AN EDUCATIONAL SUPPLEMENT TO. Importance of identifying the early emergence of metastatic disease in prostate cancer

Transcription

1 AN EDUCATIONAL SUPPLEMENT TO Importance of identifying the early emergence of metastatic disease in prostate cancer

2 2 Importance of identifying the early emergence of metastatic disease in prostate cancer Importance of identifying the early emergence of metastatic disease in prostate cancer By Christopher M. Pieczonka, MD, and Joseph F. Renzulli II, MD, FACS Dr. Pieczonka is co-director of research, Associated Medical Professionals, Syracuse, NY. Dr. Renzulli is associate professor of surgery (urology), The Warren Alpert School of Medicine at Brown University, Providence, RI. Introduction The transition from castrate-resistant prostate cancer (CRPC) to metastatic CRPC (mcrpc) is a critical step along the prostate cancer (PCa) disease continuum. Over 80% of men with CRPC (M0) will progress to mcrpc, with progression being quite rapid in over half of them. In addition, there is controversy surrounding whether all men with CRPC have metastatic disease, however, we simply do not have the diagnostic means to demonstrate their microscopic metastatic foci. Nonetheless, many patients may already have metastatic disease at the time of their CRPC diagnosis. Bone scans are considered the standard first-line modality for detection of metastases in CRPC. These scans have many limitations, however, and their ordering can be delayed in clinical practice, which can lead to a delay in diagnosis and treatment. It is critical to understand the CRPC mcrpc transition to optimize standard screening procedures and identify patients with early metastatic disease who may benefit from therapeutic intervention. Recognizing the importance of systematic scanning as the best approach for early diagnosis, the Radiographic Assessments for Detection of Advanced Recurrence (RADAR) group has developed suggested imaging guidelines. By implementing the RADAR guidelines, metastatic disease can be diagnosed earlier and appropriate treatment can be offered to patients. Introduction to CRPC Most patients with localized PCa undergo initial surgical and/or radiation therapy, after which prostate-specific antigen (PSA) levels are monitored to assess for disease progression. PSA levels differ based on whether the patient received radiation therapy (in which case a PSA nadir of 0.5 ng/ml should be achieved) or prostatectomy (in which case PSA levels should be undetectable at <0.1 ng/ml). 1 3 Following prostatectomy, all prostate cells should be removed with no PSA-producing cells remaining in the body, leading to undetectable PSA levels. This is not the case after radiation therapy, however, which is why a PSA nadir is set as the threshold for response, and subsequent rises in PSA become a potential indicator of disease recurrence. The American Society for Therapeutic Radiology and Oncology (ASTRO)/Phoenix Consensus provides guidelines for PSA failure following all forms of radiation therapy that help to guide treatment decision-making in this setting. According to these guidelines, 3 consecutive PSA rises, or a rise in PSA 2.0 ng/ml above the nadir, is predictive of treatment failure with great sensitivity and specificity after both external beam radiotherapy and interstitial prostate brachytherapy, irrespective of whether either treatment was accompanied by androgen deprivation therapy (ADT). 4 Following initial therapy, 30% to 40% of men may have a biochemical recurrence (BCR). Often, men who have had surgery initially, and subsequently experience a BCR, will undergo salvage radiation therapy. If the PSA is rising after salvage radiation therapy, or rising following definitive radiation therapy, then it must be determined whether this is a local recurrence or a distant recurrence. 4 This is challenging at low PSA levels based on the limitations of our imaging techniques. Many urologists would only consider

3 Published as an Educational Supplement to Urology Times 3 FIGURE 1 Improvement in median survival at lower baseline PSA levels Median Overall Survival (months) months 7.1 months Sipuleucel-T Control 5.4 months 2.8 months 0 Baseline PSA (ng/ml) 22.1 (n=128) > (n=128) > (n=128) >134.1 (n=128) HR 0.51 (95% CI: ) HR 0.74 (95% CI: ) HR 0.81 (95% CI: ) HR 0.84 (95% CI: ) *This post hoc analysis was not powered for statistical significance, and the population within the subgroups was not randomized. Therefore, the findings are limited by their exploratory nature. Source: Adapted from ref 20. initiation of ADT if the PSA doubling time (PSADT) is very rapid (ie, <3 6 months) or if there is demonstrable metastatic disease. Although approximately 90% of men respond to ADT, resistance inevitably develops over time, resulting in a transition to the castration-resistant phenotype known as CRPC (also referred to as M0 CRPC in strictly nonmetastatic instances). 5 CRPC is defined by cancer progression on ADT, despite a testosterone level of <50 ng/ml but preferably <20 ng/ml (regulatory authorities have historically considered a testosterone level <50 ng/ml to be the castrate level threshold, because initial laboratory testing capabilities could not discriminate at levels lower than this). 6 Emergence of metastatic disease Although treatment with ADT following BCR is effective, nearly all men will go on to develop CRPC. In addition, over 80% who have stopped responding to ADT will develop metastatic disease, a clinical state known as mcrpc or M1 CRPC. 7, 8 Differentiating between these stages can be challenging. In fact, this might be a matter of semantics given the shortcomings in commonly used imaging modalities. To maximize the potential of identifying early metastases, the RADAR guidelines (outlined later here in detail) are based on testing PSA levels every 3 months. Routine, scheduled PSA testing at this interval is therefore recommended. 9 Progression to mcrpc can be rapid, with 46% of men with CRPC developing metastases within 2 years. 10 Clinical manifestations of mcrpc include development of bone metastases (90% of patients) and development of softtissue metastases (20% of patients), most commonly in the lymph nodes followed by the lung or liver. 11,12 The different sites of metastases can greatly affect a patient s prognosis and overall mortality. 13 Clinical evidence suggests increased lethality for lung and liver metastases compared with bone and nonvisceral metastases, which has implications for treatment decision-making. 14 Studies of patients with CRPC have noted levels of absolute PSA increase, PSA velocity changes, and PSADT (in the post-adt setting) as predictors of higher risk to develop

4 4 Importance of identifying the early emergence of metastatic disease in prostate cancer FIGURE 2 Anticancer activity of immunotherapy increases over time Administration of immunotherapy Relative anticancer activity Time Initial immune response Antigen spread Slowing tumor marker kinetics (eg, PSA) Radiographic progression Clinical progression (TDRP TFOA) OS Schematic representing progression and broadening of response over time following treatment with cancer-targeting immunotherapy. Antigen spread leads to more relevant targets (eg, neoantigens) for a given patient, and this highly individualized precision response could lead to improved clinical activity. Furthermore, with subsequent treatment, the immune response may be further boosted as tumor cells are killed or modulated in an immunogenic manner, which translates into improving clinical activity over time. Abbreviations: OS, overall survival; PSA, prostate-specifi c antigen; TDRP, time to disease-related pain; TFOA, time to fi rst opioid analgesic. Source: Reprinted, with permission, from ref 24. metastatic disease. 10 In many clinical practices, there is a high prevalence of unsuspected metastatic disease in CRPC patients with rising PSA due to the high frequency of asymptomatic metastases and other issues such as delayed imaging. 15 It follows that looking for changes in PSA levels, perhaps by systematically assessing electronic medical records, might help predict the likelihood of metastases in men with CRPC and serve as an alert to prompt subsequent diagnostic testing. Several reports have shown that a substantial portion of patients with CRPC who were believed to be nonmetastatic (due to their asymptomatic disease status) were metastatic when screened via imaging. 16,17 Analysis of the screening failure rate from the Endothelin A Use (ENTHUSE) phase 3 trial of zibotentan versus placebo in patients with nonmcrpc showed that 32% of men originally believed to have non-mcrpc had metastatic disease as detected by bone scan or computed tomography (CT)/magnetic resonance imaging (MRI). 15 In the Impact of Abiraterone Acetate on Prostate Specific Antigen (IMAAGEN) study, the reported screening failure rate was even higher, at 37%. 16 The results of the ENTHUSE and IMAAGEN studies are consistent with screening failure data published from other non-mcrpc trials with similar inclusion criteria for PSA and PSADT. 18 Keep in mind that imaging was done by traditional scans in these trials. Findings may have differed if positron emission tomography (PET )/CT imaging had been conducted. Collectively, these studies indicate a high rate of unsuspected asymptomatic metastatic disease in the CRPC patient population and suggest the need to improve diagnostic practices. Risk factors for the development of mcrpc need to be proactively assessed, thereby assuring timely identification of metastases and early access to effective treatment options. Impact of early mcrpc diagnosis on optimal treatment benefit The diagnosis of mcrpc is a pivotal moment in PCa disease progression, as it informs immediate treatment decisions. Early detection of metastatic disease allows for treatment with interventions that extend survival when administered as soon as signs of metastatic disease emerge. The National Comprehensive Cancer Network (NCCN) recommends that sipuleucel-t be used as first-line treatment for men with asymptomatic or minimally symptomatic mcrpc. 19

5 Published as an Educational Supplement to Urology Times 5 In an exploratory analysis that examined the association between baseline PSA levels and overall survival benefit from sipuleucel-t, researchers found that patients with less advanced disease (as defined by lower baseline PSA values) may benefit the most from sipuleucel-t treatment. 20 As shown in Figure 1, there was a trend toward improved estimated median survival times with lower baseline PSA levels. Specifically, the lowest baseline PSA quartile ( 22.1 ng/ml) had a median survival improvement of 13 months with a 49% reduced risk of death, while the highest quartile (>134 ng/ml) had a median survival improvement of 2.8 months with a 16% reduced risk of death. 20 Interestingly, 20% of patients in the lowest quartile ( 22.1 ng/ml) had more than 10 metastatic lesions prior to receiving sipuleucel-t treatment. Of note, this post hoc analysis was not powered for statistical significance and the population within the subgroups was not randomized, making the findings limited by their exploratory nature. The survival benefit seen with immunotherapy is likely due to stimulation of the patient s immune system when tumor burden is low and while the patient still has an intact immune system These concepts were also described in a review of immunotherapy in which early treatment was shown to boost the immune system s ability to fight PCa over time (Figure 2). 24 A study using computer modeling predicted that early intervention with novel therapies in the non-mcrpc setting would reduce progression to mcrpc and cause a sustained decline in mcrpc mortality by Collectively, these data suggest that patients with mcrpc and lower baseline PSA levels may benefit the most from sipuleucel-t treatment and provide a rationale for immunotherapy as first-line treatment in sequencing algorithms for mcrpc. 20 Overall, the data reinforce the fact that patients with mcrpc should be identified via imaging as early as possible in their disease course for these patients to receive the maximum possible benefit from available therapies. Current diagnostic practices Current guidelines dictate that patients should be screened early and often using the best available tools to identify potential metastases and optimize treatment outcomes for patients with metastatic disease. When urologists are presented with a patient with CRPC, the question should naturally arise as to whether everything has been done to identify metastases. For optimal effectiveness, the following factors should be taken into consideration when deciding on the frequency of imaging: individual risk, age, PSADT, Gleason grade, and overall patient health. 9,23 Scans should be performed more frequently when PSADT is <8 months. 23 PCa has a predilection to metastasize to bone and, as such, technetium 99 m-methyl diphosphonate ( 99 mtc-mdp) scintigraphy bone scans have been considered the standard first-line modality for detection of metastases in CRPC. 23 This type of scanning, however, has several major limitations. Bone scans image the secondary effect of the tumor on bone as opposed to tumor proliferation, and false-positives and false-negatives have been widely reported. 9 Guidance for clinicians in how to use imaging for identification of metastases comes from the RADAR group. For patients with non-mcrpc, the RADAR guidelines recommend obtaining the first scan when the PSA level reaches 2 ng/ ml. Image modalities recommended for initial testing include 99 mtc-mdp scintigraphy and abdomen/pelvis/chest CT. If the imaging is negative, this should be followed by another scan when the PSA level reaches 5 ng/ml and for every doubling of PSA level thereafter (based on PSA testing every 3 months). 9 Although the RADAR guidelines are intended to address current scanning practices by providing guidance on the value of early and frequent scanning, not all urologists have adopted these recommendations. Delays in ordering bone scans are common in clinical practice, resulting in delayed diagnosis of metastases and delayed therapy, which can negatively affect patient outcomes. While advancements in imaging are on the horizon, urologists should make a commitment to using the best imaging tools currently available to them. Advances on the horizon: imaging, laboratory technology, and biomarkers Given some of the issues with specificity and sensitivity of traditional bone scans, newer options have been developed that may offer increased diagnostic accuracy of mcrpc. These include 18 F-sodium fluoride PET CT, MRI, and CT scans. 9,26 In an analysis of 10 studies, 18 F-sodium fluoride PET/CT was associated with pooled sensitivity and specificity of 96% and 98%, respectively. 27 This is in contrast to an analysis of 8 studies in which 99 mtc-mdp scintigraphy bone scans were associated with pooled sensitivity and specificity of 57% and 98%, respectively. 27 Of note, a new diagnostic product, 18 F-fluciclovine (Axumin ), was approved for the diagnosis of recurrent PCa in men with elevated levels of PSA after previous treatment. 28 Axumin is the first fluorinated radiotracer to be approved by the FDA for this purpose. It is expected to assist clinicians in detecting locally recurrent disease, and could guide biopsy procedures or assist in the planning of additional treatment. Other emerging scanning options include PET with choline tracers, targeting prostate-specific membrane antigen (PSMA), and whole body MRI. Choline PET/CT scans take

6 6 Importance of identifying the early emergence of metastatic disease in prostate cancer advantage of how PCa cells readily uptake radioactive tracers derived from choline (either 18 F-choline or 11 C-choline) and therefore allow for the early identification of recurrent tumors. 29 Many physicians, however, face limited access to choline PET/CT scans, and costs are often prohibitive. PSMA may offer improvement on the sensitivity and specificity offered by choline PET/CT scans PSMA is a transmembrane protein that is expressed at higher levels in PCa cells and has expression levels that correlate with tumor aggressiveness, metastatic disease, and disease recurrence. 35 In particular, 68 Ga-PSMA scans are better able to detect PCa metastases compared with conventional imaging techniques. 30,32 As with the case of choline PET/ CT scans, PSMA scans are often prohibitively expensive, in large part because they are still considered to be an experimental procedure. 36 With higher sensitivity and specificity, any of these newer options would likely detect more metastatic disease than traditional bone scans. Still, these newer options have not been widely adopted as first-line imaging options primarily due to their limited access and availability, and they require further evaluation of their effectiveness for assessing metastases. 9,37,38 Organizations such as the National Oncologic PET Registry, a collaboration of the American College of Radiology Imaging Network, the American College of Radiology, and the Academy of Molecular Imaging, are working to ensure access to, and reimbursement for, certain types of scans, which may help close the accessibility gap. 27 Another technology that may gain traction in the future is the analysis of circulating tumor cells (CTCs). Numerous studies indicate that higher levels of CTCs correlate with poor patient outcomes, particularly in the advanced stages of PCa Once isolated, CTCs can not only be counted but also analyzed for DNA mutations, translocations, and expression at both the mrna and protein levels, allowing for more detailed insight into the unique disease state and optimal treatment options for the patient. 42 Such evidence may provide insights into drivers of tumor growth in mcrpc. Recent data have been reported regarding measurement of the nuclear androgen-receptor splice variant-7 (AR-V7) in CTCs as a treatment-specific biomarker to predict survival outcomes for certain therapies. In a study of 202 patients with CRPC, the presence of AR-V7 was a predictor of poor outcomes with first- and second-line use of novel oral hormonal therapies. 43 The AdnaTest Prostate Cancer Panel AR-V7 assay may be commercially available later in Summary We have provided a review of the prevalence and timing of metastases in CRPC, current and future imaging practices aimed at early identification of metastases, as well as discussed the impact of early diagnosis of metastatic disease on treatment and patient outcomes. Although bone scans are considered the standard first-line modality for detection of metastases in CRPC, these scans have many limitations and their ordering is often delayed, which can lead to a delay in diagnosis and treatment. Newer imaging options are available and on the horizon that offer increased diagnostic accuracy of mcrpc. To improve patient survival, urologists should follow imaging guidelines and scan early and often in patients with CRPC to allow for timely identification of men who may benefit from early therapeutic intervention. REFERENCES 1. Koulikov D, Mohler MC, Mehedint DC, et al. Low detectable prostate specific antigen after radical prostatectomy treat or watch? J Urol. 2014;192: Mitchell RE, Desai M, Shah JB, et al. Preoperative serum prostate specific antigen remains a significant prognostic variable in predicting biochemical failure after radical prostatectomy. J Urol. 2006;175: ; discussion Nussbaum N, George DJ, Abernethy AP, et al. Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science. Prostate Cancer Prostatic Dis. 2016;19: Roach M, 3rd, Hanks G, Thames H, Jr., et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006;65: Grivas PD, Robins DM, Hussain M. Predicting response to hormonal therapy and survival in men with hormone sensitive metastatic prostate cancer. Crit Rev Oncol Hematol. 2013;85: European Association of Urology. EAU Prostate Cancer Guidelines; Kirby M, Hirst C, Crawford ED. Characterising the castrationresistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65: Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol. 2010;17 Suppl 2:S Crawford ED, Stone NN, Yu EY, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology. 2014;83: Smith MR, Cook R, Lee KA, Nelson JB. Disease and host characteristics as predictors of time to first bone metastasis

7 Published as an Educational Supplement to Urology Times 7 and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer. 2011;117: Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26: Bubendorf L, Schopfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31: Zhang T, Armstrong AJ. Clinical phenotypes of castrationresistant prostate cancer. Clin Adv Hematol Oncol. 2013;11: Halabi S, Kelly WK, Ma H, et al. Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer. J Clin Oncol. 2016;34: Yu EY, Miller K, Nelson J, et al. Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. J Urol. 2012;188: Crawford ED, DePalantino JR, Kantoff P, et al. Unsuspected metastases found during screening for a trial of patients with non-metastatic castration resistant prostate cancer. J Urol. 2015;193:e Sartor O, Eisenberger M, Kattan MW, Tombal B, Lecouvet F. Unmet needs in the prediction and detection of metastases in prostate cancer. Oncologist. 2013;18: Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebocontrolled trial. Lancet. 2012;379: National Comprehensive Cancer Network. Prostate cancer. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version ; Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-t in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81: Gulley JL, Madan RA, Arlen PM. Enhancing efficacy of therapeutic vaccinations by combination with other modalities. Vaccine. 2007;25 Suppl 2:B Gulley JL, Madan RA, Schlom J. Impact of tumour volume on the potential efficacy of therapeutic vaccines. Curr Oncol. 2011;18:e Pieczonka CM, Telonis D, Mouraviev V, Albala D. Sipuleucel-t for the treatment of patients with metastatic castrateresistant prostate cancer: considerations for clinical practice. Rev Urol. 2015;17: Gulley JL, Madan RA, Pachynski R, et al. Role of antigen spread and distinctive characteristics of immunotherapy in cancer treatment. J Natl Cancer Inst. 2017; Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and mortality in the united states: estimates using a dynamic progression model. PLoS One. 2015;10:e Abdellaoui A, Iyengar S, Freeman S. Imaging in prostate cancer. Future Oncol. 2011;7: Segall GM. PET/CT with sodium 18 F-fluoride for management of patients with prostate cancer. J Nucl Med. 2014;55: AXUMIN (fluciclovine F 18) injection, for intravenous use initial U.S. Approval: Blue Earth Diagnostics Ltd. Oxford, UK. 29. Gardner TA, Thygesen J, Cox J, et al. Quantifying the potential of C-11 acetate PET scanning in avanced prostate cancer patients. J Clin Oncol. 2016; Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41: Eiber M, Weirich G, Holzapfel K, et al. Simultaneous 68 Ga- PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer. Eur Urol. 2016;70: Maurer T, Gschwend JE, Rauscher I, et al. Diagnostic efficacy of (68)Gallium-PSMA positron emission tomography compared to conventional imaging for lymph node staging of 130 consecutive patients with intermediate to high risk prostate cancer. J Urol. 2016;195: Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of hybrid (6)(8)Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015;56: Roethke MC, Kuru TH, Afshar-Oromieh A, Schlemmer HP, Hadaschik BA, Fenchel M. Hybrid positron emission tomography-magnetic resonance imaging with gallium 68 prostate-specific membrane antigen tracer: a next step for imaging of recurrent prostate cancer-preliminary results. Eur Urol. 2013;64: Kabasakal I, Demirci E. PSMA PET/CT imaging and therapy. Imaging Med. 2015;7: Rauscher I, Maurer T, Fendler WP, Sommer WH, Schwaiger M, Eiber M. (68)Ga-PSMA ligand PET/CT in patients with prostate cancer: How we review and report. Cancer Imaging. 2016;16: Lecouvet FE, El Mouedden J, Collette L, et al. Can wholebody magnetic resonance imaging with diffusion-weighted imaging replace Tc 99m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer? Eur Urol. 2012;62: Amzalag G, Rager O, Tabouret-Viaud C, et al. Target definition in salvage radiotherapy for recurrent prostate cancer: the role of advanced molecular imaging. Front Oncol. 2016;6: Danila DC, Heller G, Gignac GA, et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007;13: de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14: Fleming MT, Morris MJ, Heller G, Scher HI. Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials. Nat Clin Pract Oncol. 2006;3: Hu B, Rochefort H, Goldkorn A. Circulating tumor cells in prostate cancer. Cancers (Basel). 2013;5: Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen receptor splice variant-7 mrna detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol. 2017;35: QIAGEN expands liquid biopsy pipeline with AR-V7 test in prostate cancer Available at: us/about-us/press-releases/pressreleaseview?id=% 7b55C014E9-91D1-4E5E-8FF0-822B A%7d&lang=en. Accessed May 19, COVER PHOTOS: EGOROV ARTEM, ROYALTYSTOCKPHOTO.COM/SHUTTERSTOCK.COM

8 8 Importance of identifying the early emergence of metastatic disease in prostate cancer Clinical Practice Highlights It is important to identify early emergence of metastatic disease to optimally sequence interventions and improve survival outcomes in advanced prostate cancer; consider the following: è Recognize that >80% of men with CRPC (M0) will progress to mcrpc (M1), with progression being quite rapid in over half of them. è Realize that approximately one-third of men may already have metastatic disease at the time of their CRPC diagnosis. è Understand that differentiating between M0 and M1 can be challenging and may be a matter of semantics because metastases need to be at least fingernail-sized to be identified by commonly used imaging modalities. è Routinely test PSA every 3 months and follow RADAR imaging guidelines to identify patients with early metastatic disease who may benefit from therapeutic intervention. è Screen early and often using the best available tools to identify appropriate patients for early intervention. è Administer first-line immunotherapy consistent with NCCN guidelines to improve survival outcomes in advanced prostate cancer. Educational Content Supported by