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Management algorithms for metastatic prostate cancer.

Introduction

Prostate cancer (PC) poses a significant lifetime risk to Canadian men. (1) In 2017, approximately 21% of all new cancer cases diagnosed among Canadian men were PC (total of 21,300 cases). Every year in Canada, an average of 1,187 (8.6%) patients are diagnosed with metastatic prostate cancer (mPC). (2)

Treatment for mPC is an active area of research, with new treatment data emerging in recent years. Guidelines and consensus statements address much of this evidence. (3-8) However, many lack a practical perspective and do not sufficiently address clinical scenarios, such as treatment sequencing, that are not directly informed by phase III data.

The Canadian Genitourinary Research Consortium (GURC) is a national multi-disciplinary network of clinical specialists treating advanced PC who collaborate on research, education and establishment of best practices. The GURC Best Practices Working Group (GURC BPW Group) identified the need to develop practical guidance on treatment options and decision-making in mPC and worked to provide physicians with an easy-to-follow practice tool that addressed management of newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC).

Methods

Algorithm development

The GURC BPW Group included 5 uro-oncologists, 2 radiation oncologists and 2 medical oncologists, and had pan-Canadian representation. The group held iterative discussions regarding the management of patients with mPC, followed by discussion with the GURC Steering Committee. Algorithms outlining treatment of mPC were developed through review of national and international guidelines and consensus statements (see Literature Search below). Final algorithms were approved by both GURC BPW Group and Steering Committee members.

Literature search

Canadian and major North American and European guidelines and consensus statements addressing management of mPC were identified. PubMed, Google Scholar and the internet were searched from January 2015 to November 4, 2018 using the search string "prostate cancer AND (guideline OR consensus OR recommendations)" and guideline databases (CMA's CPG Infobase: Clinical Practice Guidelines, National Guidelines Clearinghouse and Guidelines International Network) were searched for guidelines or consensus statements using the keyword "prostate". Recommendations on management options for newly diagnosed mCSPC or mCRPC were extracted from full-text and synthesized for review.

As existing guidelines were current only to June 2018 (NCCN 2018 v4 data cut-off of May 2018), a supplementary search for new data was also performed. PubMed was searched from June 1, 2018 to November 5, 2018 and ASCO and ESMO 2018 annual meeting abstract databases were searched using the search string "prostate cancer AND metastatic AND phase III (OR respective aliases)" for primary reports of original phase III trials investigating mPC treatment and reporting positive or practice changing outcomes. Search results were screened at the abstract level and confirmed at full text.

Results

Literature search findings and algorithm development

The literature search identified one pan-Canadian guideline (6) and five guidelines or consensus statements from major North-American and/or European organizations or groups (3-5 7,8) published since 2015 (Table 1). Canadian provincial guidelines, (9,10) Euroasian single-nation, (11-19) Asian consensus, (20) and specialty-focused guidelines (21-24) were excluded. Outcomes from two new phase III studies (25,26) and one additional randomized comparison of the phase III STAMPEDE trial (27) were considered eligible for our review. Although not explicitly stated as such, the HORRAD study was classified as a phase III study based on its randomized design, size, and primary OS end-point, (25) and both the HORRAD and the STAMPEDE analyses of radiotherapy versus standard of care were included in our review, as subgroup findings in low-volume patients were considered practice changing, even though overall outcomes were negative. (25,27)

The iterative group review and discussion of this data led to the development of two algorithms addressing the management of mPC: the first in newly diagnosed mCSPC (Figure 1 A), and the second in mCRPC (Figure 1B). This work builds on a prior publication in which GURC presents two treatment algorithms to guide the management of non-metastatic PC for consideration in the context of individualized therapy, existing guidelines and practice patterns. (28)

Recommendations for treatment of newly diagnosed metastatic castration-sensitive prostate cancer (Fig. 1A)

For patients with mCSPC, androgen deprivation therapy (ADT) should be initiated, with concurrent monitoring to ensure castrate levels of testosterone are achieved. (4,8) Clinical and disease characteristics should then be considered to determine stage and prognosis. (29) Discussion of treatment options, including clinical trial enrolment, is best carried out in the context of a multi-disciplinary consult or multi-disciplinary rounds. Consultation with an oncologist or referral to a specialized tertiary centre should be considered when available.

Systemic therapy

Three phase III studies involving five randomized comparisons have addressed the benefit of adding further systemic treatment to ADT in mCSPC (Table 2). (30-36) The phase III CHAARTED study enrolled 790 newly diagnosed mCSPC patients. (33,34) CHAARTED demonstrated a significant improvement in median overall survival (OS) with the addition of docetaxel (75 mg/[m.sup.2], q3 weeks x 6) to ADT versus ADT alone (57.6 vs. 47.2 months, HR 0.72, 95% CI, 0.59-0.89, p=0.0018). A pre-planned stratified subgroup analysis confirmed the OS benefit of docetaxel in the 65% of patients with high-volume disease, defined as those with at least one high-volume factor (i.e., visceral metastases, [greater than or equal to]4 bone lesions with >1 beyond the vertebral bodies and pelvis; 51.2 vs. 34.4 months, HR 0.63, 95% CI 0.50-0.79, p<0.001). No OS benefit was observed for docetaxel in the 35% of patients with low-volume disease (63.5 vs. NR months, HR 1.04, 95% CI 0.70-1.55, p=0.86), although the analysis may have been underpowered due to small sample size. The addition of docetaxel to ADT was considered both safe and manageable, with neutropenia, febrile neutropenia, and fatigue being the most common adverse events. (33,34) The phase III LATITUDE study enrolled a total of 1,199 patients with high-risk mCSPC, defined as a positive bone scan or metastatic lesions on CT or MRI and at least two high-risk factors based on visceral metastases, three or more bone lesions and Gleason score 8 to 10 (Table 2). (30) A significant improvement in median OS was seen for ADT plus abiraterone acetate and prednisone (AAP) compared to ADT plus placebo (not yet reached [NYR] vs. 34.7 months; HR 0.62, 95% CI, 0.51-0.76, p<0.001). (30) The addition of AAP to ADT was safe and manageable, with hypertension, hypokalemia, and alanine aminotransferase (ALT) increase being the most common adverse events. (30)

The phase III multi-arm, multi-stage STAMPEDE trial enrolled patients with newly diagnosed mCSPC, node-positive mCSPC, or high-risk locally advanced PC (Table 2), and has reported results from three randomized comparisons addressing the benefits of adding either docetaxel or AAP to ADT. (31,32,35) The first comparison (n=2,962) demonstrated a significant improvement in median OS for ADT plus docetaxel versus ADT alone (81 vs. 71 months, HR 0.78, 95% CI 0.66-0.93, p=0.006), (32) and the second (n=1,917) a significant improvement OS for ADT plus AAP versus ADT alone (3-year OS, 83% vs. 76%, HR 0.63, 95% CI 0.52-0.76, p<0.001). (31) Pre-planned subgroup analyses based on disease extent confirmed the benefit of adding either agent (docetaxel, HR 0.76, 95% CI 0.62-0.92, p=0.005 or AAP, HR 0.61, 95% CI 0.49-0.75) to ADT in metastatic patients. (31,32) A posthoc analysis of ADT plus AAP versus ADT alone assessing outcomes by risk status (per LATITUDE) and disease volume (per CHAARTED) showed a 3-year OS benefit in high-risk (HR 0.54, 95% CI 0.41-0.71, p<0.001) and low-risk (HR 0.66, 95% CI 0.44-0.98, p=0.041), as well as high-volume (HR 0.60, 95% CI, 0.46-0.78, p<0.001) and low-volume (HR 0.64, 95% CI 0.42-0.97, p=0.034) disease. (36) A third more recent pre-planned but opportunistic study compared docetaxel and AAP directly in newly diagnosed, node-positive mCSPC, or high-risk locally advanced PC patients (n=556). Both agents demonstrated comparable survival overall (HR 1.16, 95% CI 0.82-0.1.65, p=0.404), as well as in patients with metastatic disease (HR 1.13, 95% CI 0.77-1.66, p=0.528). (35) Additionally, safety was comparable between treatment arms and both agents were considered safe and manageable. The most common adverse events (grades 3-5) associated with docetaxel were high rates of febrile neutropenia (17%), as well as neutropenia (13%), and endocrine disorders (9%). Endocrine (13%), cardiovascular (9%), musculoskeletal (9%) and hepatic disorders (9%) were the most common adverse events associated with AAP. (35)

Radiotherapy

A fourth comparison from the STAMPEDE trial assessed the benefit of radiotherapy for newly diagnosed mPC patients. The trial randomized patients (n=2,061) to receive either ADT plus radiotherapy or ADT alone. (27) Although a failure-free survival benefit in favour of radiotherapy plus ADT versus ADT was observed in patients overall (HR 0.76, 95% CI 0.68-0.84, p<0.0001), it did not translate into an improvement in the primary end-point of overall survival (median OS, 48 vs. 46 months, HR 0.92, 95% CI 0.80-1.06, p=0.266). A pre-specified exploratory subgroup analysis by volume of disease per CHAARTED did, however, show improved OS with the addition of radiotherapy to ADT for patients with low metastatic burden (3-year OS, 81% vs. 73%, n=819; HR 0.68, 95% CI 0.52-0.90, p=0.007). No benefit was found for patients with high metastatic burden. Radiotherapy was well-tolerated in the intent to treat population. (27) These findings are supported by outcomes from the recently published HORRAD randomized trial, which assigned patients with primary bone metastatic PC (n=432) to receive ADT plus radiotherapy or ADT alone. The study showed a non-significant improvement in the primary end-point of OS with the addition of radiotherapy to ADT (median, 45 vs. 43 months, HR 0.90, 95% CI 0.70-1.14, p=0.4), with a trend similar to that of STAMPEDE showing improved (albeit non-significant) survival among patients with low volume disease (<5 metastases; HR 0.68, 95% CI 0.42-1.10). (25)

Level 1 evidence supports the addition of docetaxel or AAP to ADT for high-volume/risk mCSPC. (30,31,33,34,36) The addition of docetaxel to ADT has been used in high-volume, fit patients in Canada (37-39) since release of CHAARTED data in 2015, (33) and the addition of AAP to ADT recently received Health Canada approval (February 2018) for use in high-risk mCSPC. (40) NCCN and EAU guidelines recommend both docetaxel and AAP as options for high-volume or high-risk groups (4,8) and, given the high degree of concordance between the definitions of high-volume and high-risk disease as indicated in the CHAARTED and LATITUDE studies (86%), (41) GURC recommends the addition of either agent to ADT for newly diagnosed mCSPC patients with high-volume/risk disease (Figure 1 A).

GURC recommends the addition of either docetaxel or AAP to ADT for newly diagnosed mCSPC patients with high-volume/risk disease

Recommendations for low-volume/risk disease vary across guidelines. (3,4,8) Based on results of STAMPEDE demonstrating improved OS for the addition of radiotherapy or AAP to ADT in newly diagnosed mCSPC with a low-volume disease (27,36) and AAP to ADT in low-risk disease, (36) GURC suggests the addition of radiotherapy to ADT as a treatment option in mCSPC with low-volume disease and/or AAP to ADT in low-volume or low-risk disease (Figure 1A). However, AAP is not yet approved for use in the treatment of low-volume disease in Canada. Upon clinical, radiologic, or PSA progression, as defined by PCWG2 criteria, (42) treatment for mCRPC should be considered. (4,8)

GURC suggests the addition of radiotherapy or AAP to ADT for newly diagnosed mCSPC patients with low-volume disease and/or AAP to ADT for low-volume or low-risk disease

Recommendations for treatment of newly diagnosed metastatic castration-resistant prostate cancer (Fig. 1B)

CRPC is diagnosed when a patient has rising PSA or clinical or radiological progression, despite castrate levels of testosterone. (4-6,8,43) At this stage, management is best explored in the context of a genitourinary multi-disciplinary consult. GURC recommends consultation with either a urooncologist and/or medical oncologist for staging and prognostic assessment.

Prognostic stratification

The APCCC guidelines stratify patients with mCRPC based on features indicative of clinical outcome. Poor prognosis features include small cell histology on a tumour biopsy and/or low or absent androgen receptor expression, exclusive visceral metastases, rapid clinical progression without correlation with PSA kinetics, low PSA levels relative to tumour burden, predominantly lytic bone metastases, short response to ADT ([less than or equal to]12 mo.), and bulky tumour masses. (3) GURC suggests consideration of a similar set of poor prognostic factors including elevated LDH, widespread and/or visceral metastasis, poor performance status (ECOG PS >2), low hemoglobin, short response (<12 months) to initial ADT, clinical symptoms, elevated alkaline phosphatase, and small cell pathology. (44-47)

First-line treatment of metastatic CRPC

First-line mCRPC therapy largely depends on patient prognosis. For patients with a poor prognosis, disease progression can be rapid. Therefore, GURC recommends referral to a medical oncologist or multi-disciplinary genitourinary team for monitoring and management. In this setting, treatment should include consideration of docetaxel, enrolment in a clinical trial, or other therapeutic strategies. Current guidelines recommend that treatment selection be made with consideration of performance status, symptoms, comorbidities, location and extent of disease, patient preference, and previous treatment for hormone-sensitive mPC. (4,8)

First-line treatments for non-poor prognosis patients include androgen receptor-axis-targeted (ARAT) treatment, chemotherapy, radio-isotope therapy and immunotherapy (Table 3). Two phase III trials have demonstrated improved median OS for sipuleucel-T versus placebo in asymptomatic or minimally symptomatic mCRPC (25.8 vs. 21.7 mo., HR 0.78, 95% CI: 0.61-0.98, p=0.03 (48) and 25.9 vs. 21.4 mo., HR 1.70, 95% CI, 1.13-2.56, p=0.01, (49) respectively). Sipuleucel-T is not approved or available in Canada and, therefore, will not be discussed further in this article.

Two phase III trials have assessed ARAT therapy in asymptomatic or mildly symptomatic CRPC with no prior docetaxel. PREVAIL showed a significant improvement in median OS for enzalutamide (n=872) versus placebo (n=845; 32.4 vs. 30.2 months, HR 0.71, 95% CI 0.60-0.84, p<0.001) (50) while the COU-AA-302 demonstrated significantly improved median OS for AAP (n=546) versus placebo plus prednisone (n=542; 34.7 vs. 30.3 mo., HR 0.81, 95% CI 0.70-0.93, p=0.0033 with pre-specified efficacy boundary, [alpha]=0.0035). (51) Two phase III trials showed improved survival for docetaxel among chemotherapy naive, mCRPC patients. SWOG 99-16 demonstrated improved median OS for docetaxel plus estramustine (n=338) versus mitoxantrone plus prednisone (n=336; 17.5 vs. 15.6 months, HR 0.80, 95% CI 0.67-0.97, p=0.02) (52) and TAX 327 demonstrated improved OS with docetaxel (every 3 weeks) plus prednisone (n=335) versus mitoxantrone plus prednisone (n=337; 18.9 vs. 16.5 months, HR 0.76, 95% CI 0.62-0.94, p=0.009) (53)--a benefit that remained consistent with extended follow-up. (54) The phase III PRINCE trial demonstrated the non-inferiority of an intermittent schedule of docetaxel based on the primary endpoint of 1-year survival (two-sided 95% CI -12-18, p=0.022). (26)

The phase III ALSYMPCA trial demonstrated improved median OS for radium-223 (n=614) versus placebo (n=307) in patients with symptomatic bone metastases and free of visceral metastases (14.9 vs. 11.3 months, HR 0.70, 95% CI 0.58-0.83, p<0.001) (55) as well as in patients with no prior docetaxel (n=349; 16.1 vs. 11.5 months, HR 0.69, 95% CI 0.52-0.92, p=0.01). (56)

There is level 1 evidence to support use of ARAT therapy, docetaxel or radium-223 for symptomatic mCRPC and ARAT or docetaxel for asymptomatic mCRPC, (26,50-56) as well as associated recommendations from the NCCN and EAU guidelines. (4,8) GURC recommends ARAT therapy alone for first-line mCRPC, keeping in mind that treatment strategy may vary depending on prior therapy received for mCSPC. A recent survey showed that 94% of responding clinicians treating PC in Canada (n=49) selected ARAT therapy as first-line mCRPC therapy. (57) AAP is now approved for use in mCSPC and as such, the use of AAP in earlier settings may lead to an increase in the use of docetaxel for first-line mCRPC. Upon clinical, radiologic, or PSA progression, as defined by PCWG2 criteria reflective of common clinical practice, consideration of further therapy is recommended.

GURC recommends ARAT therapy first-line for the majority of mCRPC patients, although patients with poor prognosis should be referred to a medical oncologist or multi-disciplinary genitourinary team for monitoring and management

Later lines of metastatic CRPC therapy

Selection of second-line treatment is dependent on many factors, including prior treatment exposure as well as clinical and disease characteristics. EAU guidelines recommend consideration of performance status, symptoms, patient preference, comorbidities and extent of disease. (4) Treatment options for later lines include ARAT therapy, chemotherapy or radium-223 in patients receiving prior docetaxel (Table 4).

Two phase III trials support use of ARAT therapy for mCRPC following docetaxel. COU-AA-301 showed a significant improvement in median OS for AAP (n=797) versus placebo plus prednisone (n= 398; 15.8 vs. 11.2 months, HR 0.74, 95% CI 0.64-0.86, p<0.0001), (58) while AFFIRM showed a similar significant improvement in median OS for enzalutamide (n=800) versus placebo (n=399; 18.4 vs. 13.6 months, HR 0.63, 95% CI 0.53-0.75, p<0.001). (59) Chemotherapy and radium-223 are also second-line treatment options. The phase III TROPIC trial showed a significant improvement in median OS for cabazitaxel plus prednisone and (n=378) versus mitoxantrone plus prednisone (n=377; 15.1 vs. 12.7 months, HR 0.70, 95% CI 0.59-0.83, p<0.0001) for patients progressing on first-line docetaxel. (60) More recently, the phase III ALSYMPCA trial demonstrated a significant improvement in median OS for radium-223 (n=352) versus placebo (n=174) in a subgroup receiving prior docetaxel (n=526; 14.4 vs. 11.3 months, HR 0.70, 95% CI 0.56-0.88, p=0.002). (56)

There is level 1 evidence for use of ARAT, cabazitaxel and radium-223 as second-line therapy following docetaxel, (56,58-60) and support for use of docetaxel in this setting is derived primarily from first-line phase III trials, (52-54) as well as prospective and retrospective cohort studies demonstrating >25% PSA response to docetaxel re-challenge following a good response to initial therapy. (61-65) However, there is little evidence to guide optimal sequencing following first-line treatment of mCRPC with intensive therapy, (4-6,8,43) and national and international treatment recommendations for later lines of therapy vary. (5,6,8,43) GURC recommendations take into account available evidence, patterns of practice and access to therapy in providing sequencing options following first-line ARAT therapy (Figure 1B); an individualized approach to treatment sequencing is encouraged, along with special consideration of disease burden, symptomatology, prior therapy, drug eligibility and patient preference. At each mCRPC treatment juncture, management strategies should include consideration of palliative and supportive care measures as well as clinical trial eligibility.

For patients with visceral metastases and/or bulky nodes >3 cm following first-line ARAT therapy, GURC recommends docetaxel followed by cabazitaxel or ARAT. Referral to a tertiary care centre should be considered for docetaxel ineligible patients. In cases of ARAT or cabazitaxel ineligibility, the alternate agent should be considered. For patients with no visceral metastases or bulky nodes >3 cm following first-line ARAT therapy, consideration of patient symptoms is important in guiding therapy. For second and third-line treatment of symptomatic patients, GURC recommends consideration of docetaxel or radium-223 followed by the alternate agent upon progression. For asymptomatic patients, GURC recommends docetaxel while referral to a tertiary care centre is warranted for patients ineligible for docetaxel. For patients progressing on either radium-223 or docetaxel, GURC recommends ARAT or cabazitaxel. In cases of drug ineligibility or lack of access for any line of therapy, the alternate agent should be considered.

GURC recommends an individualized approach to treatment sequencing for later lines of mCRPC therapy, which may include docetaxel, radium-223, ARAT, and cabazitaxel

Discussion

Strengths and limitations

The treatment algorithms are presented as practical tools to guide the management of mPC. The therapeutic options suggested for consideration by clinicians are inspired by evidence and reflect the clinical expertise of a multi-disciplinary team of Canadian clinical experts specializing in PC. Although not comprehensive in representation of all available evidence or potential treatments, the algorithms are designed to inspire multi-disciplinary discussion that considers individual disease characteristics, patient history and preferences.

Summary

The GURC recommendations reflect results of multi-disciplinary clinical discussion, with the goal of providing clear and practical guidance on the management of mPC. The treatment algorithms indicate the addition of ARAT or docetaxel to ADT for newly diagnosed high-volume/high-risk mCSPC, the addition of radiotherapy to ADT for low-volume mCSPC, and/or AAP to ADT for low-volume or low-risk mCSPC. ARAT therapy is recommended for first-line treatment of mCRPC, and sequencing of later lines of therapy should be carried out in an individualized manner, accounting for clinical and disease characteristics, and may include docetaxel, radium-233, cabazitaxel or ARAT therapy.

Disclosures: Dr. Malone has served on advisory boards and/or received honoraria from Janssen, Astellas Sanofi, Abbvie, Tersera and Bayer, and has participated in clinical trials sponsored by Janssen and Bayer. Dr. Basappa has served on advisory boards and received honoraria and/or grants from Janssen, Astellas, Bayer, BMS, Pfizer, AstraZeneca, Merck, Ipsen, Eisai and Roche. Dr. Chi has served on advisory boards and received honoraria and/or grant funding from Astellas, Bayer, Janssen, Roche and Sanofi. Dr. Conter has received grants and/or honoraria from Janssen, Astellas, BMS, Novartis and Eli Lilly, and has participated in clinical trials sponsored by Merck, Roche, Takeda, Pfizer and AstraZeneca. Dr. Hamilton has served on advisory boards and/or received honoraria from Janssen, Astellas, Abbvie, Amgen, Tersera and Bayer and has participated in clinical trials sponsored by Janssen and Bayer. Mr. Hew is employed by Janssen Canada. Dr. Hotte has received institutional research funding or consulting honoraria from Astellas, Janssen and Bayer. Ms. McLeod owns Kaleidoscope Strategic, who received funding for preparing this review by Janssen Canada. Ms. Park-Wyllie is employed by Janssen Canada. Dr. Saad has served as a consultant for, and received funding from, Amgen, Astellas, AstraZeneca, Bayer, BMS, Janssen and Sanofi. Dr. Shayegan has received grants or honoraria from Astellas, Janssen, Abbvie and Sanofi, and participated in clinical trials sponsored by Janssen and Astellas. Dr. So has received honoraria and served on advisory boards for Amgen, Astellas, Abbvie, Ferring, Jannsen, Bayer and Sanofi, and participated in clinical trials sponsored by Janssen and Astellas. Dr. Gotto -has received honoraria and served on advisory boards for Amgen, Astellas, Astra Zeneca, Bayer, Janssen, Merck, Sanofi, and Roche, and has participated in clinical trials sponsored by Amgen, Astellas, Astra Zeneca, Bayer, Janssen, and Myovant.

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(49.) Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089-94.

(50.) Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-33.

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(52.) Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-20.

(53.) Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12.

(54.) Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-5.

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

(56.) Hoskin P, Sartor O, O'Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014;15:1397-406.

(57.) Hotte SJ, Finelli A, Malone S, et al. Real world patterns of treatment sequencing in Canada for metastatic castrate-resistant prostate cancer. J Clinc Oncol 36 (Suppl 6):Abstr 320.

(58.) Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012; 13:983-92.

(59.) Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97.

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

(61.) Caffo O, Pappagallo G, Brugnara S, et al. Multiple rechallenges for castration-resistant prostate cancer patients responding to first-line docetaxel: assessment of clinical outcomes and predictive factors. Urology. 2012;79:644-9.

(62.) Di Lorenzo G, Buonerba C, Faiella A, et al. Phase II study of docetaxel re-treatment in docetaxel-pretreated castration-resistant prostate cancer. BJU Int. 2011;107:234-9.

(63.) Eymard JC, Oudard S, Gravis G, et al. Docetaxel reintroduction in patients with metastatic castration-resistant docetaxel-sensitive prostate cancer: a retrospective multicentre study. BJU Int. 2010;106:974-8.

(64.) Mountzios I, Bournakis E, Efstathiou E, et al. Intermittent docetaxel chemotherapy in patients with castrate-resistant prostate cancer. Urology. 2011;77:682-7.

(65.) Oudard S, Kramer G, Caffo O, et al. Docetaxel rechallenge after an initial good response in patients with metastatic castration-resistant prostate cancer. BJU Int. 2015;115:744-52.

(66.) 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.

(67.) Bahl A, Oudard S, Tombal B, et al. Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial. Ann Oncol. 2013;24:2402-8.

Figures and Tables

Shawn Malone (1); Bobby Shayegan (2); Naveen S. Basappa (3); Kim Chi (4); Henry J. Conter (5); Robert J. Hamilton (6); Sebastien J. Hotte (2); Fred Saad (7); Alan So (8); Laura Park-Wyllie (9); Huong Hew (9); Deanna McLeod (10); Geoffrey Gotto (11)

(1) The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada; (2) Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada; (3) Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada; (4) BC Cancer Agency, Vancouver, BC, Canada; (5) William Osier Health System, University of Western Ontario, Brampton, ON, Canada; (6) Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; (7) Centre Hospitalier de l'Universite de Montreal, University of Montreal, Montreal, QC, Canada; (8) Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada; (9) Medical Affairs, Janssen Inc., Toronto, ON, Canada; (10) Kaleidoscope Strategic Inc., Toronto, ON, Canada; (11) University of Calgary, Calgary, AB, Canada

Acknowledgements: The authors would like to thank Janssen Canada for funding this initiative, Drs. Jeffrey Spodek, Scott Morgan, Lome Aaron, Tony Finelli, and Christina Canil for their contributions to algorithm development, and Ilidio Martins and Loretta Collins of Kaleidoscope Strategic Inc. for research and editorial support in preparing the manuscript.

http://dx.doi.org/10.5489/cuaj.5840

Caption: Fig. 1. Management of metastatic prostate cancer. (A) Management of newly diagnosed metastatic castration-sensitive prostate cancer. (1) Ensure castrate levels of testosterone; (2) Consider determination of alkaline phosphatase levels as prognostic factor (Gravis et al. Eur Urol 2015;68:196-204); (3) Patients identified according to CHAARTED criteria (see respective box; Sweeny et al. N Engl J Med 2015;373:737-46); (4) Patients identified according to LATITUDE criteria (see respective box; Fizazi et al. N Engl J Med 2011,311-.352-60); (5) Patients who are ineligible for either docetaxel or abiraterone for medical reasons or patient preference should be offered alternate agent, if appropriate; (6) PS A Progression as defined by PCWG2 criteria. (B) Management of newly diagnosed metastatic castration-resistant prostate cancer. (1) Clinician should consider performance status, symptoms, comorbidities, location and extent of disease, patient preference, and previous treatment for hormone-sensitive mPC; (2) ARAT=abiraterone + prednisone, or enzalutamide; (3) Use of docetaxel for first-line mCRPC may become more common, given approval of AAP for metastatic castration-sensitive prostate cancer; (4) PSA progression as defined by PCWG2 criteria; (5) Consider palliative care options; (6) If docetaxel-ineligible for medical reasons or patient preference, consider referral to tertiary care centre; (7) If docetaxel or radium-223 ineligible for medical reasons or patient preference, consider use of alternate agent if appropriate; (8) Radium-223 is indicated for patients with symptomatic bone metastases; (9) If cabazitaxel or ARAT therapy ineligible for medical reasons or patient preference, consider use of alternate agent if appropriate. AAP: abiraterone acetate and prednisone; ADT: androgen-deprivation therapy; ARAT: androgen receptor axis targeted therapy; GU: genitourinary; LDH: lactate dehydrogenase; mCRPC: metastatic castration-resistant prostate cancer; mPC: metastatic prostate cancer; PCWG2: prostate cancer working group 2; PSA: prostate-specific antigen.
Table 1. Guidelines, consensus-based guidance considered in development
of the GURC algorithms

Guidelines and consensus statements                 Year  Region

NCCN prostate cancer guidelines                     2018  American
EAU-ESTRO-ESUR-SIOG guidelines on prostate cancer   2018  European
Advanced Prostate Cancer Consensus Conference       2017  International
(APCCC)
CUA-CUOG CRPC guidelines                            2015  Canadian
ESMO clinical practice guidelines on prostate       2015  European
cancer
AUA CRPC guidelines                                 2015  American
Phase 3 addressing treatment of metastatic                Year
prostate cancer
PRINCE (intermittent vs. continuous docetaxel)            2018
STAMPEDE (addition of radiotherapy to ADT vs. ADT)        2018
HORRAD (addition of radiotherapy to ADT vs. ADT           2018

AUA: American Urological Association; CUA-CUOG: Canadian Urological
Association-Canadian Urologic Oncology Group; CRPC:
castration-resistant prostate cancer; EAU-ESTRO-ESUR-SIOG: European
Association of Urology-European Society for Radiotherapy &
Oncology-European Society of Urogenital Radiology-International
Society of Geriatric Oncology; GURC: Genitourinary Research
Consortium; NCCN: National Comprehensive Cancer Network.

Table 2. Survival in phase 3 trials for newly diagnosed mCSPC

Study name         Setting
and
Author/Year

Docetaxel
CHAARTED           --Newly diagnosed
Kyriakopoulos,       metastatic PCa
et al. 2018 (34)   --ECOG PS 0-2
                   --Prior ADT allowed
                     if started [less than or equal to] 120
                     days before
                     randomization
STAMPEDE           --Newly diagnosed
James, et al.        metastatic or high-risk
2016 (32)            locally advanced
                     PCa or
                     relapsing with
                     high-risk features
                     after prior RP, RT
                     or both
                   --Prior ADT allowed
                     if started [less than or equal to] 12
                     weeks before
                     randomization
AAP
LATITUDE           --High-risk PCa
Fizazi, et al.     --Chemo, RT-naive
2017 (30)          --No prior surgery
                     for metastatic
                     disease
                   --[less than or equal to]3 mo. ADT or
                     orchiectomy [+ or -] AR
                     antagonists
STAMPEDE           --Newly diagnosed
James, et al.        metastatic or high-risk
2017 (31)            locally
Hoyle et al.         advanced PCa or
2018 (36)            after prior RP, RT
                     or both and
                     relapsing with
                     high-risk features
                   --Prior ADT allowed
                     if started [less than or equal to]12
                     weeks before
                     randomization
Docetaxel vs. AAP
STAMPEDE           --Newly diagnosed
Sydes, et al.        metastatic or high-risk
2018 (35)            locally
                     advanced PCa or
                     after prior RP, RT
                     or both and
                     relapsing with
                     high-risk features
                   --Prior ADT allowed
                     if started [less than or equal to]12
                     weeks before
                     randomization
Radiotherapy
STAMPEDE           --Newly diagnosed
Parker, et al.       metastatic PCa
2018 (27)            with no prior
                     radical treatment
                   --Intended for long-term
                     ADT
                   --Prior ADT allowed
                     if started [less than or equal to]12
                     weeks before
                     randomization
HORRAD             --Newly diagnosed,
Boeve et al.         primary bone
2018 (25)            metastatic PCa
                   --PSA >20 ng/ml

Study name         Comparison
and                stratification
Author/Year

Docetaxel
CHAARTED           ADT + docetaxel
Kyriakopoulos,     (n=397) vs. ADT
et al. 2018 (34)   (n=393)
                   Stratified by extent
                   of metastases:
                   --High-volume
                     (defined as the
                     presence of
                     visceral
                     metastases or [greater than or equal to]4
                     bone lesions
                     with [greater than or equal to] 1 beyond
                     the vertebral
                     bodies and
                     pelvis) vs. low-volume
STAMPEDE           SOC (ADT) +
James, et al.      docetaxel (n=592)
2016 (32)          vs. SOC (ADT;
                   n=1184)
                   --Stratified by
                     metastasis status,
                     nodal status and
                     Gleason score
                     (among others)
AAP
LATITUDE           ADT + AAP (n=
Fizazi, et al.     597) vs. ADT +
2017 (30)          dual placebos
                   (n=602)
                   Stratified by:
                   --Presence or
                     absence of
                     measurable
                     visceral disease
                   --ECOG PS (0 or
                     1 vs. 2)
STAMPEDE           SOC (ADT) + AAP
James, et al.      (n=960) vs. SOC
2017 (31)          (ADT; n=957)
Hoyle et al.
2018 (36)          --Stratified by
                     metastasis status,
                     nodal status and
                     Gleason score
                     (among others)
Docetaxel vs. AAP
STAMPEDE           SOC (ADT) +
Sydes, et al.      docetaxel (n=189)
2018 (35)          vs. SOC (ADT) +
                   AAP (n=377)
                   --Stratified by
                     metastasis status,
                     nodal status and
                     Gleason score
                     (among others)
Radiotherapy
STAMPEDE           SOC (ADT) + RT
Parker, et al.     (n=1032) vs. SOC
2018 (27)          (ADT; n=1029)
                   --Stratified by nodal
                     involvement,
                     WHO
                     performance
                     status, metastatic
                     burden, planned
                     ADT, and planned
                     docetaxel use
                     (among others)
HORRAD             ADT + RT(n=215)
Boeve et al.       vs. ADT (n=216)
2018 (25)

Study name         Main outcome(s)
and
Author/Year
Docetaxel
CHAARTED           Median followup: 53.7
Kyriakopoulos,     months
et al. 2018 (34)   Median OS
                   ITT: 57.6 vs. 47.2 months
                   (HR 0.72; 95% CI 0.59-0.89;
                   p=0.0018)
                   High-volume disease
                   (n=513): 51.2 vs. 34.4 months
                   (HR 0.63; 95% CI 0.50-0.79;
                   p<0.001)
                   Low-volume disease
                   (n=277): 63.5 vs. NR months
                   (HR 1.04; 95% CI 0.70-1.55;
                   p=0.86)
STAMPEDE           Median followup: 43 months
James, et al.      Median OS
2016 (32)          ITT: 81 vs. 71 months (HR
                   0.78; 95% CI 0.66-0.93;
                   p=0.006)
                   Ml subgroup: 60 vs. 45
                   months (HR 0.76; 95% CI
                   0.62-0.92; p=0.005)
AAP
LATITUDE           Median followup: 30.4
Fizazi, et al.     months
2017 (30)          Median OS
                   ITT: NYR vs. 34.7 months
                   (HR 0.62; 95% CI 0.51-0.76;
                   p<0.001)
STAMPEDE           Median followup: 40 months
James, et al.      Median OS
2017 (31)          ITT: NYR
Hoyle et al.       3-year survival
2018 (36)          ITT: 83% vs. 76% (HR
                   0.63; 95% CI 0.52-0.76;
                   p<0.001)
                   Ml subgroup: HR 0 61
                   (0.49-0.75)
                   High-risk M1: 64.7% vs.
                   45% (HR 0.54; 95% CI 0.41-0.70;
                   p<0.001)
                   Low-risk M1: 82.4% vs
                   78% (HR 0.66; 95% CI 0.44-0.98;
                   p=0.041)
                   High-volume M1: HR 0.60;
                   95% CI 0.46-0.78; p<0.001
                   Low-volume M1: HR 0 64;
                   95% CI 0.42-0.97; p=0.034
Docetaxel vs. AAP
STAMPEDE           Median followup: 48 months
Sydes, et al.      Median OS: NYR
2018 (35)          3-year survival (b)
                   ITT: 83% vs. 78% (HR 1.16;
                   95% CI 0.82-1.65; p=0.404)
                   M1 subgroup: HR 1.13; 95%
                   CI 0.77-1.66; p=0.528
Radiotherapy
STAMPEDE           Median followup: 37 months
Parker, et al.     Median OS
2018 (27)          ITT: 48 vs. 46 months (HR
                   0.92; 95% CI 0.80-1.06;
                   p=0.266)
                   3-year survival
                   Low-volume: 81% vs. 73%
                   (HR 0.68; 95% CI 0.52-0.90;
                   p=0.007)
HORRAD             Median followup: 47 months
Boeve et al.       Median OS
2018 (25)          45 vs. 43 months (HR 0.90;
                   95% CI 0.70-1.14; p=0.4)
                   Low-volume: HR 0.68; 95%
                   CI 0.42-1.10

(a) At least two of the following high-risk factors: visceral
metastasis, [greater than or equal to]3 bone lesions, Gleason score
[greater than or equal to]8. (b) Estimated from Kaplan-Meier survival
plot for ITT. AAP: abiraterone acetate plus prednisone; ADT:
androgen-deprivation therapy; AR: androgen receptor; CI: confidence
interval; ECOG PS: Eastern Cooperative Oncology Group performance
status; HR: hazard ratio; ITT: intention to treat population; LHRHA:
luteinizing hormone releasing hormone antagonist; Ml: metastatic;
mCSPC: metastatic castration-sensitive prostate cancer; NR: not
reported; NYR: not yet reached; OS: overall survival; PCa: prostate
cancer; PFS: progression-free survival; PSA: prostate-specific
antigen; rPFS, radiographic progression-free survival; RP: radical
prostatectomy; RT: radiation therapy; SOC: standard of care. WHO:

Table 3. Survival outcomes in phase 3 trials for first-line treatment
of mCRPC (*)

Study name and              Setting
author/year

Sipuleucel-T
Kantoff, et al. 2010 (48)   Some with previous
                            docetaxel; ECOG PS
                            0-1; asymptomatic or
                            mildly symptomatic
Small, et al. 2006 (49)     No corticosteroids;
                            ECOG PS 0-1; no
                            bone or cancer pain;
                            no visceral
                            metastases
Docetaxel
SWOG 99-16                  Chemo-naive;
Petrylak, et al. 2004 (52)  SWOG PS 0-3;
                            asymptomatic or
                            symptomatic
TAX 327                     Chemo-naive; 13%
Tannock, et al.             with Karnofsky PS
2004 (53)                   >70%; asymptomatic
                            or symptomatic
PRINCE                      Chemo-naive with
Cash, etal. 2018 (26)       primarily bone
                            metastatic disease;
                            Karnofsky PS [greater than or equal to]60%
Abiraterone
COU-AA-302                  No previous
Ryan, etal. 2015 (51)       docetaxel;ECOG PS
                            0-1; PSA or
                            radiographic
                            progression;
                            asymptomatic or
                            mildly symptomatic;
                            no visceral
                            metastases
Enzalutamide
PREVAIL                     No previous
Beer, et al. 2014 (50)      docetaxel;ECOG PS
                            0-1; PSA or
                            radiographic
                            progression;
                            asymptomatic or
                            mildly symptomatic;
                            10% had visceral
                            metastases
Radium-233
ALSYMPCA                    Previous or no
Parker, et al. 2013 (55)    previous docetaxel;
Hoskin, et al. 2014 (56)    ECOG PS 0-2; two
                            or more symptomatic
                            bone metastases; no
                            visceral metastases

Study name and              Comparison
author/year

Sipuleucel-T
Kantoff, et al. 2010 (48)   Sipuleucel-T (n=341)
                            vs. placebo (n=171)
Small, et al. 2006 (49)     Sipuleucel-T (n=82)
                            vs. placebo (n=45)
Docetaxel
SWOG 99-16                  docetaxel/EMP every
Petrylak, et al. 2004 (52)  3 weeks + EMP 3
                            times/day (n= 338)
                            vs.
                            mitoxantrone every 3
                            weeks + prednisone
                            BID (n=336)
TAX 327                     Docetaxel every 3
Tannock, et al.             Weeks + prednisone
2004 (53)                   BID (n=335)
                            vs. mitoxantrone
                            every 3 weeks +
                            prednisone BID
                            (n=337)
PRINCE                      Intermittent weekly
Cash, etal. 2018 (26)       or 3-weekly
                            docetaxel (35 mg/[m.sup.2]
                            or 75 mg/[m.sup.2],
                            respectively)
                            vs.
                            continuous weekly or
                            3-weekly docetaxel
                            (35 mg/[m.sup.2] or 75
                            mg/[m.sup.2], respectively)
Abiraterone
COU-AA-302                  Abiraterone +
Ryan, etal. 2015 (51)       prednisone (n=546)
                            vs. placebo +
                            prednisone (n=542)
Enzalutamide
PREVAIL                     Enzalutamide
Beer, et al. 2014 (50)      (n=872; rPFS n=832)
                            vs. placebo (n=845;
                            rPFS n=801)
Radium-233
ALSYMPCA                    Radium-223 (n=614;
Parker, et al. 2013 (55)    docetaxel-naive
Hoskin, et al. 2014 (56)    n=236)
                            vs. placebo (n=307;
                            docetaxel-naive
                            n=113)

Study name and              Main outcome
author/year

Sipuleucel-T
Kantoff, et al. 2010 (48)   Followup: 34.1
                            months
                            OS: 25.8 vs. 21.7
                            months (HR 0.78;
                            95% CI 0.61-0.98;
                            p=0.03)
Small, et al. 2006 (49)     followup: 36 months
                            OS: 25.9 vs. 21.4
                            months (log-rank
                            HR 1.70; 95% CI
                            1.13-2.56; p=0.01)
Docetaxel
SWOG 99-16                  Follow-up: 32
Petrylak, et al. 2004 (52)  months
                            OS: 17.52 vs. 15.6
                            months (HR 0.80,
                            95% CI 0.67-0.97,
                            p=0.02)
TAX 327                     Followup: 20.8
Tannock, et al.             months
2004 (53)
                            OS: 18.9 vs. 16.5
                            months for weekly
                            (HR 0.76; 95% CI
                            0.62-0.94; p=0.009)
PRINCE                      Followup: 26.8
Cash, etal. 2018 (26)       months vs. 33.8
                            months (p=0.396)
                            1-year OS: 78% vs.
                            75% (non-inferiority
                            criteria met; two-sided
                            95% CI-12-18;
                            p=0.022)
Abiraterone
COU-AA-302                  Followup: 49 2
Ryan, etal. 2015 (51)       months
                            OS: 34.7 vs. 30.3
                            months (HR 0.81;
                            95% CI 0.70-0.93;
                            p=0.0033)
Enzalutamide
PREVAIL                     Followup: 22 months
Beer, et al. 2014 (50)
                            OS: 32.4 vs. 30.2
                            months (HR 0.71;
                            95% CI 0.60-0.84;
                            p<0.001)
Radium-233
ALSYMPCA                    OS (ITT): 14.9 vs.
Parker, et al. 2013 (55)    11.3 months (HR
Hoskin, et al. 2014 (56)    0.70; 95% CI 0.58-0.83;
                            p<0.001)
                            OS (docetaxel-
                            naive): 16.1 vs. 11.5
                            months (HR 0.69;
                            95% CI 0.52-0.92;
                            p=0.01)

(*) Only studies reporting survival outcomes as primary endpoints have
been included. BID: twice a day; CI: confidence interval; ECOG: Eastern
Cooperative Oncology Group; EMP: estramustine; FU: followup; HR, hazard
ratio; mCRPC: metastatic castration-resistant prostate cancer; OS:
overall survival; PFS: progression-free survival; PS: performance
status; PSA: prostate-specific antigen; rPFS: radiographic
progression-free survival.

Table 4. Survival outcomes of phase 3 trials for second-line treatment
of mCRPC (*)

Study name and            Setting              Comparison
author/year

Abiraterone
COU-AA-301                Previous docetaxel;  Abiraterone +
Fizazi, et al. 2012 (58)  ECOG PS 0-2; PSA     prednisone (n=797)
                          or radiographic      vs. placebo +
                          progression          prednisone (n=398)
COU-AA-301                Previous docetaxel;  Abiraterone +
de Bono, et al.           ECOG PS 0-2; PSA     prednisone (n=797)
2011 (66)                 or radiographic      vs. placebo +
                          progression          prednisone (n=398)
Radium-223
ALSYMPCA                  Previous or no       Radium-223 (prior
Hoskin, et al. 2014 (56)  previous docetaxel;  docetaiel n=352)
                          ECOG PS 0-2; two     vs. placebo (prior
                          or more              docetaxel n=174)
                          symptomatic bone
                          metostases; no
                          visceral metastases
Cabazitaxel
TROPIC                    Previous docetaxel;  Cabazitaxel +
de Bono, et al.           ECOG PS 0-2          prednisone (n=378)
2010 (60)                                      vs. mitoxantrone +
Bahl, et al. 2013 (67)                         prednisone (n=377)
Enzalutamide
AFFIRM                    Previous docetaxel;  Enzalutamide
Scher, et al. 2012 (59)   ECOG PS 0-2          (n=800)
                                               vs. placebo (n=399)

Study name and            Main outcome
author/year

Abiraterone
COU-AA-301                Followup: 20.2 months
Fizazi, et al. 2012 (58)
                          OS: 15.8 vs. 11.2
                          months (HR 0.74; 95%
                          CI 0.64-0.86; p0.0001)
COU-AA-301                Followup: 12.8 months
de Bono, et al.
2011 (66)                 OS: 14.8 vs. 10.9
                          months (HR 0.65; 95%
                          CI 0.54-0.77; p<0.001)
Radium-223
ALSYMPCA                  OS (prior docetaxel):
Hoskin, et al. 2014 (56)  14.4 vs. 11.3 months
                          (HR 0.70; 95% CI 0.56-0.88;
                          p=0.002)
Cabazitaxel
TROPIC                    Followup: 12.8 months
de Bono, et al.
2010 (60)                 OS: 15.1 vs. 12.7
Bahl, et al. 2013 (67)    months (HR 0.70; 95%
                          CI 0.59-0.83; p0.0001)
                          Followup: 25.5 months
                          OS: 318/378 vs.
                          346/377 events (odds
                          ratio 2.11; 95% CI 1.33-3.33)
                          OS[greater than or equal to]2 years 27% vs.
                          16%
Enzalutamide
AFFIRM                    Followup: 14.4 months
Scher, et al. 2012 (59)
                          OS: 18.4 vs. 13.6
                          months (HR 0.63; 95%
                          CI 0.53-0.75; p<0.001)

(*) Only studies reporting survival outcomes as primary endpoints have
been included. CI: confidence interval; ECOG: Eastern Cooperative
Oncology Group; HR: hazard ratio; OS: overall survival; PFS:
progression-free survival; PSA: prostate-specific antigen; rPFS:
radiologic progression-free survival.


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Author:Malone, Shawn; Shayegan, Bobby; Basappa, Naveen S.; Chi, Kim; Conter, Henry J.; Hamilton, Robert J.;
Publication:Canadian Urological Association Journal (CUAJ)
Geographic Code:1CANA
Date:Jun 27, 2019
Words:8597
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