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“Non-metastatic, Castration-resistant Prostate Cancer: Diagnostic and Treatment Recommendations by an Expert Panel from Brazil”

Open AccessPublished:September 09, 2022DOI:https://doi.org/10.1016/j.clgc.2022.09.005

      Abstract

      Introduction

      Non-metastatic, castration-resistant prostate cancer (nmCRPC) is an important clinical stage of prostate cancer, prior to morbidity and mortality from clinical metastases. In particular, the introduction of novel androgen-receptor signaling inhibitors (ARSi) has changed the therapeutic landscape in nmCRPC. Given recent developments in this field, we update our recommendations for the management of nmCRPC.

      Methods

      A panel of 51 invited medical oncologists and urologists convened in May of 2021 with the aim of discussing and providing recommendations regarding the most relevant issues concerning staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up in nmCRPC. Panel members considered the available evidence and their practical experience to address the 73 multiple-choice questions presented.

      Results

      Key recommendations and findings include the reliance on prostate-specific antigen doubling time for treatment decisions, the absence of a clear preference between conventional and novel (i.e., positron-emission tomography-based) imaging techniques, the increasing role of ARSis in various settings, the general view that ARSis have similar efficacy. Panelists highlighted the slight preference for darolutamide, when safety is of greater concern, and a continued need to develop high-level evidence to guide the intensity of follow-up in this subset of prostate cancer.

      Discussion

      Despite the limitations associated with a consensus panel, the topics addressed are relevant in current practice, and the recommendations can help practicing clinicians to provide state-of-the-art treatment to patients with nmCRPC in Brazil and other countries with similar healthcare settings.

      Keywords

      Introduction

      Prostate cancer is currently responsible for one out of seven new cancer cases in males worldwide.
      • Sung H
      • Ferlay J
      • Siegel RL
      • et al.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      For clinical practice, prostate cancer can be divided into clinical states, with specific diagnostic evaluation and therapeutic options. Progression during androgen-deprivation therapy (ADT) is a key milestone in that attempt, marking the onset of the castration-resistant state in a given patient.
      • Mateo J
      • Fizazi K
      • Gillessen S
      • et al.
      Managing Nonmetastatic Castration-resistant Prostate Cancer.
      ,
      • Scher HI
      • Morris MJ
      • Stadler WM
      • et al.
      Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3.
      When biochemical progression is detected in patients on ADT, generally after radical prostatectomy and/or radiotherapy to the prostate, and distant disease cannot be identified by imaging, non-metastatic, castration-resistant prostate cancer (nmCRPC) is defined.
      • Scher HI
      • Morris MJ
      • Stadler WM
      • et al.
      Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3.
      ,
      • Smith MR
      • Kabbinavar F
      • Saad F
      • et al.
      Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.
      More specifically, a 25% increase in prostate-specific antigen (PSA) levels from nadir (considering a starting value ≥1.0 ng/mL, and a minimum rise of 2.0 ng/mL) is required in the presence of castrate testosterone levels (<50 ng/dL) and absence of disease identified by computed tomography (CT) or magnetic resonance imaging (MRI), in lymph nodes beyond the true pelvis or in visceral organs, and by bone scan.
      • Scher HI
      • Morris MJ
      • Stadler WM
      • et al.
      Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3.
      The prevalence of nmCRPC is estimated to be between 2% and 8% in different countries.
      • Liede A
      • Arellano J
      • Hechmati G
      • Bennett B
      • Wong S.
      International prevalence of nonmetastatic (M0) castration resistant prostate cancer (CRPC).
      In recent years, there has been an increased ability to identify these patients, partly as a result of more frequent PSA testing for men on treatment with ADT.
      • Cornford P
      • van den Bergh RCN
      • Briers E
      • et al.
      EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. Part II-2020 Update: Treatment of Relapsing and Metastatic Prostate Cancer.
      Moreover, there is growing interest in identifying patients with nmCRPC, for a variety of reasons. First, results from placebo arms in clinical trials among patients with nmCRPC suggest that up to 60% of these patients develop overt metastatic disease within 3 to 5 years.
      • Smith MR
      • Kabbinavar F
      • Saad F
      • et al.
      Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.
      ,
      • Smith MR
      • Cook R
      • Lee KA
      • Nelson JB.
      Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer.
      ,
      • Smith MR
      • Saad F
      • Oudard S
      • et al.
      Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.
      The presence of clinical metastases is associated with morbidity from the disease and metastatic CRPC (mCRPC) is considered a lethal state of prostate cancer.
      • 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.
      Based on the previously mentioned model, nmCRPC represents a patient population for whom preventing or delaying a transition to mCRPC is the primary therapeutic objective, with potential impact even in the public-health perspective.
      • 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.
      Secondly, the introduction of the novel androgen-receptor signaling inhibitors (ARSi, apalutamide, darolutamide and enzalutamide) has changed the therapeutic landscape in the various states along the continuum of prostate cancer progression and offered improved options in nmCRPC.
      • Mateo J
      • Fizazi K
      • Gillessen S
      • et al.
      Managing Nonmetastatic Castration-resistant Prostate Cancer.
      ,
      • Esther J
      • Dorff TB
      • Maughan BL.
      Recent developments in the treatment of non-metastatic castration resistant prostate cancer.
      Finally, novel imaging methods are more accurate in detecting lymph-node and distant metastases in patients with biochemical recurrence, thus bringing a new perspective to disease staging in patients with CRPC.
      • Mateo J
      • Fizazi K
      • Gillessen S
      • et al.
      Managing Nonmetastatic Castration-resistant Prostate Cancer.
      ,
      • Cornford P
      • van den Bergh RCN
      • Briers E
      • et al.
      EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. Part II-2020 Update: Treatment of Relapsing and Metastatic Prostate Cancer.
      ,
      • Gupta R
      • Sheng IY
      • Barata PC
      • Garcia JA.
      Non-metastatic castration-resistant prostate cancer: current status and future directions.
      ,
      • Perera M
      • Papa N
      • Roberts M
      • et al.
      Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer-Updated Diagnostic Utility, Sensitivity, Specificity, and Distribution of Prostate-specific Membrane Antigen-avid Lesions: A Systematic Review and Meta-analysis.
      Our group has previously reviewed and provided recommendations for staging, diagnosis and treatment of nmCRPC in Brazil through a consensus conference.
      • Maluf F
      • Soares A
      • Avanco G
      • et al.
      Consensus on diagnosis and management of non-metastatic castration resistant prostate cancer in Brazil: focus on patient, selection, treatment efficacy, side effects and physician's perception according to patient comorbidities.
      Given recent developments in imaging and treatment modalities, we sought to update our recommendations for practicing physicians in Brazil, especially due to the epidemiological importance of prostate cancer in this country.
      Brasil. Instituto Nacional de Câncer José Alencar Gomes da Silva
      Estimativa 2020: incidência de câncer no Brasil.

      Patients and Methods

      Panel organization, composition, and goals

      The expert panel was composed by 51 invited medical oncologists and urologists with expertise in genitourinary malignancies in Brazil. The number of experts in the panel was increased compared to prior consensus to better assess the regional differences in Brazil. In addition, specialists were selected based on local clinical practices, and usually urologists and oncologists assist patients with nmCRPC. Radiotherapy was discussed as part of the questions, but there were no radiotherapists as panel members, as no recommendations of radiotherapy were derived from first consensus edition. The meeting was organized and coordinated by the two senior authors (DLJ and FM) and aimed at discussing the most relevant issues concerning the diagnosis and treatment of patients with nmCRPC, including staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up. A total of 73 multiple-choice questions were developed on these topics. In a modified Delphi process, a scientific committee reviewed questions in three rounds for inputs and recommendations. Questions were presented to the expert panel, which convened in May of 2021 (see Supplementary Materials for the complete text of these questions, which appear in Results in an abbreviated format). In order to provide their recommendations, panel members considered the published scientific evidence and their practical experience on the issues discussed. For all the questions, it was assumed that the interventions discussed were approved and available, whereas those not yet approved in Brazil were not presented among the possible options.

      Statistical analysis

      Results were computed descriptively for each of the multiple-choice questions addressed by the panel. When answering each question, the option “abstain” was to be used when a panel member felt impeded to provide a qualified response for a lack of knowledge or the presence of conflicts of interest. The consensus was considered to be present for a question if at least 75% of the voting members selected a particular answer, considering the number of voters and the option “abstain” in the denominator of this proportion. When an answer garnered between 50.0% and 74.9% of votes, this was considered as a majority recommendation.

      Results

      Staging methods

      As shown in Table 1, there was no consensus for any of the three questions on staging methods. Regarding imaging modalities for patients with nmCRPC, voters were equally divided between (1) positron-emission tomography (PET)-CT with prostate-specific membrane antigen (PSMA) (or PET-MRI with PSMA), with or without pelvic MRI and (2) chest CT or X-ray, CT of the abdomen and pelvis (or pelvic MRI) and bone scan, both in case of recurrences after radical prostatectomy and after curatively intended radiotherapy. Regarding the preferred method for calculating PSA doubling time (PSAdt), two-thirds of voters recommended using an electronic calculator and the last three PSA values above 0.1 ng/mL. Table 1 also shows a question addressing treatment options, which is presented here because the recommendation with the largest percentage of votes (45.2%) was for PSMA-based PET scanning in a hypothetical patient with small pelvic lymph nodes.
      Table 1Questions related to staging methods.
      QuestionRecommendations and percentages
      Imaging for a nmCRPC patient after radical prostatectomyPSMA PET-CT (or PSMA PET-MRI) +/- pelvic MRIWhole-body MRIBone scanPelvic MRIPelvic MRI and bone scanChest CT/X-ray, CT of the A & P (or pelvic MRI), and bone scanNoneAbstain
      48.5%0003.0%48.5%00
      Imaging for a nmCRPC patient after curatively intended radiotherapyPSMA PET-CT (or PSMA PET-MRI) +/- pelvic MRIWhole-body MRIBone scanPelvic MRIPelvic MRI and bone scanChest CT/X-ray, CT of the A & P (or pelvic MRI), and bone scanNoneAbstain
      47.2%0002.8%50%00
      Calculation of PSA doubling time (based on values (>0.1 ng/mL)Do not calculate itLast 2 values, manuallyLast 2 values, electronicallyLast 3 values, manuallyLast 3 values, electronicallyAt least 4 values, manuallyAt least 4 values, electronicallyAbstain
      2.6%015.4%2.6%66.7%5.1%7.7%0
      Approach to nmCRPC with pelvic lymph nodes <2.0 cm in minor axisApaEnzaDaroApa or enza or daroBic or fluta or niluPelvic radiotherapyStereotactic body radiotherapy for oligometastatic lymph nodesLymphadenectomyPET-PSMA for therapeutic decisionAbstain
      2.4%0040.5%02.4%4.8%045.2%4.8%
      Answers to some questions may not total 100% due to rounding.
      A & P, abdomen and pelvis; Apa, apalutamide; Bica, bicalutamide; CT, computed tomography; Daro, darolutamide; Enza, enzalutamide; Fluta, flutamide; MRI, magnetic resonance imaging; Nilo, nilutamide; nmCRPC, non-metastatic, castration-resistant prostate cancer; PET, positron-emission tomography; PSMA, prostate-specific membrane antigen.

      Antineoplastic therapy

      There were 65 questions addressing systemic antineoplastic therapy for patients with nmCRPC, one of which presented in Table 1. The first eight of the remaining 64 questions elicited recommendations for a newly diagnosed patient with different combinations of PSA level, PSAdt, and life expectancy. The panel recommendations for these eight hypothetical patients are summarized in Figure 1. There was consensus for five of these questions, majority vote for one, and relatively similar division of votes between two different recommendations for two questions.
      Figure 1
      Figure 1Questions related to immediate management of patients with non-metastatic, castration-resistant prostate cancer. Answers to some questions may not total 100% due to rounding.
      Abbreviations: nmCRPC, non-metastatic, castration-resistant prostate cancer; PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time.
      Table 2 presents recommendations regarding the specific choice of agents, particularly novel ARSi. There was consensus for only one of eight questions, namely about the adequacy of any novel ARSi when taking overall survival results into account. There was also a general trend for recommending any of these agents instead of anyone in particular, except for a preference for darolutamide when safety or tolerability was taken into account. Toxicity and access were the main reasons for recommendations regarding the choice of novel ARSi. Of note, there was a considerable lack of consensus about whether positive PSMA-based imaging should change management when conventional imaging has disclosed no metastatic disease, and on how to treat these patients.
      Table 2Questions related to drug choice.
      QuestionRecommendations and percentages
      Antiandrogen preference in nmCRPCApaEnzaDaroApa or enza or daroAbirateroneBica or fluta or niluAbstain
      4.4%2.2%17.8%68.9%4.4%2.2%0
      Change of management if positive PSMA-based and negative conventional imagingYesNoAbstain
      52.3%47.7%0
      Treatment if positive PSMA-based and negative conventional imagingApaEnzaDaroApa or enza or daroBic or fluta niluDocetaxel (based on disease volume)Local therapy if oligometastatic diseaseLocal therapy if oligometastatic disease plus Apa or enza or daroAbstain
      08.8%2.9%38.2%0020.6%23.5%5.9%
      Drug preference given survival dataApaEnzaDaroApa or enza or daroAbstain
      2.4%019.0%76.2%2.4%
      Drug preference given QOL dataApaEnzaDaroApa or enza or daroAbstain
      0030.2%67.4%2.3%
      Drug preference given safetyApaEnzaDaroApa or enza or daroAbstain
      0065.1%27.9%7.0%
      Drug preference given tolerabilityApaEnzaDaroApa or enza or daroAbstain
      2.4%058.5%34.1%4.9%
      Reason for drug preferenceToxicity profileExperienceCostAccessAbstain
      50.0%4.8%035.7%9.5%
      When to stop treatment and start a new one in nmCRPCPSA progression aloneClinical progression aloneRadiological progression aloneAt least two criteriaClinical and radiological progressionAny progressionAbstain
      2.3%09.3%51.2%27.9%9.3%0
      Answers to some questions may not total 100% due to rounding.
      Apa, apalutamide; Bica, bicalutamide; Daro, darolutamide; Enza, enzalutamide; Fluta, flutamide; Nilo, nilutamide; nmCRPC, non-metastatic, castration-resistant prostate cancer; PSMA, prostate-specific membrane antigen; QOL, quality of life.
      The next series of questions addressed drug choice in view of concern with specific comorbidities or age groups among patients with a reasonable life expectancy. As shown in Table 3, voters generally indicated any ARSi as the first option for most groups of patients with specific comorbidities. Exceptions to this were the preference for darolutamide specifically for patients with mental impairment or a history of falls or of seizures, as well as the use of drugs that increase the risk of seizures. Of note, the panel emphasized the importance of checking for drug interactions before treatment decisions for patients on multiple medications.
      Table 3Questions related to comorbidities.
      QuestionRecommendations and percentages
      Drug choice for most patients with reasonable life expectancy and…
      Moderate/severe diabetesApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      81.0%02.4%9.5%07.1%
      Moderate/severe hypertensionApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      54.8%7.1%035.7%02.4%
      Congestive heart failure ≥ Class IIApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      59.1%4.5%029.5%06.8%
      Coronary artery diseaseApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      71.4%4.8%016.7%07.1%
      History of seizure or drugs that increase risk of seizureApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      11.1%8.9%071.1%2.2%6.7%
      Mental impairmentApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      15.6%2.2%073.3%08.9%
      Renal insufficiencyApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      78.6%02.4%11.9%07.1%
      Age >75 yearsApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      78.6%0016.7%04.8%
      History of fallsApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      34.9%2.3%2.3%58.1%02.3%
      Osteopenia/osteoporosisApa or enza or daroApaEnzaDaroBica or fluta or niluAbstain
      75.0%04.5%13.6%06.8%
      On multiple medicationsApa or enza or daroApaEnzaDaroBica or fluta or niluChecking drug interactions before decidingAbstain
      17.4%008.7%073.9%0
      Answers to some questions may not total 100% due to rounding.
      Apa, apalutamide; Bica, bicalutamide; Daro, darolutamide; Enza, enzalutamide; Fluta, flutamide; Nilo, nilutamide; nmCRPC, non-metastatic, castration-resistant prostate cancer.
      The following 30 questions aimed to elicit the level of concern among panel members regarding specific types of toxicity from each of the three novel ARSi. The results are displayed graphically in Figure 2. For most combinations of toxicity types and agents, the level of concern indicated by the panel was low (green in Figure 2) or moderate (yellow). However, as a general rule, there was higher concern with enzalutamide, intermediate with apalutamide, and lower with darolutamide.
      Figure 2
      Figure 2Level of concern regarding specific toxicities and agents. Green, low; yellow, moderate; red, high; grey, abstentions. Values of 0.0% more often indicate abstentions.
      The final seven questions related to treatment addressed various decisions that are often required upon observation of clinical events (Table 4). There was consensus for only two of those questions: (1) docetaxel is the treatment of choice (90.7%) for patients developing clinical metastases during treatment for nmCRPC who previously progressed to castration resistance in less than 12 months; and (2) the ARSi should not be discontinued (81.8%) in patients with nmCRPC and a profound PSA response (<0.2 ng/mL). There was majority recommendation for three questions: (1) 51.2% of panel members indicated that two methods (among PSA, clinical and radiological) should be used to decide on changing treatment due to progression in patients with nmCRPC; and docetaxel was recommended as treatment of choice upon progression to mCRPC (2) for patients on ARSi with short metastasis-free survival (59.1%) and (3) for patients who progressed to mCRPC after previous progression to castration resistance in more than 12 months (56.8%). For the remaining two questions, there was considerable division of opinion among panel members.
      Table 4Questions related to decisions during treatment.
      QuestionRecommendations and percentages
      When to stop treatment and start a new one in nmCRPCPSA progression aloneClinical progression aloneRadiological progression aloneAt least two criteriaClinical and radiological progressionAny progressionAbstain
      2.3%09.3%51.2%27.9%9.3%0
      Choice for a patient requiring interruption of ASI for toxicityDiscontinue ASI and maintain castrationWait for resolution and re-initiate same ASISwitch to a different antiandrogenAbstain
      6.8%47.7%45.5%0
      Next choice for a patient on ASI for nmCRPC with short PFSEnza if not used beforeAbirateroneDocetaxelRadium-223 if only bone metastasesCabazitaxelBic or fluta or niluPARPi if DDR positiveAbstain
      9.1%15.9%59.1%9.1%004.5%2.3%
      Next choice for a patient on ASI for nmCRPC with long PFSEnza if not used beforeAbirateroneDocetaxelRadium-223 if only bone metastasesCabazitaxelBic or fluta or niluPARPi if DDR positiveAbstain
      7.0%23.3%44.2%16.3%004.7%4.7%
      Choice for a patient with clinical metastases after failing treatment for nmCRPC who previously progressed to CRPC in less than 12 monthsEnza if not used beforeAbirateroneDocetaxelRadium-223 if only bone metastasesCabazitaxelBic or fluta niluPARPi if DDR positiveAbstain
      2.3%2.3%90.7%2.3%0002.3%
      Choice for a patient with clinical metastases after failing treatment for nmCRPC who previously progressed to CRPC in more than 12 monthsEnza if not used beforeAbirateroneDocetaxelRadium-223 if only bone metastasesCabazitaxelBic or fluta or niluPARPi if DDR positiveAbstain
      4.5%25.0%56.8%6.8%004.5%2.3%
      Choice for a nmCRPC patient on ASI and PSA response to <0.2 ng/mLContinue therapyDiscontinue antiandrogen after 1 yearDiscontinue antiandrogen after 2 yearsConsider intermittent therapyAbstain
      81.8%4.5%2.3%11.4%0
      Answers to some questions may not total 100% due to rounding.
      ASI, androgen-signal inhibitor; Bica, bicalutamide; DDR, DNA-damage repair; Enza, enzalutamide; Fluta, flutamide; MFS, metastasis-free survival; Nilo, nilutamide; nmCRPC, non-metastatic, castration-resistant prostate cancer; PARPi, poly (ADP-ribose) polymerase inhibitor.

      Osteoclast-targeted therapy

      Four questions were posed to the panel to elicit recommendations on the use of osteoclast-targeted therapy to prevent skeletal-related events (SREs) in patients with nmCRPC (Table 5). Even though the percentage of panel members stating they do not recommend osteoclast-targeted therapy in this setting is below 75% for the first question, the other three questions make it clear that there was consensus that these agents are not indicated to prevent SREs in patients with nmCRPC.
      Table 5Questions related to osteoclast-targeted therapy.
      QuestionRecommendations and percentages
      Choice of osteoclast-targeted therapy to prevent SREs in nmCRPCZoledronic acidDenosumabEitherAnother osteoclast-targeted therapyI do not use this therapy in this setting, but may supplement calcium and vitamin DAbstain
      4.3%6.5%15.2%071.7%2.2%0
      Treatment frequency for zoledronic acid as prevention of SREs in nmCRPCEvery 12 monthsEvery 6 monthsEvery 3 monthsEvery monthI do not use this therapy in this settingAbstain
      011.9%2.4%2.4%81.0%2.4%
      Treatment frequency for denosumab as prevention of SREs in nmCRPCEvery 12 monthsEvery 6 monthsEvery 3 monthsEvery monthI do not use this therapy in this settingAbstain
      07.3%02.4%82.9%7.3%
      Duration of osteoclast-targeted therapy for SRE prevention in nmCRPC1 year2 yearsUntil first SREUntil second SREIndefinitelyUntil disease progressionI do not use this therapy in this settingAbstain
      002.5%02.5%087.5%7.5%
      Answers to some questions may not total 100% due to rounding.
      nmCRPC, non-metastatic, castration-resistant prostate cancer; SRE, skeletal-related event.

      Patient follow-up

      Regarding the overall strategy for following-up patients with nmCRPC on active therapy, 50.0% of panelists recommended physical examination and PSA levels every 3-6 months and a bone scan every 3-6 months, whereas 37.5% recommended physical examination and PSA levels every 3-6 months and imaging only in the case of symptoms. Physical examination and PSA levels every 3-6 months and a bone scan every 3-6 months, plus a chest CT or X-ray and CT of the abdomen every 3-6 months was recommended by 5% of members. No panel members recommended PET-PSMA and whole-body MRI, and 2.5% of voters recommended either (1) physical examination and PSA levels every 3-6 months with abdominal ultrasound and chest X-ray every 3-6 months and bone scan annually or (2) physical examination and PSA levels every 3-6 months and a chest CT or X-ray and CT of the abdomen and pelvis every 3-6 months. Finally, the abstention rate was 2.5%.

      Discussion

      Staging methods

      Likely because of its established role in risk stratification, the PSAdt is used by the vast majority of panel voters, notwithstanding differences in the number of PSA values used (Table 1). As in the previous edition of this expert panel, the predominant recommendation (66.7%) is to compute the PSAdt using the last three PSA levels and an electronic system. Interestingly, the lack of consensus—and dichotomy of recommendations between conventional and novel techniques—for the questions on imaging methods also recapitulates the results of the first version of this expert panel (Table 1).
      • Maluf F
      • Soares A
      • Avanco G
      • et al.
      Consensus on diagnosis and management of non-metastatic castration resistant prostate cancer in Brazil: focus on patient, selection, treatment efficacy, side effects and physician's perception according to patient comorbidities.
      These recommendations are consistent with individual clinical practice and likely related to the technology available in different institutions. PET-CT (or PET-MRI) imaging with PSMA is not available in public centers and is only available in some private centers in Brazil, a country with a dual healthcare system whereby services are provided under government funding or through private insurance. However, it is conceivable that different opinions about the role of novel imaging methods stem from different philosophical perceptions about the role of systemic therapy in different stages of the continuum of prostate cancer, particularly the transition between the non-metastatic and the oligometastatic state. Since this possibility has not been addressed by the panel, it remains speculative.
      Of note, the National Comprehensive Cancer Network (NCCN) guidelines support the use of conventional imaging in this setting.
      National Comprehensive Cancer Network
      NCCN Practice Guidelines in Oncology.
      Moreover, the definition of nmCRPC is not yet based on the need to rule out metastatic disease by more sensitive imaging modalities and is still largely based on conventional imaging.
      • Mateo J
      • Fizazi K
      • Gillessen S
      • et al.
      Managing Nonmetastatic Castration-resistant Prostate Cancer.
      In randomized trials of systemic therapy for patients with nmCRPC, eligibility was based on absence of metastases by conventional imaging.
      • Hussain M
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer.
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.
      However, this is an evolving field, and a recent randomized trial indicated that PET-CT with PSMA is superior to conventional imaging for detection of systemic disease in the setting of high-risk disease before curative-intent surgery or radiotherapy.
      • Hofman MS
      • Lawrentschuk N
      • Francis RJ
      • et al.
      Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.
      Likewise, a meta-analysis assessing the role of 68Gallium-PSMA scanning showed that, among patients with biochemical recurrence, the percentage of positive scans rises proportionally according to PSA levels.
      • Perera M
      • Papa N
      • Roberts M
      • et al.
      Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer-Updated Diagnostic Utility, Sensitivity, Specificity, and Distribution of Prostate-specific Membrane Antigen-avid Lesions: A Systematic Review and Meta-analysis.
      Finally, a recent large retrospective study showed that PSMA-PET is able to detect M1 disease in 55% of patients previously diagnosed with nmCRPC.
      • Fendler WP
      • Weber M
      • Iravani A
      • et al.
      Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer.
      Therefore, further studies are needed to clarify the role of PSMA-based imaging in defining nmCRPC.
      • Crawford ED
      • Andriole G
      • Freedland SJ
      • et al.
      Evolving understanding and categorization of prostate cancer: preventing progression to metastatic castration-resistant prostate cancer: RADAR IV.
      ,
      • Heidegger I
      • Brandt MP
      • Heck MM.
      Treatment of non-metastatic castration resistant prostate cancer in 2020: What is the best?.
      Of note, as of today, no prospective trial demonstrated a clinical benefit in adding next-generation imaging for staging nmCRPC. Furthermore, there is no evidence that metastasis-directed therapy beside newer systemic treatments with novel ARSi will modify the natural course of nmCRPC.
      Finally, the recommendation by nearly half of the panel members to consider PSMA-based imaging in patients with small pelvic lymph nodes was balanced by a similar percentage of recommendations for immediate treatment. It should be noted that the Selective Prostate Androgen Receptor Targeting with ARN-509 (SPARTAN) trial of apalutamide, the Androgen Receptor Antagonizing Agent for Metastasis-free Survival (ARAMIS) trial of darolutamide, and the PROSPER trial of enzalutamide allowed the inclusion of patients presenting pelvic lymph nodes below the aortic bifurcation (measuring <2 cm for SPARTAN and ARAMIS, and <1.5 cm for PROSPER).
      • Hussain M
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer.
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.
      ,
      • Small EJ
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide.
      • Sternberg CN
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.

      Antiandrogen therapy for nmCRPC

      Considering a newly diagnosed patient with nmCRPC, there was consensus among panel members (87.2%) that any of the novel ARSi would be the treatment of choice for initial management of most men with a life expectancy >10-15 years, a PSAdt ≤10 months and a serum PSA ≥2 ng/mL. These characteristics are consistent with the criteria that led to eligibility to the three pivotal trials of these agents.
      • Hussain M
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer.
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.
      ,
      • Small EJ
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide.
      • Sternberg CN
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.
      Likewise, there was also consensus for no systemic therapy in three other combinations of these patient characteristics which were not consistent with the eligibility criteria to the pivotal trials, as well as majority vote (68.3%) for no systemic therapy for a fourth combination. However, the specific setting of life expectancy <10-15 years PSAdt ≤10 months and a serum PSA ≥2 ng/mL also led to consensus recommendation (78.6%) of any of the novel androgen-signal inhibitors, even though life expectancy was not defined in this way as an entry criterion for the pivotal trials. Finally, for two combinations of PSAdt ≤10 months and a serum PSA <2 ng/mL, panel members were similarly divided between recommending any of the novel androgen-signal inhibitors or no systemic therapy until further PSA rises, something that reflects the current uncertainty in this field.
      The panel reached consensus or majority vote for some of the various decisions that are often required during treatment of patients with nmCRPC. Chemotherapy plays a key role in the management of patients progressing to mCRPC, and consensus or majority recommendations were achieved for the use of docetaxel for patients who progressed to mCRPC (regardless of time to castration resistance of PFS while on ARSi). These results are supported in the literature by the description of cross-resistance between ARSi and findings of limited responses when sequencing treatment with two ARSi.
      • Basch E
      • Loblaw DA
      • Oliver TK
      • et al.
      Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline.
      • Buck SAJ
      • Koolen SLW
      • Mathijssen RHJ
      • de Wit R
      • van Soest RJ.
      Cross-resistance and drug sequence in prostate cancer.
      • Khalaf DJ
      • Annala M
      • Taavitsainen S
      • et al.
      Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial.
      When asked about the decision to change treatment in patients with nmCRPC, nearly half of panel members indicated that two methods (PSA, clinical and radiological assessment) to ascertain progression should be used to trigger such a change, whereas nearly a third recommended clinical and radiological progression as the triggers. In ARAMIS, PROSPER and SPARTAN, the experimental agent (respectively darolutamide, enzalutamide and apalutamide) was discontinued when there was clinical or radiological progression, or given prespecified levels of toxicity.
      • Hussain M
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer.
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.

      Choice of specific novel androgen-signal inhibitors

      The lack of consensus about whether a positive PSMA-based imaging should change management when conventional imaging has disclosed no metastatic disease reflects the corresponding doubts in the current literature.
      • Fendler WP
      • Weber M
      • Iravani A
      • et al.
      Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer.
      ,
      • Heidegger I
      • Brandt MP
      • Heck MM.
      Treatment of non-metastatic castration resistant prostate cancer in 2020: What is the best?.
      Regarding the specific choice of novel ARSi, only apalutamide and enzalutamide were approved by the Brazilian regulatory authority (Anvisa) when the first edition of this expert panel was conducted.
      • Maluf F
      • Soares A
      • Avanco G
      • et al.
      Consensus on diagnosis and management of non-metastatic castration resistant prostate cancer in Brazil: focus on patient, selection, treatment efficacy, side effects and physician's perception according to patient comorbidities.
      Likewise, another previous consensus-development panel from Brazil was conducted before the approval of darolutamide in this country.
      • Pereira FMT
      • Silva AGE
      • Dettino ALA
      • et al.
      Consensus on the Treatment and Follow-Up for the Nonmetastatic Castration-Resistant Prostate Cancer: A Report From the First Prostate Cancer Consensus Conference for Developing Countries.
      Given the recent approval of darolutamide by Anvisa, there was considerable interest in assessing the comparative perception of these three agents. Interestingly, the panel indicated a seeming lack of clear preference for any specific agent when taking overall survival or quality of life into account, given positive results from all three agents.
      • Small EJ
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide.
      • Sternberg CN
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.
      ,
      • Saad F
      • Cella D
      • Basch E
      • et al.
      Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.
      • Smith MR
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide and health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: An analysis of the phase III ARAMIS trial.
      • Tombal B
      • Saad F
      • Penson D
      • et al.
      Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial.
      Nevertheless, when one specific agent was indicated in light of considerations about safety, tolerability and quality of life, darolutamide was the drug garnering more votes, likely as a consequence of more impactful results in these domains in comparison with placebo in the ARAMIS trial
      • Smith MR
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide and health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: An analysis of the phase III ARAMIS trial.
      and in indirect comparison with apalutamide and enzalutamide.
      • Hird AE
      • Magee DE
      • Bhindi B
      • et al.
      A Systematic Review and Network Meta-analysis of Novel Androgen Receptor Inhibitors in Non-metastatic Castration-resistant Prostate Cancer.
      • Kumar J
      • Jazayeri SB
      • Gautam S
      • et al.
      Comparative efficacy of apalutamide darolutamide and enzalutamide for treatment of non-metastatic castrate-resistant prostate cancer: A systematic review and network meta-analysis.
      • Mori K
      • Mostafaei H
      • Pradere B
      • et al.
      Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.
      • Wenzel M
      • Nocera L
      • Colla Ruvolo C
      • et al.
      Overall survival and adverse events after treatment with darolutamide vs. apalutamide vs. enzalutamide for high-risk non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.
      Even though novel ARSi are generally safe, toxicity is a major consideration when choosing treatment for this patient population, asymptomatic from the viewpoint of prostate cancer and typically with a long life expectancy. Apalutamide, darolutamide and enzalutamide are associated with variable rates of decreased appetite, fatigue, nausea, hot flashes, fractures, falls, skin rash, hypertension, cardiovascular complications, mental impairment, seizures, among other adverse events. For example, apalutamide was associated with rash of any grade in 23.8% of patients in the SPARTAN trial (versus 5.5% for placebo).
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      Fatigue was reported in 30.4% of nmCRPC patients treated with apalutamide, 33% of those treated with enzalutamide, and 12.1% of those treated with darolutamide, in all cases at higher rates than placebo.
      • Hussain M
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer.
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.
      The panel recommendations according to specific types of toxicity from each of the three novel ARSi mirror the recommendations related to safety and tolerability discussed above, and are generally supported by indirect comparisons between the agents, which as a rule have shown a better safety profile for darolutamide than the other two agents.
      • Hird AE
      • Magee DE
      • Bhindi B
      • et al.
      A Systematic Review and Network Meta-analysis of Novel Androgen Receptor Inhibitors in Non-metastatic Castration-resistant Prostate Cancer.
      • Kumar J
      • Jazayeri SB
      • Gautam S
      • et al.
      Comparative efficacy of apalutamide darolutamide and enzalutamide for treatment of non-metastatic castrate-resistant prostate cancer: A systematic review and network meta-analysis.
      • Mori K
      • Mostafaei H
      • Pradere B
      • et al.
      Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.
      • Wenzel M
      • Nocera L
      • Colla Ruvolo C
      • et al.
      Overall survival and adverse events after treatment with darolutamide vs. apalutamide vs. enzalutamide for high-risk non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.

      Prevention of skeletal-related events

      Bone is the leading metastatic site and a major cause of morbidity for patients with mCRPC, among whom both zoledronic acid and denosumab play a key role in delaying SREs.
      • Graff JN
      • Beer TM.
      Reducing Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.
      Only denosumab has been assessed in a randomized trial among patients with nmCRPC, and it significantly increased bone-metastasis-free survival when compared with placebo, although by only 4.2 months.
      • Smith MR
      • Saad F
      • Oudard S
      • et al.
      Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.
      Nevertheless, denosumab has not been approved for this patient population, given the unclear clinical relevance of the results. Although the literature in this regard is still relatively scant, there is no solid evidence that osteoclast-targeted therapy improves patient-relevant outcomes in patients with nmCRPC.
      • Smith MR
      • Kabbinavar F
      • Saad F
      • et al.
      Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.
      ,
      • Smith MR
      • Saad F
      • Oudard S
      • et al.
      Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.
      Probably as a reflection of the literature, there was consensus among panel members that neither zoledronic acid nor denosumab are indicated to prevent SREs in patients with nmCRPC.

      Patient follow-up

      There is no high-level evidence to guide the overall strategy for following-up patients with nmCRPC on active therapy. Nevertheless, physical examination and PSA levels every 3-6 months are recommended by the vast majority of panel members; nearly half would also add a bone scan every 3-6 months, whereas 37.5% recommended imaging only in the case of symptoms. Importantly, there is no perceived role for novel imaging methods currently.

      Conclusion

      As highlighted previously,
      • Maluf F
      • Soares A
      • Avanco G
      • et al.
      Consensus on diagnosis and management of non-metastatic castration resistant prostate cancer in Brazil: focus on patient, selection, treatment efficacy, side effects and physician's perception according to patient comorbidities.
      this type of survey has limitations. The opinions are elicited through a voting system, which assumes prior knowledge on the topics discussed. The recommendations by individual panel members may be influenced by individual access to newer diagnostic tools or treatment modalities; since that access may be subject to constraints in different healthcare settings in Brazil, there is a potential influence on recommendations. This may be particularly relevant for novel imaging methods. We also consider that with advances in new imaging modalities a multidisciplinary team should be an optimal approach for nmCRPC, including discussions with radiotherapists for oligometastatic disease. We should point out, however, that the extent to which lack of consensus for some of the questions was due to characteristics at the country level or at the professional level, such as respectively specificities of the healthcare system or physician specialty, lack of sufficient data, has not been ascertained in the current work. Nevertheless, the low percentages of abstentions suggest that the topics chosen are relevant in current practice and that panel members indeed have variable preferences for many of the clinical issues discussed. Regardless of these limitations, we believe the current recommendations—and future updates in light of new knowledge—can help practicing clinicians best provide state-of-the-art treatment to patients with nmCRPC (Table 6).
      Table 6Areas of consensus (≥75% agreement) and important topics with no consensus in nmCRPC.
      TopicResult
      Areas of Consensus
      Preferred systemic therapy considering survival dataAny of the ARSi (apalutamide, darolutamide, enzalutamide)
      Drug of choice for most patients with nmCRPC and osteoporosisAny of the ARSi (apalutamide, darolutamide, enzalutamide)
      Choice for a patient with clinical metastases after failing treatment for nmCRPC, who previously progressed to CRPC in less than 12 monthsConsensus was obtained for Docetaxel
      What to do in patients with nmCRPC and PSA response to <0.2 ng/mL after ARSiContinue therapy with no interruption
      Consideration about osteoclast-targeted therapy in nmCRPC patientsPanelists recommended against osteoclast-targeted therapy to prevent SREs
      Topics with no Consensus
      Staging imaging for nmCRPC patientsNo consensus, with similar number of panelists recommending next generation imaging (PSMA-PET) and conventional imaging
      Change of management if positive PSMA-based and negative conventional imagingHalf of the panel would change management in case of PSMA-only detected lesions
      ARSi preference in nmCRPCAny of the ARSi (apalutamide, darolutamide, enzalutamide) was generally recommended, with increase preference for darolutamide when safety, tolerability and mental impairment was considered
      Abbreviations: ARSi: androgen receptor signaling inhibitor; SREs: skeletal-related events

      Credit Author Statement

      Denis L. Jardim: Conceptualization, Methodology, Investigation, Writing – Original Drafting, Review & Editing, Data Curation, Adriano Gonçalves e Silva, Alexandre Saad Fere Lima Pompeo, Alvaro Sadek Sarkis, Ana Paula Garcia Cardoso, Andre Deeke Sasse, Andre Poisl Fay, Andrey Soares, Antonio Carlos Lima Pompeo, Arie Carneiro, Ariel Galapo Kann, Camilla Fogassa, Celso Heitor De Freitas Junior, Daher Cezar Chade, Daniel Herchenhorn, Daniel Vargas Pivato De Almeida, Diogo Augusto Rodrigues Da Rosa, Evanius Garcia Wiermann, Fabio Augusto Barros Schutz, Fabio Roberto Kater, Fernando De Moura, Fernando Korkes, Fernando Meyer, Fernando Nunes Galvao De Oliveira, Fernando Sabino, Gilberto Laurino Almeida, Guilherme Avanço, Gustavo Cardoso Guimaraes, Gustavo Caserta Lemos, Gustavo Franco Carvalhal, Hanna Kim, Igor Protzner Morbeck, Joao Carlos Campagnari, Jose Augusto Rinck Junior, José Ricardo Tuma Da Ponte, Karine Martins Da Trindade, Leonardo Atem, Leonardo Borges, Lucas Mendes Nogueira, Lucas Teixeira e Aguiar Batista, Manuel Caitano Maia, Marcus Vinicius Sadi, Maria Alzira Almeida Rocha, Murilo De Almeida Luz, Oren Smaletz, Paulo Sergio Moraes Lages, Raquel Midori Koga Matuda, Rodolfo Borges Dos Reis, Rodrigo Frota Indio, Roni De Carvalho Fernandes, Sandro Roberto Cavallero, Vinicius Carrera Souza, Wilson Busato Jr, Wladimir Alfer Junior: Investigation and Writing –Review & Editing, Fernando Maluf: Conceptualization, Methodology, Investigation, Writing – Original Drafting, Review & Editing, Data Curation, Supervision, Funding acquisition

      Clinical Practice Points

      • Medical oncologists and urologists managing patients with non-metastatic, castration-resistant prostate cancer face in increasing number of choices to be made regarding staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up. Importantly, novel androgen-receptor signalling inhibitors are changing the therapeutic landscape for this disease. This paper reports recommendations of an expert panel convened to address these issues.

      Funding

      This study was funded by Bayer.

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