newer agents (including abiraterone, enzalutamide, sipuleucel-T, cabazitaxel and radium 223) and to reach agreement, among this small group of experts, on evidence-based best clinical practice for patients with mCRPC. Specific objectives of the group included: • The need to clarify treatment options for mCRPC by discussing the natural history of the disease. • Discussion of the continued relevance of conventional approaches to first-line treatment in mCRPC. © 2014 The Authors BJU International © 2014 BJU International | doi:10.1111/bju.12736 Published by John Wiley & Sons Ltd. www.bjui.org

Implementing newer agents for the management of CRPC

• Consideration of what can be expected from novel treatments and how to choose between hormonal agents and chemotherapy as first-line treatment. • Provision of a clear rationale for what the next steps should be after first-line treatment failure. • To assess the need for bone protection and the optimum supportive care. Participants were assigned to specific topics and conducted PUBMED searches on the recent literature in the field of mCRPC management. Assigned participants presented on these topics during the meeting, and all participants then developed the recommendations and contents of this paper based on all the reports presented. As such, the contents of this paper are the conclusions of the authors, but do not represent a wider ’European consensus’.

Predictors of Outcome in CRPC Life Expectancy It is important to consider the life expectancy, co-morbidity and progression of symptoms in patients with CRPC, as these factors are variable and influence treatment decisions. In non-curatively treated patients with prostate cancer, age is not an important factor in determining death from prostate cancer after 15 years [12], probably because co-morbidities, e.g. cardiovascular disease, account for a greater proportion of deaths in older men. In CRPC, recent clinical trials indicate that age by itself does not determine survival [6–8]. Health status is one of the key determinants of life expectancy and this alone may influence treatment decisions [13,14]. However, older men are less likely to receive curative treatment for prostate cancer [15]. The International Society of Geriatric Oncology (SIOG) guidance for treatment of older men with prostate cancer is of relevance to many patients with CRPC; these state that unless patients are frail (≥2 co-morbidities, dependent in ≥1 Instrumental Activities of Daily Living or severe malnutrition) or too sick, they should receive treatment equivalent to that given to younger patients [16]. Symptom Progression The presence of symptoms of prostate cancer may have a negative impact upon survival [1], and in the last year of life, local and clinical progression is rapid [17]. The effect of disease progression on the emergence or seriousness of individual symptoms is not well defined. However, as prostate cancer progresses locally, the symptomatology can worsen and include: haematuria, unilateral or bilateral ureteric obstruction, renal insufficiency, acute or chronic bladder urinary retention, pelvic pain and rectal obstruction or fistula. Metastatic progression can result in a further worsening in symptoms with additional problems, e.g. skeletal-related events (SREs; bone pain, fractures and

spinal cord compression), anaemia, urinary problems affecting the upper and/or lower urinary tract and toxic shock syndrome. There are limited data on how to predict the worsening of symptoms in CRPC. With the evolving therapeutic options in CRPC, previously used nomograms need re-evaluation [14], and it is crucial to realise that nomograms have to be validated for each population of patients.

Conventional Second-Line Hormonal Treatment Until the recent approval of novel agents for the treatment of patients with mCRPC the options for secondary hormonal manipulation after conventional ADT was limited [1]. This usually comprised supplementation of GnRH agonists with an anti-androgen: combined androgen blockade (CAB). This therapy results in a decrease in PSA levels in ≈20% of patients, lasting for a median of 2–3 months. This effect is not predictable in individual patients. CAB can also improve PFS and a further improvement can occur after subsequent anti-androgen withdrawal [18–23]. Alternative hormonal manipulations upon failure of ADT and/or CAB include switching to an alternative anti-androgen therapy [23], adding ketoconazole at the same time as the anti-androgen withdrawal [22], or the use of oestrogens [24–26]. These conventional second-line hormonal manipulations produce a PSA response in a proportion of patients. Despite the recorded PSA changes, OS benefit has not been proven with any conventional second-line hormonal regimen [22,27–30]. The lack of evidence for OS benefit is related to the lack of data from large-scale, well-designed trials. Data have to be drawn from studies with few patients, and therefore, definitive guidance on the use of conventional second-line hormonal treatment is not available. Panel Recommendations In practice, conventional second-line hormonal treatment may be useful in asymptomatic patients with slow-growing metastases, especially where the newer hormonal agents are not yet available. A potential benefit of this is to try to postpone initiation of chemotherapy. In other situations, conventional second-line hormonal treatment is not useful and cytotoxic chemotherapy is usually more effective. In such situations and when patients fail second-line hormonal therapy, many patients receive taxane-based cytotoxic chemotherapy with docetaxel. This has proven beneficial in a proportion of patients, improving OS and HRQL [5]. When patients do not receive docetaxel therapy because of poor performance status, co-morbidity or patient preference, best supportive care (often supplemented with steroid use or © 2014 The Authors BJU International © 2014 BJU International

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Review

Table 1 Summary of clinical trials of newer agents for pre-chemotherapy use in mCRPC (and comparison with data for docetaxel chemotherapy). Drug (study)

Treatment arms

Abiraterone (COU-AA-302) [10,39]

Abiraterone + prednisone vs placebo + prednisone

Radium 223 (ALSYMPCA) [11]

Radium 223 + best standard care vs placebo + best standard care

Sipuleucel-T (IMPACT) [9]

Sipuleucel-T vs control arm

Docetaxel (TAX327) [5]

Docetaxel (every 3 weeks) + prednisone vs mitoxantrone + prednisone

Second-Line Treatment in Light of Newer Agents The lack of proven OS benefit with conventional second-line hormone treatments emphasises the need for novel agents and treatment strategies in mCRPC. Treatments under investigation for chemo-naïve mCRPC include orteronel (TAK-700) [34], enzalutamide [35], PROSTVAC-VF [36], ipilimumab [37], and tasquinimod [38], but their place in the management of mCRPC is yet to be defined. The PREVAIL study of enzalutamide vs placebo in chemotherapy-naïve patients with mCRPC was recently stopped early and all

mCRPC asymptomatic

Hormone therapy

mCRPC mildly symptomatic

Endpoints

Progressive CRPC Chemotherapy naïve Asymptomatic or mildly symptomatic No known visceral metastases Symptomatic CRPC ≥2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel (>40% of recruited patients) CRPC Chemotherapy naïve Asymptomatic or mildly symptomatic CRPC Chemotherapy naïve 45% were symptomatic

rPFS: 16.5 vs 8.3 months (P < 0.001) OS: 35.3 vs 30.1 months (P = 0.015; non-significant)

C h e m o

Sipuleucel-T

mCRPC post-chemo

Docetaxel

Cabazitaxel Enzalutamide

Radium 223 PLUS bone targeted agents (e.g., denosumab/bisphosphonates/b-emitters) Continue ADT Approved for use by FDA/EMA Positive Phase III trial data ??? Denotes that the definition on when to start bone targeted therapy is unclear

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© 2014 The Authors BJU International © 2014 BJU International

OS: 18.9 vs 16.5 months (P < 0.001)

Fig. 1 Simplified overview of possible drug

Abiraterone

Enzalutamide

???

OS: 25.8 vs 21.7 months (P = 0.032)

Data on the use of radium 223, abiraterone and sipuleucel-T as second-line treatment are summarised in Table 1

mCRPC symptomatic pre-chemo

Abiraterone

OS: 16.1 vs 11.5 months (P = 0.039) in chemotherapy naïve sub-group Time to first SRE: 15.6 vs 9.8 months (P < 0.001) in total population

patients were offered enzalutamide, due to a significant improvement in the two co-primary endpoints, OS and PFS with active treatment in the pre-planned interim analysis. The full peer-reviewed publication of these data and the impact on approval of this agent in the pre-chemotherapy setting is eagerly awaited. Three new agents have been assessed and approved by the European Medicines Agency (EMA) and/or the USA Food and Drug Administration (FDA) by January 2014 (radium 223, abiraterone and sipuleucel-T) as therapy for patients with mCRPC before the use of chemotherapy (a simplified overview of patient eligibility for these agents is given in Fig. 1).

third-line ADT with oestrogen-based therapies) was the only treatment available [31–33].

Hormone sensitive

Patients

treatments for mCRPC before and after chemotherapy.

Implementing newer agents for the management of CRPC

[5,9–11,39]: the data from the TAX327 trial of docetaxel are included for comparison. Panel Recommendations An individualised approach to management of mCRPC is needed, based upon aims and expectations of individual patients and the clinician’s expectations of efficacy with minimal toxicity. These expectations include the need to improve survival, palliate symptoms, control PSA levels, prevent the complications of bone metastases, and delay the use of chemotherapy. Newly published data with abiraterone, radium 223 and sipuleucel-T do allow tentative recommendations to be made. Asymptomatic or mildly symptomatic mCRPC • Abiraterone (with continued ADT) may be considered before chemotherapy, even in the absence of definitive evidence for survival benefit. In the COU-AA-302 trial, OS was increased with abiraterone (P = 0.015; hazard ratio 0.79). However, as it was a pre-planned preliminary analysis (the third one) the P-value had to be below a pre-specified significance level of 0.0035, thus leading to a non-statistically significant difference. Patients with visceral metastases were excluded from the COU-AA-302 trial [10,39], and therefore, there are currently no data to support abiraterone use in asymptomatic patients with visceral metastases before docetaxel. • The effect of sipuleucel-T on OS may be better in patients with lower PSA levels [40], which leads to the possibility that this agent may be an early option in patients with asymptomatic mCRPC. However, more data are needed to confirm this. Symptomatic mCRPC • In patients with symptomatic mCRPC there are currently no data to support the use of abiraterone or sipuleucel-T before chemotherapy. The COU-AA-302 and IMPACT trials included patients with no symptoms or mild symptoms (defined by the Brief Pain Inventory-Short Form score), and there are no other prospective data for the use of these agents in patients with symptomatic mCRPC. • Considering the limited data relating to therapy in patients with symptomatic mCRPC one could argue that chemotherapy with docetaxel should be considered first. In practice, the perceived lower side-effect profile of abiraterone may result in this drug being prescribed in preference to docetaxel. However, there are no data to support this sequence of therapy. • Radium 223 may be an option for the treatment of symptomatic, bone-predominant mCRPC before chemotherapy (the label for radium 223 is for patients with no known visceral metastasis), in light of the positive effects on SREs [11,41], and in those ineligible for chemotherapy.

Influence of Performance Status The three pivotal trials of abiraterone, radium 223 and sipuleucel-T have generally included patients with better health status (i.e., >90% of participants have a performance status of

Implementing newer agents for the management of castrate-resistant prostate cancer: what is known and what is needed?

Men receiving androgen-deprivation therapy will in time develop metastatic castrate-resistant prostate cancer (mCRPC). Whilst effective treatment opti...
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