Guidelines Evolving for the Treatment of Bone Metastases in Castration-Resistant Prostate Cancer

Special ReportsProstate Cancer (Issue 1)
Volume 1
Issue 1

Androgen deprivation therapy has been the standard of care for patients with advanced prostate cancer (PC), because these agents inhibit cancer progression in the early stages of disease.

Androgen deprivation therapy has been the standard of care for patients with advanced prostate cancer (PC), because these agents inhibit cancer progression in the early stages of disease. However, a majority of patients on androgen deprivation become unresponsive to treatment 18 to 24 months after initial response.1Castration-resistant prostate cancer (CRPC) is partially identified by rising levels of prostate-specific antigen (PSA) despite chemical castration, and more than 90% of patients with CRPC develop bone metastases.2(Figure 1).

Figure 1. Disease progression despite hormonal therapy.

The metastatic CRPC (mCRPC) treatment portfolio is expanding rapidly. Numerous broad-spectrum and targeted therapies undergoing clinical testing are impacting overall treatment options for patients with CRPC. After approval of docetaxel in 2004, five new agents have recently been approved by the FDA to treat CRPC: abiraterone acetate (Zytiga), enzalutamide (Xtandi), cabazitaxel (Jevtana), radium-223 (Xofigo), and sipuleucel-T (Provenge).3

NCCN Prostate Cancer 2015 Guidelines

The management of mCRPC is evolving rapidly. Unprecedented recent approvals make identification of optimal therapeutic strategies for patients with mCRPC a challenging task. The NCCN’s clinical practice, disease-specific guidelines, a reference for standard of care in the United States, were updated for prostate cancer in 2015. Most of the updates in the 2015 guidelines are centered on use of new systemic agents in the field. In first-line therapy for CRPC patients with no visceral metastases, the following recommendations were added4:

  • Enzalutamide added (category 1)
  • Abiraterone acetate added with prednisone (category 1)
  • Docetaxel added with prednisone (category 1)
  • Radium-223 added for men with symptomatic bone metastases (category 1).

Enzalutamide for men with asymptomatic or mildly symptomatic bone metastases

This recommendation was based on results from the multinational, double-blind, randomized phase III PREVAIL trial, which examined the effect of enzalutamide administration in asymptomatic or mildly symptomatic chemotherapy-naive men with mCRPC. The trial showed that treatment with enzalutamide significantly improved OS (30% reduction in risk of death) and radiographic PFS (81% reduction in risk of radiographic PFS) in men with chemotherapy-naive mCRPC.5

Abiraterone with prednisone for men with asymptomatic or mildly symptomatic mCRPC

This recommendation was based on interim analyses of the COU-AA-302 trial. In this placebo-controlled, double-blind, randomized phase III study on 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive PC, abiraterone acetate plus prednisone significantly improved radiographic progression-free survival (PFS) compared with placebo plus prednisone. OS was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months 32.7 vs 30.3 months).6

Docetaxel with prednisone for hormone-naïve mCRPC

Changes to the NCCN guidelines also recognize the results from CHAARTED trial showing docetaxel can be repurposed in metastatic CRPC. In this study, the median OS was 13.6 months longer with the combination of androgen-deprivation therapy (ADT) plus docetaxel than with ADT alone, and in men with high-volume metastatic disease, median OS was 17.0 months longer.7

Radium-223 for men with symptomatic bone metastases

This treatment is based on results from the ALSYMPCA phase III study in patients with CRPC with symptomatic bone metastases who received docetaxel, who were unfit to receive docetaxel or declined docetaxel. Study interim analysis on 921 patients showed improved OS benefit (median of 14.9 months versus 11.3). Other phase I-IIa studies are ongoing to study the use of radium-223 in combination with docetaxel for mCRPC.8

ESMO Magnitude of Clinical Benefit Scale

With so many treatment options on the horizon, it is important for the oncology community to present clear and unbiased statements regarding the magnitude of clinical benefit from new therapeutic approaches. A standardized approach for quantifying the clinical benefit and credible comparison of therapeutic effectiveness of various treatments is necessary. This will prevent overestimation and overstatement of benefits for new interventions, which can harm patients undertaking these treatments based on exaggerated expectations and may subject them to risk of adverse events, inconvenience, or substantial personal costs.

The European Society for Medical Oncology (ESMO) is developing a validated and reproducible tool to assess the magnitude of clinical benefit of anticancer interventions, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), based on initial recommendations from 276 members of the ESMO faculty and a team of 51 expert biostatisticians. With this scoring tool, ESMO aims to highlight treatments that provide substantial improvements to the duration of survival and/or the quality of life (QoL) of cancer patients and distinguish them from treatments where benefits are more modest, limited, or marginal. ESMO intends to apply this scale prospectively to each new anticancer drug/intervention that will be European Medicines Agency (EMA) approved. Drugs or treatment interventions that obtain the highest scores on the scale will be highlighted in the ESMO guidelines with the aim of prompting rapid endorsement by health authorities across the European Union.10

The ESMO Magnitude of Clinical Benefit Scale version 1 (ESMO-MCBS v1.0) has been developed only for solid cancers. Given the profound differences between the curative and palliative settings, the tool is presented in two parts. Form 1 is used to evaluate adjuvant and other treatments with curative intent. Form 2 (a, b, or c) is used to evaluate noncurative interventions, with form 2a for studies with OS as the primary outcome, form 2b for studies with PFS or time to progression (TTP) as primary outcomes, and form 2c for studies with QoL, toxicity, or response rate as primary outcomes and also for noninferiority studies. Form 2a is prognostically substratified for studies where the control arm produced OS greater or less than or equal to 1 year and form 2b for studies where the control arm produced PFS greater or less than or equal to 6 months (Figure 2)

Adapted from11

Figure 2. The ESMO Magnitude of Clinical Benefit Scale version 1 (ESMO-MCBS v1.0).

Using this rational, structured, and consistent approach to stratify a drug’s clinically meaningful benefit, 77 cancer medicines across 10 cancer types were analyzed. The results were published recently in Annals of Oncology.11The section for PC used data from clinical trials listed in the Table to score medications indicted.

Adapted from11

Table 1. Field-Testing ESMO-MCBS v1.0, Prostate Cancer.

ALSYMPCA trial using radium-223 with chemotherapy or radiotherapy treatment scored 5, the highest score. Abiraterone with or without prednisone and enzalutamide vs placebo treatments scored next highest, 4. The Tropic trial that utilized cabazitaxel and prednisone vs mitoxantrone and prednisone came at the bottom of the list with a score of 2. Based on this analysis, radium-223 demonstrated the highest clinical benefit in patients with mCRPC.

NCCN Evidence Blocks

Similar to the ESMO scale, the NCCN evidence blocks are guidelines for treatment providers to effectively collaborate with their patients in the United States. Levels of evidence are presently based on four elements:

  • Efficacy
  • Safety
  • Quality of evidence
  • Consistency of evidence

Inclusion of treatment cost in evidence blocks was discussed at the 2015 NCCN 20thAnnual Conference.12The proposed use of evidence blocks with five elements, including cost, will use visual tools to indicate levels of evidence within the NCCN guidelines to compare treatments. This will provide physicians with a tool to truly identify optimal treatments based on what is most important to the patient.

Rapidly evolving treatment scenarios for mCRPC makes quantifiable benefit comparison difficult to discern among the various treatment options. Development of tools like NCCN evidence blocks and ESMO-MCBS in conjunction with guidelines from professional organizations like NCCN are facilitating the analysis of personalized treatment options for patients based on individual preferences and will allow the medical community to stay synced with the rapidly evolving treatment options.


  1. Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castration-resistant prostate cancer.Nat Rev Clin Oncol. 2011;8(1):12-23.
  2. Crawford ED, Petrylak D. Castration-resistant prostate cancer: descriptive yet pejorative?J Clin Oncol. 2010;28(23):e408.
  3. Agarwal N, Di Lorenzo G, Sonpavde G, et al. New agents for prostate cancer.Ann Oncol. 2014;25(9):1700-1709.
  4. 4.NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): 2015 Updates.,-2015/nccn-clinical-practice-guidelines-in-oncology-(nccn-guidelines%C2%AE)-2015-updates.aspx. Accessed September 29, 2015.
  5. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate vancer before chemotherapy.N Engl J Med. 2014. 371(5):424-433
  6. Ryan CJ, Smith MR, Fizazi K et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.Lancet Oncology. 2015;16(2):152-160.
  7. Sweeney C, Chen YH, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. Program and abstracts of the American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2014; Chicago, Illinois. Abstract LBA2.
  8. Neal D. Shore. Radium-223 Dichloride for Metastatic Castration-resistant Prostate Cancer: The Urologist's Perspective.Urology. 2015;85(4):717-724
  9. George DJ, Nabhan C, DeVries T et al. Survival outcomes of Sipuleucel-T phase 3 studies: impact of control arm cross-over to salvage immunotherapy. 2015.Cancer Immunol Res. 3(9): 1063-1069.
  10. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO MCBS) Accessed September 29, 2015.
  11. Cherny NI, Sullivan R, Dafni U et al. A standardized generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti- cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Annals Onc. 2015;26:1547-1573.
  12. Future NCCN Guidelines to Include Evidence Blocks. Accessed September 29, 2015.

Related Videos
Toni K. Choueiri, MD, with the Oncology Brothers presenting slides
Toni K. Choueiri, MD, with the Oncology Brothers presenting slides
Toni K. Choueiri, MD, with the Oncology Brothers presenting slides
Toni K. Choueiri, MD, with the Oncology Brothers presenting slides
Toni K. Choueiri, MD, with the Oncology Brothers presenting slides
Related Content