920067 research-article20202020 TAM0010.1177/1758835920920067Therapeutic Advances in Medical OncologyJ Puente, U Anido1 Therapeutic Advances in Medical Oncology Original Research Expert recommendations on the Ther Adv Med Oncol 2020, Vol. 12: 1­–12 management of patients with metastatic DOI: 10.1177/ https://doi.org/10.1177/1758835920920067 https://doi.org/10.1177/1758835920920067 1758835920920067 castration-resistant prostate cancer who © The Author(s), 2020. Article reuse guidelines: sagepub.com/journals- progress after CHAARTED or LATITUDE permissions Javier Puente, Urbano Anido, Miguel Ángel Climent, Enrique Gonzalez-Billalabeitia, Nuria Lainez, Julio Lambea, José Pablo Maroto, Maria Jose Mendez-Vidal, Álvaro Montesa, Angel Rodriguez, Curro Zambrana and Aránzazu González-del-Alba Correspondence to: Aránzazu González-del- Alba Medical Ongology Abstract Department, Hospital Universitario Puerta de Objective: Our aim was to provide practical recommendations on the management of patients Hierro Majadahonda, with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after Calle Joaquin Rodrigo 2, Majadahonda, Madrid docetaxel plus androgen-deprivation therapy (ADT) or abiraterone plus ADT. 28222, Spain aranzazu.gonzalezalba@ Methods: Systematic literature review (SLR), nominal group meeting, and Delphi process. salud.madrid.org A panel of 12 experts was established who defined the scope, users, and sections of the Javier Puente document. We performed an SLR in order to assess the efficacy and safety of available drugs Medical Oncology Department, Hospital in patients with mCRPC. Abstracts from the American Society of Oncology and European Clínico San Carlos, Instituto de Investigación Society for Medical Oncology meetings were also examined. The results were discussed Sanitaria del Hospital during an expert meeting in which 14 recommendations were generated. The level of Clínico San Carlos (IdISSC), CIBERONC, agreement with the recommendations was also tested by 13 additional experts following Madrid, Spain the Delphi process. Recommendations were voted by means of scores ranging from 0 (total Urbano Anido Oncology Department, disagreement) to 10 (total agreement). We defined agreement when at least 70% of the Complejo Hospitalario experts voted ⩾7. Next, we assigned a level of evidence and grade to the recommendation Universitario de Santiago, Santiago de Compostela, using the Oxford Centre for Evidence-based Medicine Levels of Evidence, following which the Spain final document was drafted. Miguel Ángel Climent Medical Oncology Results: The literature search did not find any articles meeting the inclusion criteria. Department, Instituto Valenciano de Oncología Finally, 13 out of 14 recommendations were accepted after two Delphi rounds (two were (IVO), Valencia, Spain modified after the first round). They pertain to general and individual case-based treatment Enrique Gonzalez- recommendations. Billalabeitia Hematology & Medical Conclusions: In mCRPC patients who have progressed after docetaxel or abiraterone plus ADT Oncology Department, Hospital Universitario in the metastatic hormone-sensitive prostate cancer setting, these recommendations may Morales Meseguer, IMIB- support treatment decision-making, due to the lack of evidence or other globally accepted Universidad de Murcia, Murcia, Spain; Universidad sequencing algorithms. Católica San Antonio de Murcia-UCAM, Murcia, Spain Keywords: abiraterone acetate, androgen-deprivation therapy, chemotherapy, enzalutamide, Nuria Lainez Medical Oncology metastatic castration-resistant prostate cancer, radium-223 Department, Complejo Hospitalario de Navarra, Pamplona, Spain Received: 29 July 2019; revised manuscript accepted: 19 March 2020. Julio Lambea Medical Oncology Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain Introduction hormone-sensitive prostate cancer (mHSPC), José Pablo Maroto Prostate cancer is still a leading cause of death continuous androgen-deprivation therapy (ADT) Medical Oncology Department, Hospital de worldwide largely due to metastatic disease.1 For represented the standard of care until 2015, when la Santa Creu i Sant Pau, patients with an initial diagnosis of metastatic trials such as the Androgen Ablation Therapy Barcelona, Spain journals.sagepub.com/home/tam 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Medical Oncology 12 Maria Jose Mendez- with or without Chemotherapy in Treating other comprehensive literature searches across Vidal Medical Oncology Patients with Metastatic Prostate Cancer international oncology congresses. All processes Department, Hospital (CHAARTED)2 showed that ADT combined were supervised by a methodologist. The expert Universitario Reina Sofia, Córdoba, Spain with six courses of docetaxel (DOC) significantly panel comprised 12 oncologists with recognized Álvaro Montesa prolonged/extended the overall survival (OS) of experience in the management of prostate cancer. Medical Oncology patients with high-volume disease. Similarly, in Two were also coordinators of the project. Department, Hospital Regional de Málaga, 2017, the LATITUDE trial demonstrated that Málaga, Spain adding abiraterone acetate (ABI) and prednisone Angel Rodriguez to ADT significantly increased OS and radio- SLR Medical Oncology Department, Hospital de graphic progression-free survival in mHSPC men A SLR was performed to address the experts’ León, León, Spain with high-risk features.3 These trials contributed questions regarding the management of patients Curro Zambrana Medical Oncology to modifying the initial treatment approach of with mCRPC who have progressed after on ADT Department, Hospital mHSPC. plus DOC or ADT plus ABI. For this purpose, a Universitario Infanta Sofía, San Sebastián De protocol was defined with the coordinators and Los Reyes, Spain In the previous years, several agents were approved the preferred reporting items for systematic for the management of men with mCRPC, includ- reviews and meta-analyses (PRISMA) statement ing ABI,4 enzalutamide (ENZ),5 radium-223,6 was followed.9 cabazitaxel (CAB),7 and sipuleucel-T.8 None­ theless, little is known about optimal sequencing and combination strategies, or how cross-resist- Search strategy ance is likely to affect subsequent treatments in Studies were identified by sensitive search strate- the continuum of patient care. gies in the main bibliographic databases (supple- mental data). An expert librarian collaborated On the other hand, patients following with the expert panel and checked the search CHAARTED and LATITUDE strategies will strategies. The following bibliographic databases likely progress later on to metastatic castration- were screened: Medline and Embase from 1961 resistant prostate cancer (mCRPC). Therefore, to 11 January 2018, and Cochrane Central regis- in the near future, many patients presently on ter of Controlled Trials (CENTRAL) up to 11 these new schemes will progress and be seen in January 2018. We used specific Medical Subject daily practice, while the available evidence to Headings (MeSH) and additional keywords to define the best next step proves to be scarce. identify studies. The strategy combined disease and treatment terms as listed above, with a con- In 2018, there was no robust evidence to define trolled vocabulary to describe any of them. All the the best next step for patients progressing to the retrieved references were managed using Endnote castration-resistant state after ADT plus DOC X5 (Thomson Reuters). (CHAARTED) or ABI (LATITUTE). Therefore, the aim of this document is to provide practical The abstracts of the scientific meetings of the recommendations for the management of patients American Society of Oncology (ASCO/ in this setting. These recommendations are based ASCOGU; 2017, 2018) and European Society on the available evidence and experience of a for Medical Oncology (ESMO; 2016, 2017) were panel of prostate cancer experts, covering com- similarly examined through simple keywords in mon clinical scenarios and the characteristics of the organizations’ websites. patients attended in daily practice. We are confi- dent that these recommendations are likely to support health professionals involved in the treat- Study selection ment of these patients in the decision-making The studies retrieved by the search strategies were process. incorporated if they met the following pre-estab- lished inclusion criteria: (a) involving mCRPC patients who have progressed after on ADT plus Methods DOC or ADT plus ABI; (b) focusing on those The nominal group and Delphi techniques were who start a new available antineoplastic treatment, employed to elaborate the consensus. The docu- such as DOC, CAB, ABI, ENZ, or radium-223; ment was created following the distribution of (c) analyzing outcomes that are usually evaluated tasks and comments to the participants with the in mCRPC trials, such as OS, PFS, prostate-spe- help of a systematic literature review (SLR) and cific antigen (PSA) response or progression, 2 journals.sagepub.com/home/tam J Puente, U Anido et al. radiographic response or progression, quality of recommendations were rephrased several times life, and safety; (d) meta-analyses, systematic during the meeting in order to achieve the best reviews, randomized clinical trials (RCT) were wording and the maximum level of agreement. solely selected, as were English and Spanish For each clinical scenario, specific patient profiles ­articles. We excluded articles on animals, basic sci- and treatments were similarly considered, in addi- ence, as well as publications analyzing sipuleucel-T, tion alternative treatment possibilities. as this product has been withdrawn from use in the European Union. Delphi and final document Finally, a hand search was conducted by review- After several expert reviews, definitive recom- ing the references of the included studies, along mendations were generated and subsequently with all the publications or other information submitted to on-line Delphi voting. Delphi was related to the SLR provided by the experts. extended to a group of 24 oncologists with experi- ence in the management of patients with prostate cancer. The participants voted each recommen- Screening of studies, data collection, quality dation using a scale ranging from 0–10 (0 = totally evaluation, and data analysis disagree; 10 = totally agree). Agreement was These processes were performed by two review- obtained when at least 70% of the participants ers. Both reviewers independently screened the voted ⩾7. The recommendations with a lower titles and abstracts of the retrieved articles for level of agreement (LA) were reassessed and, if selection criteria. When the reviewers encoun- appropriate, re-edited and voted in a second tered any discrepancy, a consensus was reached Delphi round. by including a third reviewer (LC). After the arti- cles originating from the selection process had Subsequently, the final document was written. been read in detail following the same principles, For each recommendation, the level of evidence a list of studies to be included was established. (LE) and grade of recommendations (GR) were Afterwards, the reviewers collected the articles applied according to the Oxford Centre for data independently. As in previous phases, in the Evidence Based Medicine Guidelines,11 along event of discrepancies, a consensus was reached with the LA according to the Delphi process, as by looking at the original article or by including a previously presented. The document was then third reviewer (LC). distributed to the experts for final assessment and comments. To grade the quality, we used the Jadad score10 for RCT and a modification of The Oxford Centre for Evidence-based Medicine Levels of Results Evidence in its updated version of May 201111 for the remaining study designs. Evidence tables SLR and Delphi results were produced. Meta-analysis was only sched- The SLR retrieved more than 5000 articles. We uled when enough homogeneity existed among additionally analyzed 633 abstracts from ASCO/ the included studies. ASCO-GU and ESMO meetings, yet none met the inclusion criteria (see supplemental data). As described in the methods section, due to a lack of Nominal group meeting robust evidence the experts based their recom- The expert panel held a nominal group meeting mendations on other aspects like their experience, in which objectives, scope, and users were patients/disease/health system characteristics, defined. Then, the results of the SLR and of the indirect data from other RCTs, and preliminary ASCO/ASCOGU and ESMO meetings were pre- published data. Finally, we show the preliminary sented and discussed. Taking into account the data (from observational studies or phase I–II lack of robust evidence, the experts considered RCTs) captured from the project. their experience, patients/disease/health system characteristics, indirect data from other RCTs, The expert panel generated 14 recommendations and preliminary published data (observational that were voted. The Delphi response rate was studies). Through a guided discussion, different 70%. All but one recommendation achieved the clinical scenarios were addressed and recommen- pre-established LA in the first round. During this dations for optimal treatment proposed. These round, however, the Spanish Medicine Agency journals.sagepub.com/home/tam 3 Therapeutic Advances in Medical Oncology 12 issued a press release recommending a restriction General recommendations are presented below in the use of radium-223 (Xofigo©) to only and in Table 1, with a treatment algorithm patients who have undergone two previous treat- depicted in Figure 1. ments for mCRPC or were not eligible for any other systemic treatment (see recommendations 12 and 13). As two of the recommendations were Recommendations (general settings and related to the use of radium-223 (one did not specific profiles) obtain agreement), they were re-formulated and Recommendation 1. In patients with mCRPC evaluated in a second Delphi round, with only who have progressed after ADT+DOC treat- one eventually accepted. ment (1st line) and present a time-to-­ progression up to 6 months from the last cycle of DOC, the panel considers CAB to be General considerations and other evidence preferable (LE 4; GR D; LA 90%). Despite the lack of robust evidence, there are some observational data concerning patients with The panel considers it important to highlight that mCRPC who have progressed after undergoing time-to-progression is an essential factor to con- DOC plus ADT or ABI plus ADT that we would sider. Although it is not possible to establish what like to briefly describe. this time should be, 6 months seem to be an acceptable cut-off. A small case series supports A recent retrospective study has shown that the use of CAB if the time-to-progression is less rechallenging with DOC at castration-resistance than 6 months following upfront DOC.17 In any was only active in a limited number of patients case, close monitoring is highly recommended. (14%) treated upfront with ADT plus DOC for metastatic castration-naive prostate cancer.12 As previously exposed, there are factors that must Though based on a small number of patients, similarly be considered, such as previous toxicity anticancer activity was observed with ABI or ENZ of chemotherapy and the patient′s health status. in this article.12 In line with this finding, another For example, for patients with poor chemother- small-sized retrospective observational study apy tolerance, ABI or ENZ should be considered. seemed to support these data.13 These drugs have shown benefits in a small-sized case series of patients who progressed after We would like to point out that the decision-mak- ADT+DOC treatment.18 ing process for these patients must take into account several aspects, especially the time-to- Similarly, for patients who develop asymptomatic progression, patient’s performance status and fit- or PSA-only progression, ABI or ENZ are alter- ness for a specific treatment,14 and previous and native options, whereas in this setting, the panel potential drugs toxicities or cross-resistance recommends close monitoring of drug efficacy so between treatments. Yet, there are also patients as to allow for switching to other treatments in the with other characteristics (high volume, visceral event of inefficacy or of clinical doubts regarding disease, aggressive variants, etc.) for whom an efficacy. individual case-based strategy appears to be most appropriate, as we will further explain later on. Recommendation 2. In patients with mCRPC who have progressed during treatment with In addition, the panel considers that treatment ADT+DOC (1st line), the panel considers decisions should be individualized according to CAB to be preferable (LE 5; GR D; LA the physicians’ experience and patients’ charac- 90%). teristics and preferences. Therefore, patient infor- mation and discussions prove to be crucial. Considering the rapid progression during ADT, it could be assumed or should be borne in mind Of note is that there is evidence supporting drug- that these patients will not respond as expected to sequencing in mCRPC patients who were only second-generation antihormonal drugs. Although treated following progression after ADT, and more studies are required to confirm this, CAB these data may likewise contribute to the decision can be beneficial in patients with rapid progres- making.15,16 sion during DOC.17,19 4 journals.sagepub.com/home/tam J Puente, U Anido et al. Table 1. Recommendations and results of the Delphi process. # Recommendation Mean SD Median P25 P75 Min Max % ⩾7 LE GR 1 In patients with mCRPC who have 8.04 2.3 9 7 9 1 10 90% 4 D progressed after ADT+DOC treatment (1st line) and present a time-to-progression up to 6 months from the last DOC cycle, the panel considers CAB to be preferable 2 In patients with mCRPC who have 8.72 1.3 9 8 10 6 10 90% 5 D progressed during treatment with ADT+DOC (1st line), the panel considers CAB to be preferable 3 In patients with mCRPC who have 7.4 2.7 8 7 9 1 10 75% 5 D progressed after ADT+DOC treatment (1st line) and only present biochemical progression, the panel considers either ABI or ENZ to be preferable 4 In patients with mCRPC who have 8.16 2.3 9 8 10 1 10 85% 5 D progressed after ADT+DOC treatment (1st line) and present clinical or radiographic progression, the panel considers it appropriate to analyze other factors before making a final treatment decision 5 In patients with mCRPC who have 8.72 1.7 9 8 10 3 10 90% 5 D progressed after ADT+DOC treatment (1st line) and present visceral metastases (hepatic), the panel considers chemotherapy to be preferable 6 In patients with mCRPC who have 6.6 2.6 7 6 8 1 10 70% 5 D progressed after ADT+DOC treatment (1st line) and present an ECOG score ⩾2, the panel considers either ABI or ENZ to be preferable 7 In patients with mCRPC who have 8.2 1.8 9 7 10 3 10 85% 5 D progressed after ADT+DOC treatment (1st line) and present an ECOG score ⩾2, deemed to be cancer-related, the panel considers chemotherapy to be a potential treatment option 8 In patients with mCRPC who have 8.88 1.3 9 8 10 5 10 95% 5 D progressed after ADT+DOC treatment (1st line) and present aggressive disease, the panel considers platinum-based combinations as treatment option 9 In patients with mCRPC who have 8.8 1.7 9 8 10 2 10 95% 5 D progressed after ADT+DOC treatment (1st line) and present neuroendocrine variants without aggressive disease criteria, the panel considers that platinum-based combinations are preferable (Continued) journals.sagepub.com/home/tam 5 Therapeutic Advances in Medical Oncology 12 Table 1. (Continued) # Recommendation Mean SD Median P25 P75 Min Max % ⩾7 LE GR 10 In patients with mCRPC who have 6.92 2.5 8 7 8 1 10 70% 5 D progressed after ADT+DOC treatment (1st line) and exhibit poor tolerance to chemotherapy, the panel considers either ABI or ENZ to be preferable 11 In patients with mCRPC who have 8.92 1.9 10 9 10 1 10 90% 5 D progressed after ADT+ABI treatment (1st line), the panel considers DOC to be generally preferable 12 Taking into account the new EMA 7.41 3.2 9 5 10 1 10 71% 5 D restrictions regarding the use of radium-223 in patients with mCRPC who have progressed after ADT+ DTX treatment, the panel considers radium-223 as an treatment option in patients with symptomatic bone metastases without visceral disease, and with high-volume disease, but only in patients who have previously failed two previous treatments for mCRPC or have no other treatment alternatives 13 In patients with mCRPC who have 4.41 2.6 4 3 6 1 10 24% 5 D progressed after ADT+ABI treatment (1st line) and are unfit according to SIOG criteria, the panel considers ENZ to be preferable, taking into account thatradium-223 is restricted to patients who have previously failed in two treatments for mCRPC or have no other cancer treatment alternatives 14 In any treatment decision-making, the 8.24 2.4 9 7 10 1 10 85% 5 D panel considers it crucial to take into account the patient’s preferences ABI, abiraterone; ADT, androgen-deprivation therapy; CAB, cabazitaxel; DOC, docetaxel; ECOG, Eastern Cooperative Oncology Group; EMA, European Medicines Agency; GR, grade of recommendation; LE, level of evidence; Max, maximum; mCRPC, metastatic castration-resistant prostate cancer; Min, minimum; p25, percentile 25; p75, percentile 75; SD, standard deviation; SIOG, International Society of Geriatric Oncology. Recommendation 3. In patients with mCRPC into account both the patients comorbidities and who have progressed after ADT+DOC treat- drug characteristic features. ment (1st line) yet only present biochemical progression, the panel considers ABI or ENZ Recommendation 4. In patients with mCRPC (LE 5; GR D; LA 75%) to be preferable. who have progressed after ADT+DOC treat- ment (1st line) and present clinical or radio- The COU-AA-3013,20 and AFFIRM trials21 eval- graphic progression, the panel considers it uated the efficacy and safety of ABI and ENZ ver- appropriate to analyze other factors before sus placebo in patients with mCRPC progressing making a final treatment decision (LE 5; GR after DOC. Both trials depicted a dramatic PSA- D; LA 85%). response. Given that there is no direct comparison between ABI and ENZ and because of apparent Given this clinical scenario, due to the lack of direct similar efficacy and acceptable safety profiles, or indirect evidence in favor of a specific drug, the treatment selection must be individualized, taking panel proposes to base treatment decisions on other 6 journals.sagepub.com/home/tam J Puente, U Anido et al. variables and outcomes, (such as time-to-progres- sion, the presence of symptoms and symptom without visceral disease + high- Symptomac bone metastases volume disease + failure to 2 ABI, abiraterone acetate; ADT, androgen-deprivation therapy; CAB, cabazitaxel; CT, Chemotherapy; DOC, docetaxel; ECOG, Eastern Cooperative Oncology Group performance status; alternave treatments intensity, previous therapeutic response and treat- treatments or have no ment toxicity, location of metastases, comorbidi- P: Radium-223 ties, etc.) SP* Recommendation 5. In patients with mCRPC Progressed aer ADT + ABI who have progressed after ADT+DOC treat- ment (1st line) and present hepatic metasta- ses, the panel considers chemotherapy to be preferable (LE 5; GR D; LA 90%). In general Owing to the poor cancer prognosis when associ- P: DOC SP* ated with many visceral metastases (in general), but especially hepatic metastases, the panel Figure 1. Treatment algorithm for patients with mCRPC upon DOC or ABI plus ADT (1st line) in metastatic prostate cancer. agreed on recommending chemotherapy. Yet, there may be patients, such as those with elevated 2. Neuroendocrine variants without aggressive disease PSA levels or poor health status, in whom ENZ P: Pt combinaons 1. Aggressive disease administration could be assessed. If ENZ turns out to be the final treatment decision, close moni- SP* toring of ENZ efficacy must be performed. In other cases, such as small number/size of metasta- *Check within the main test the treatment options according to other patients or disease particular characteristics. ses, certain metastasis localizations, or longer time-to-progression, a different treatment to Paents with mCRPC mCRPC, metastatic castration-resistant prostate cancer; P, preferable; PT, platinum; SP, special profiles. chemotherapy could be considered as well. Assess other radiographic progression Clinical or factors Recommendation 6. In patients with mCRPC who have progressed after ADT+DOC treat- ment (1st line) and present an ECOG score ⩾2, the panel considers ABI or ENZ to be ECOG ≥2 due P: ABI, ENZ, CT to cancer preferable (LE 5; GR D; LA 70%). SP* Recommendation 7. In patients with mCRPC who have progressed after ADT+DOC treat- ment (1st line) and present an ECOG score ⩾2, deemed to be cancer-related, the panel metastases Visceral considers chemotherapy to be a potential P: CT Progressed aer ADT + DOC SP* treatment option (LE 5; GR D; LA 85%). A patient with an impaired performance status 1. Biochemical progression may, in general, be ruled out for chemotherapy, 3. Poor tolerance to CT as this setting is associated with both poor prog- P: ABI, ENZ nosis and reduced drug tolerance.22 However, if SP* 2. ECOG ≥2 the performance status is deemed to be related to disease progression and when the clinician con- siders it to be possibly reversible, chemotherapy could be discussed with the patient and, if agreed 1. Time to progression ≤6 months upon, delivered following appropriate dose and 2. Progression during ADT+DOC schedule adjustments. Recommendation 8. In patients with mCRPC P: CAB who have progressed after ADT+DOC treat- SP* ment (1st line) and present aggressive dis- ease, the panel considers platinum-based combinations as treatment option (LE 5; GR D; LA 95%). journals.sagepub.com/home/tam 7 Therapeutic Advances in Medical Oncology 12 The sequence of first-line carboplatin plus DOC to be generally preferable (LE 5; GR D; LA followed by second-line etoposide plus cisplatin 90%). was evaluated in a phase II trial that involved 120 mCRPC patients with at least one anaplastic As in other general settings, patients with poor clinical criterion.23 It was found that, of the seven ECOG performance status may benefit from “anaplastic” criteria, bulky tumor mass was sig- other treatment options. The panel has addition- nificantly associated with poor outcome, lactic ally considered the possibility of cross-resistance acid dehydrogenase strongly predicted OS (and between ABI and ENZ.30,31 It should indeed be rapid progression), and serum carcinoembryonic noted that cross-resistance among different treat- antigen concentration strongly predicted OS (but ments for mCRPC was reported.19,32 not rapid progression), whereas neuroendocrine markers were unable to predict outcome or Recommendation 12. Considering the new response to therapy. The authors conclude that EMA restrictions with respect to radium-223, patients with “anaplastic” prostate cancer are a for patients with mCRPC who have pro- recognizable subset, characterized by a high gressed after ADT+DOC treatment (1st response rate of short duration to platinum-con- line), the panel considers the possibility of taining chemotherapies. More recently, a phase using radium-223 in patients with sympto- I–II RCT has shown promising activity with car- matic bone- and high-volume disease, yet boplatin added to CAB in metastatic castration- only in those who have failed in two previous resistant prostate cancers.24 Although the results treatments for mCRPC or for whom no require further confirmation, these findings may alternative treatments are available (LE 5; support decision-making in patients with mCRPC GR D; LA 71%). and aggressive disease. We have previously commented that, as a conse- Recommendation 9. In patients with mCRPC quence of the EMA restriction press release dur- who have progressed after ADT+DOC treat- ing the first Delphi round, the original ment (1st line) and present neuroendocrine recommendation that stated that radium-223 variants without other “anaplastic” disease could be considered in patients with mCRPC criteria, the panel considers platinum-based who have progressed after ADT+ABI treatment combinations as treatment option (LE 5; GR (1st line) and present symptomatic bone metasta- D; LA 95%). ses without visceral disease was rephrased, thereby clearly limiting the indications for Different non-randomized, retrospective studies radium-223. Despite the EMA restrictions, this have demonstrated platinum-based chemothera- recommendation reached the stated agreement pies to be active in men with neuroendocrine level. prostate cancer.25–27 Therefore, platinum-based chemotherapy is a treatment option for these Recommendation 13. In patients with patients with poor prognosis. mCRPC who have progressed after ADT+ABI treatment (1st line), yet are unfit Recommendation 10. In patients with mCRPC for chemotherapy according to the Inter­ who have progressed after ADT+DOC treat- national Society of Geriatric Oncology ment (1st line) and exhibit poor tolerance to (SIOG) criteria, the panel considers ENZ to chemotherapy, the panel considers ABI or be preferable, taking into account that using ENZ to be preferable (LE 5; GR D; LA 70%). radium-223 is restricted to patients who have previously failed in two treatments for Poor tolerance to previous chemotherapy generally mCRPC or have no alternative cancer treat- guides the selection of a different drug class for sub- ments available (LE 5; GR D; LA 24%). sequent treatment lines.28,29 Nevertheless, as ABI and ENZ are also associated with undesirable The original recommendation claimed that, in effects, clinicians must be familiar with the diagno- this patient group, radium-223 could be consid- sis and management of these undesirable effects.29 ered in those with symptomatic bone metastases without visceral disease, or for palliative care. Recommendation 11. In patients with Following the EMA restrictions, this recommen- mCRPC who have progressed after ADT+ABI dation was, however, rephrased the same way as treatment (1st line), the panel considers DOC the previous recommendation, thereby restricting 8 journals.sagepub.com/home/tam J Puente, U Anido et al. the use of radium-223. Nonetheless, the level of like the ENZAMET and TITAN trial might also agreement obtained for this case scenario turned contribute.33,36,37 To formulate recommenda- out to be poor. tions, we therefore considered several different scenarios, such as pattern of progression, time to This recommendation will be further discussed in develop mCRPC, presence of clinical aggressive the next section. disease, patient health status, prior tolerance to chemotherapy, cross-resistance between drugs, as Recommendation 14. For any treatment well as tumor histology. decision, the panel considers it essential that clinicians and patients work together to The lack of evidence in mCRPC following the make healthcare choices that primarily con- referred schemes thus resulted in recommenda- sider the patient’s preferences and values tions with a very low evidence level. Nevertheless, (LE 5; GR D; LA 85%). we would like to highlight that following the Delphi process, for all except one recommenda- To select the optimal treatment for a given tion, agreement was reached with a high level of patient, the decision-making process must unde- agreement for most recommendations. In our niably seek the patient′s participation, evidence- view, this markedly increases the validity of the based information regarding treatment options, recommendations herein presented. and experience and knowledge of the treatment provider. As described in the results section, two recom- mendations that included radium-223 were rephrased following the release of EMA restric- Discussion tions, with one not reaching the pre-established The results of CHAARTED and LATITUDE level of agreement. This recommendation pro- trials,2,3,33 along with the approval of several new posed ENZ to be the first preference in patients drugs,4–8 have raised new questions and issues as with mCRPC who have progressed after for the management of mCRPC. In this setting, ADT+ABI treatment and are unfit according to the impact of upfront DOC or ABI plus ADT on SIOG criteria. Given this context, the disagree- subsequent therapies has so far been poorly ment may be partly accounted for by the fact explored. that DOC could be a therapeutic option, yet with some reservation as for the patient health In this research, we sought to create practical rec- status. This could still be an option, bearing in ommendations for different clinical scenarios, mind the possibility of cross-resistances between which prove to be quite common in daily prac- ABI and ENZ. Yet, this could be a clear sce- tice. As there are no randomized controlled trials nario for radium-223 administration in other pertaining to this clinical setting, we performed a patients. Nevertheless, radium-223 is now rec- comprehensive literature search using not only ommended for patients who have either previ- the main medical databases, but also the proceed- ously failed in two treatments or have no ings of international congresses and scientific alternative cancer treatments available. meetings. We decided to deliver a treatment algo- Likewise, this may explain the disagreement rithm and formulate recommendations for gen- concerning this recommendation. eral clinical scenarios, and provide some guidance for specific situations within these scenarios. In summary, treating metastatic prostate cancer is Finally, we limited our work so as to define the proving increasingly complex and challenging. first-line treatment for mCRPC following pro- While the introduction of the CHAARTED, gression in the metastatic hormone-naïve state. STAMPEDE, and LATITUDE schemes have clearly improved the prognosis of patients with Concerning the different clinical scenarios, we metastatic hormone-naïve prostate cancer, they would like to comment on several issues that were have also altered the traditional sequencing when discussed during the project. Recent observa- castration-resistance occurs, yet with only scarce tional studies have shown that baseline character- evidence available to guide treatment decisions. istics of CRPC disease could help identify the Therefore, we are now confident that our recom- best therapy option for patients previously treated mendations for different clinical scenarios will with DOC or ABI+ADT in mHSPC.34,35 The support health professionals involved in the care same way data from RCTs in mHSPC patients of these patients. journals.sagepub.com/home/tam 9 Therapeutic Advances in Medical Oncology 12 Acknowledgements location. Am J Mens Health 2018; 12: We would like to thank Luis León Mateos, 1807–1823. Natalia Fernández Nuñez, Martín Lázaro 2. Sweeney CJ, Chen YH, Carducci M, et al. Quintela, Sergio Vázquez Estevez, Ovidio Chemohormonal therapy in metastatic hormone- Fernández Calvo, Francisco Javier Afonso sensitive prostate cancer. N Engl J Med 2015; Afonso, Rodrigo Lastra, Pablo Gajate Borau, 373: 737–746. Carlos Aguado, Guillermo de Velasco, Carlos 3. Fizazi K, Scher HI, Molina A, et al. Abiraterone Álvarez Fernández, María Sereno Moyano, and acetate for treatment of metastatic castration- Diego Soto de Prado for their participation in the resistant prostate cancer: final overall survival Delphi process. analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Author contributions Lancet Oncol 2012; 13: 983–992. All of the authors contributed in the study design, 4. de Bono JS, Logothetis CJ, Molina A, et al. analysis and interpretation of data, drafting the Abiraterone and increased survival in metastatic article, and revising it critically. All of them have prostate cancer. N Engl J Med 2011; 364: also approved the final draft. 1995–2005. 5. Beer TM, Armstrong AJ, Rathkopf DE, et al. Conflict of interest statement Enzalutamide in metastatic prostate cancer before Javier Puente has received honoraria as consult- chemotherapy. N Engl J Med 2014; 371: ant on advisory boards from Pfizer, Astellas, 424–433. Janssen, MSD, Bayer, Roche, BMS, Boehringer, Astra Zeneca, Ipsen, Novartis, Eusa Pharma, 6. Parker C, Nilsson S, Heinrich D, et al. Alpha Eisai and Sanofi; and as speaker from Kyowa, emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: Celgene, Lilly and Merck; Aranzazu González del 213–223. Alba has received honoraria for advisory boards, consultancy, speaker and for travel support from 7. de Bono JS, Oudard S, Ozguroglu M, et al. Pierre Fabre, Roche, Bristol-Myers Squibb, Prednisone plus cabazitaxel or mitoxantrone MSD, Pfizer, Novartis, Bayer, Janssen, Sanofi, for metastatic castration-resistant prostate Astellas, EUSA pharma, Ipsen, EISAI and Astra- cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: Zeneca; Pablo Maroto has received honoraria for 1147–1154. consulting or advisory role from Sanofi, Janssen, Astellas, and Bayer. Urbano Anido has received 8. Kantoff PW, Higano CS, Shore ND, et al. honoraria from Pfizer, Novartis, Bayer, Bristol- Sipuleucel-T immunotherapy for castration- Myers Squibb, EUSA Pharma, and Eisai; Nuria resistant prostate cancer. N Engl J Med 2010; Lainez has received honoraria for consulting or 363: 411–422. advisory role from Pfizer, Sanofi, Ipsen, BMS, 9. Moher D, Liberati A, Tetzlaff J, et al.; PRISMA Roche, and Astra Zéneca. The rest of authors Group. Preferred reporting items for systematic declare no conflicts of interest. reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097. Funding 10. Jadad AR, Moore RA, Carroll D, et al. Assessing The authors disclosed receipt of the following the quality of reports of randomized clinical trials: financial support for the research, authorship, is blinding necessary? 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