ORIGINAL RESEARCH published: 14 July 2022 doi: 10.3389/fonc.2022.891886 Phase II Study of ENZAlutamide Combined With Hypofractionated Radiation Therapy (ENZART) for Localized Intermediate Risk Prostate Cancer Pedro C. Lara 1*, Juan I. Rodrı́guez-Melcón 2, Amalia Palacios-Eito 3, Antonio Lozano 4, Asunción Hervás-Morón 5, Elena Villafranca 6, Alfonso Gómez-Iturriaga 7, Gemma Sancho 8 and Xavier Maldonado 9 Edited by: 1Canarian Comprehensive Cancer Center, San Roque University Hospital, Fernando Pessoa Canarias University, Las Constantinos Zamboglou, Palmas, Spain, 2 Radiation Oncology. Dr. Negrı´n University Hospital, Las Palmas, Spain, 3 Radiation Oncology, Reina Sofı´a German Oncology Center, Cyprus University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain, 4 Radiation Oncology, Reviewed by: Virgen de la Arriexaca University Hospital, Murcia, Spain, 5 Radiation Oncology, Ramon y Cajal University Hospital, Madrid, Markus Grabbert, Spain, 6 Radiation Oncology, Navarra University Hospital, Pamplona, Spain, 7 Radiation Oncology, Cruces University Hospital, University of Freiburg Medical Biocruces Bizkaia Health Research Institute, Barakaldo, Spain, 8 Radiation Oncology, San Creu I San Pau University Hospital, Center, Germany Barcelona, Spain, 9 Radiation Oncology, Vall d´Hebron University Hospital, Barcelona, Spain Stefano Arcangeli, University of Milano-Bicocca, Italy Background: Intermediate-risk prostate cancer (PCa) is usually treated by a combination *Correspondence: Pedro C. Lara of external beam radiation therapy (EBRT) and a short course of androgen deprivation plara@ufpcanarias.es therapy (ADT). ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, anti-androgen monotherapy is generally better Specialty section: This article was submitted to tolerated in spite of higher rates of gynecomastia. Radiation Oncology, Objective: This study assessed the effectiveness of enzalutamide monotherapy a section of the journal Frontiers in Oncology combined with hypofractionated EBRT (Hypo-EBRT) for treating intermediate risk Received: 08 March 2022 prostate cancer. Accepted: 01 June 2022 Method: This trial was a multicenter, open-label phase II study of 6 months of Published: 14 July 2022 enzalutamide monotherapy combined with Hypo-EBRT for intermediate-risk prostate Citation: Lara PC, Rodrı´guez-Melcón JI, cancer. Hypo-EBRT was initiated 8–12 weeks after initiating enzalutamide. The primary Palacios-Eito A, Lozano A, endpoint was PSA decline >80% measured at the 25th week of enzalutamide Hervás-Morón A, Villafranca E, Gómez-Iturriaga A, Sancho G and administration. Secondary end-points included assessment of toxicity, changes in Maldonado X (2022) Phase II anthropomorphic body measurements, sexual hormones, and metabolic changes. Study of ENZAlutamide Combined With Hypofractionated Radiation Results: Sixty-two patients were included in the study from January 2018 to February Therapy (ENZART) for Localized 2020. A PSA decline of >80% was observed in all evaluable patients at the end of Intermediate Risk Prostate Cancer. Front. Oncol. 12:891886. enzalutamide treatment and 92% achieved PSA values under 0.1 ngr/ml. All patients doi: 10.3389/fonc.2022.891886 remain in PSA response (<80% reduction of the initial values) 6 months after the end of Frontiers in Oncology | www.frontiersin.org 1 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer enzalutamide treatment. The most frequent adverse events were hypertension, asthenia, and gynecomastia. There were no significant changes in bone density, body mass index (BMI), or patient-reported outcomes (PROs). Conclusion: Enzalutamide monotherapy is very effective along with hEBRT in reducing PSA levels for patients with intermediate-risk prostate cancer. Longer follow-up is needed to confirm the potential use of this combination in future randomized trials. Keywords: prostate cancer, intermediate risk, enzalutamide monotherapy, hypofractionated, radiotherapy INTRODUCTION LHRH antagonist degarelix (27). The use of enzalutamide has a better tolerance profile than LH-RH agonists in terms of body Radiation therapy (RT) is the standard treatment for localized mass, lipid profile, or bone density. The quality of life of the prostate cancer patients (1). When external beam radiotherapy patients did not change with the treatment, and from the sexual (EBRT) is used, conventionally fractionated external beam RT perspective, the results were similar to those of bicalutamide. As (cEBRT) with total escalated doses of 75.6–79.2 Gy (2) is testosterone levels remain elevated during enzalutamide usually prescribed. treatment, sexual toxicity is lower than that observed with Due to the favorable a/b ratio of prostatic cancer, as ADT therapy, but there was a higher rate of disorders related compared to the surrounding normal tissues (3), the use of to the breast (24–26). hypofractionated schedules would be of interest. For patients, Therefore, enzalutamide in monotherapy in men with previously hypofractionated EBRT (Hypo-EBRT) is very convenient, as it untreated prostate cancer produces an adequate level of suppression reduces the treatment time, improves access to treatment, and of the disease as measured by a long and sustained decrease in PSA lowers the treatment cost (4). Hypo-EBRT administered in 4 to 5 with less toxicity than LH-RH agonists (26). weeks had resulted, in an equivalent disease control rate, Then, if localized intermediate-risk prostate cancer is to be compared with escalated cEBRT administered at 8 weeks, with managed with a combination of radiotherapy and hormonal similar acute and late toxicity rates in non-inferiority therapy (28), the possibility of improving the toxicity profile of randomized trials (5–7). this treatment, using enzalutamide monotherapy, would be of Androgen deprivation therapy is usually combined as great benefit to these patients with a good prognosis, who should adjuvant treatment with EBRT in localized and locally not suffer bothersome undesirable effects. advanced prostate cancers (8). Although it is effective in Enzalutamide monotherapy radiosensitizes prostate cancer reducing tumor mass and prostate-specific antigen (PSA) levels cells to radiation (29) by inducing the suppression of DNA repair (9), limitations to the use of adjuvant ADT in these localized mechanisms, mainly through non-homologous end-joining tumors mainly derive from the short- and long-term adverse repair suppression mediated by DNAPKc proteins (30). This effects (AEs), which may worsen the quality of life of the patient sensitizing effect was also demonstrated in androgen-sensitive or be potentially harmful (10–12). and resistant prostate cancer cell lines, animal models, and Antiandrogens are considered an alternative to ADT along xenografts on castration-resistant human prostate cancers (31). with EBRT. The use in monotherapy of the first-generation Enzalutamide provides a stronger radiosensitation than ADT antiandrogen, bicalutamide, along with cEBRT, improves (32) and, furthermore, this effect is more relevant when higher survival in prostate cancer patients in very unfavorable than 2 Gy doses per fraction (29) are used and enzalutamide is situations without resulting in testosterone-suppression- administered concurrently with RT (31). This improved effect on induced side effects (13–15). concomitant-adjuvant hormonal therapy with radiotherapy has Enzalutamide is a second-generation oral androgen receptor also been observed for standard ADT in the clinical setting (33). (AR) inhibitor (16) that, unlike classical antiandrogens, blocks Therefore, if we consider the use of enzalutamide along with different steps in the AR signaling pathway (17, 18). In castration radiotherapy for localized prostate cancer, several questions still resistant metastatic patients, enzalutamide resulted in better need to be answered. First, the immediate acute tumor response clinical outcomes and reduced toxicity when compared with estimated by PSA decline of combined enzalutamide with the new bicalutamide and ADT (19). Enzalutamide plus ADT is standard modern Hypo-EBRT. This Hypo-EBRT schedule would approved for treating adult men with castration-sensitive or favor radiosensitization induced by enzalutamide and improve resistant metastatic prostate cancer (20–23). tumor response. Second, there is no evidence about the possibility The possibility of using enzalutamide as monotherapy has of a durable PSA response after cessation of enzalutamide been extensively studied by Tombal et al. (24–26) as the first treatment. This issue is of particular interest as it would treatment in patients with localized and metastatic prostate encourage the development of future trials comparing standard cancer. They chose the PSA response (<80% PSA decline over ADT with enzalutamide monotherapy in this particular setting. pretreatment levels) to assess the activity of enzalutamide, Third, the toxicity of such a combination and the quality of life of according to previous results from prospective studies with the prostate cancer patients are still unknown. Frontiers in Oncology | www.frontiersin.org 2 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer Based on the clinical and biological findings, we analyze fiducial markers placed within the prostate. The External Beam for the first time the use of modern hEBRT along with Radiation Dose was normalized such that exactly 98% of the PTV concurrent enzalutamide monotherapy as treatment for (planned target volume) receives the prescription dose and will be localized intermediate-risk prostate cancer. scored as per protocol. The maximum allowable dose within the PTV is 107% of the prescribed dose to a volume that is at least 0.03 cc. The minimum allowable dose within the PTV is >95% of the prescribed dose to a volume that is at least 0.03 cc. The EBRT/IGRT PATIENTS AND METHODS protocol delivered a total dose to the PTV (CTV including the This open-label, single-arm, phase 2 study was done across 8 prostate and the proximal seminal vesicles with a 4 mm posterior recruiting sites in Spain. Patients were enrolled if they were aged margin, 8 mm lateral margin, and 5 mm margin in all other 18 years or older; had histologically confirmed localized (after directions) of 70 Gy delivered in 28 fractions of 2.5 Gy each. The diagnostic work-up, namely, pelvic MRI and/or abdomen CT- EQD2 (considering the alpha/beta ratio of 1.5 Gy) was 80 Gy (34). scan and bone-scan) intermediate risk prostatic adenocarcinoma Blood samples to establish PSA and circulating hormone (defined as PSA 10–20 ng/ml and/or T2b-C and/or Gleason score levels were collected at screening, at the 4th and 25th weeks, 7, if all three factors were present, less than 50% of cores were and 1, 3, and 6 months after the end of enzalutamide. All patients required to be positive); had an Eastern Cooperative Oncology had monthly clinical visits during treatment and safety follow-up Group (ECOG) score of 0–1, adequate renal/liver function, and visits at 1, 3, and 6 months after their last dose of enzalutamide, normal blood counts. recording adverse events graded according to the National Exclusion criteria included previous or current hormonal Cancer Institute Common Terminology Criteria for Adverse manipulation, prior treatment for prostate cancer, previous Events, version 4.0. radiation therapy for a pelvic tumor, history of cancer in the last 5 Blood samples assessing renal, liver, and blood counts were years, history of seizure or treatment with antiepileptic drugs. The performed at screening and monthly until the end of full inclusion/exclusion criteria are given in Supplementary Material enzalutamide administration. Fasting serum lipids and fasting Table 1. glucose levels were assessed on samples collected on day 1, the All patients provided written informed consent. This study was 12th, and the 25th weeks. conducted in accordance with the Helsinki Declaration and the Changes in bone mineral density were assessed by a dual- International Conference on Harmonization: Harmonized energy X-ray absorptiometry scan on day 1 and the 25th week. Tripartite Guideline: Guideline for Good Clinical Practice. The HRQoL was assessed with self- administered EORTC QLQ-C30 protocol was approved by local institutional review boards of each and EORTC QLQ-PR25 instruments (35, 36) completed by center, independent ethics committees, and the Anonymized for patients on day 1, at the 12th and 25th week, and at the safety Review Government Competent Authority in Spain. The trial was follow-up visit 1 month after the end of enzalutamide. registered at ClinicalTrials.gov, NCT01302041. Outcomes Procedures The primary outcome was PSA response, defined as a decline from After a 4-week screening period, the participants were given a baseline in PSA level of 80% or greater at the 25th week, based on study drug-dosing diary for each of the 6 treatment cycles. Each the PSA response observed in registration trials of enzalutamide and treatment cycle lasted 28 days (4 weeks), while the participant other hormonal treatments (24, 27). Enzalutamide-induced PSA received the study drug enzalutamide orally. Starting on Day 1, decline after 1, 3, and 6 months of cessation of enzalutamide all patients will ingest enzalutamide 160 mg/day at the same time treatment for the primary analysis has also been considered a each day, without breaks (except as outlined for toxicity), for 6 relevant treatment response marker to assess the activity of (28 days ±3 days) cycles. The dose reduction of enzalutamide to enzalutamide combined with hypofractionated radiotherapy. 120 mg/day was allowed with the approval of the principal Secondary outcomes were, changes from baseline in hormone investigator of the study. Patients were instructed to return all level, bone mineral density, fasting serum lipids and quality of unused capsules at each study visit to assess compliance and life. Safety outcomes included the frequency and severity of adverse received the study drug every 28 days ( ± 3 days) for 6 cycles. events as scored by the CTCAE 4.0. In patients suffering from grade 3 or greater toxic side effects that cannot be reduced by the use of standard medical intervention, Statistical Analysis treatment should be interrupted until these adverse effects improve. The primary activity outcome was the proportion of patients with a PSA Then, patients could restart on a reduced enzalutamide dose with responseatthe25thsincethestartofenzalutamideand1,3,and6months the written approval of the principal investigator of the study. after the cessation of enzalutamide treatment. This was calculated as the Between 8 and 12 weeks after starting enzalutamide, the patients numberofpatientswithPSAresponse(≥80%PSAdeclinefrombaseline) were treated with Hypo-EBRT for a duration of 5.5 weeks. at the prespecified time-points, divided by the number of patients who Treatment was administered on an outpatient basis. Hypo-EBRT started treatment, and presented as the percentage of patients was administered under Image Guided Radiation Therapy (IGRT) responding. Patients who discontinued enzalutamide treatment were technology. The participant centers were required to routinely use included in the intention-to-treat analysis. Secondary and exploratory IGRT in these patients, either by ConeBeam CT study and/or outcomes are summarized descriptively. Frontiers in Oncology | www.frontiersin.org 3 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer The primary endpoint for this trial was to assess the number to 4 February 2020. The study was closed earlier than expected to of patients with a more or equal 80% reduction in baseline PSA at achieve the maximum recruiting schedule (31 March 31 2020), the 25th week. We assume a null hypothesis if 70% of patients do due to the COVID-19 pandemic that strongly affected Spain. The not achieve PSA declines of over 80% and a positive hypothesis if number of recruited patients at that time was already over the more than 85% of the patients achieve such a decline at the 25th expectation of the standard calculated sample size, heading for week. We aimed for a “maximum” recruiting scenerio, an alpha = 0.05 and beta = 0.2 error. calculating the target evaluable sample size for an alpha = 0.05 Four patients resulted in screening failure, and one patient and beta = 0.1 error to be 66 patients, resulting in 70 cases of retracted consent after the screening period. Patients and tumor target recruiting size if a 5% patient loss was considered. A characteristics for the 57 patients who started enzalutamide second “standard” calculation of the target evaluable sample size treatment are described in Table 1. Most patients (32/57, for an alpha = 0,05 and beta = 0.2 error, resulted in 47 evaluable 73.7%) were classified as unfavorable intermediate NCCN patients to be recruited, reaching 50 patients if a 5% loss risk subgroups. was considered. Safety analyses were performed on all patients who had taken Protocol Compliance and Security at least one dose of the study drug. All reported toxicities were One of the 57 patients taking enzalutamide, retract consent to summarized as acute toxicity regardless of attribution by participate in the study at the 4th week due to general discomfort, maximum grade and were sorted by the number of patients unrelated to any objective toxicity. Therefore, 56 patients were experiencing the toxicity during the enzalutamide and Hypo- finally included in the study (Figure 1). EBRT treatments and until 1 month post-treatment. Late toxicity During enzalutamide treatment, three severe adverse effects was recorded at 6 months after cessation of enzalutamide. were reported. One severe hepatic toxicity (Grade 4) related to Activity analysis was performed according to the “intention to enzalutamide, displaying a rise in liver enzymes at the 7th week, treat” analysis, including patients who had taken at least one dose normalized after complete and definitive enzalutamide cessation. of study drug and had both pretreatment and at least one activity The responsible investigator considered this adverse effect as evaluation after treatment initiation. related to enzalutamide. Anyhow, the patient continued with the The mean, standard deviation, range, and 95% confidence study program evaluations and tests. Two patients suffered interval of the mean were calculated to describe the quantitative severe adverse effects non-related to enzalutamide. One patient variables. The Shapiro–Wilk (n ≤50) or Kolmogorov–Smirnov had sepsis after fiducial implantation in the prostate for IGRT in (n >50) test was used to verify the normality of the data of the the 2nd week, and one patient suffered an ictus in the 9th week. quantitative variables as a function of the sample size. The This patient had a previous hypertensive clinical history, and the qualitative variables have been described by means of the event was not related by the responsible investigator to absolute frequency, relative frequency, and the CI (95%) enzalutamide treatment. Both patients completed the calculated using the Clopper–Pearson method. When the enzalutamide treatment but with a dosage reduction to 120 sample size is greater than 30, the Student’s t-test has been mg/day as per protocol in the hypertensive patient. used for paired data to compare numerical variables at two One patient abandoned enzalutamide treatment at week 11 due different moments of time. In the opposite case, and if the to general discomfort unrelated to any objective toxicity. The patient variables do not follow a normal distribution, we have used the agreed to continue the study follow-up. Two patients from the same Wilcoxon test for paired data. A p-value of less than 0.05 is center misunderstood the trial instructions and stopped considered significant. The statistical program used was R Core enzalutamide during the 5 weeks of radiotherapy treatment. Team 2021, version 4.1.1 (37). Radiotherapy was administered as scheduled (total dose of 70 Gy in 28 fractions, 2.5 Gy per fraction) to all 56 patients. All 56 Role of the Funding Source cases but one (a patient who started radiotherapy in the 5th This is an independent academic study supported by an week) started radiotherapy between the 8th and the 13th week as unrestricted educational grant from Astellas. The authors scheduled. Radiotherapy was completed in all cases, for a total performed the protocol design, data analysis, interpretation, treatment time of 41.63 ± 3.30 days (CI 95% 40.75–42.51). and preparation of this report. Data analysis was performed by Dosimetry recommendations were well accomplished in all an independent statistician (JMGM). All authors had access to cases. IIn most cases, PTV coverage and OAR constraints were the study data. All decisions relating to the manuscript writing achieved in most cases (Supplementary Material Table 2). and content were made jointly by the authors, including the final Acute toxicity was recorded as the maximum toxicity observed decision to submit it for publication. during treatment and until one month after cessation of enzalutamide (Table 2). Two patients, as described above, presented grade 4 toxicity (hypertensive in one case, liver enzyme elevation in the other case). Severe grade 3 acute systemic toxicity RESULTS observed was related to hypertension (systolic in all cases) in 19/56 (33.93%). Urinary and gastrointestinal toxicity 2 were present in 18/ Patient’s Characteristics 56 (32.14%) and 5/56 (8.9%) patients, respectively. Common (one Sixty-two out of the maximum recruiting scenery of 70 patients third of the cases) mild toxicity included asthenia, breast pain, were finally included in the present study from 16 January 2018 gynecomastia, urinary pain, and polaquiuria (Table 3). Other acute Frontiers in Oncology | www.frontiersin.org 4 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer TABLE 1 | Patient Characteristics (n = 57). N Age (years) 71.7 (50–83) T Stage T1c 35 (61.4%) T2a 15 (26.3%) T2b 3 (5.3%) T2c 4 (7.0%) N stage Nx 0 (0%) N0 57 (100%) N1 0 (0%) M stage Mx 0 (0%) M0 57 (100%) M1 0 (0%) Gleason Score 6 3 (5.3%) 7 54 (94.7%) 3+4 29 (53.7%) 4+3 25 (46.3%) Affected biopsy cores (%) 38.7 (8–100) Pretreatment PSA ng/ml ≤10 46 (80.70%) >10 11 (19.30%) FIGURE 1 | Protocol Flow Chart. NCCN risk subgroup Favorable 15 (26.3%) Unfavorable 32 (73.7%) ECOG PSA 0 56 (98.24%) All 56 patients included in the study were analyzed for PSA 1 1 (1.76%) response in an intention-to-treat analysis and evaluated Charlson score 0–1 48 (84.21%) according to the PSA response data time-point available. All 56 2 5 (8.77%) patients evaluable for PSA treatment-induced modifications at 3 3 (5.30%) pre-specified time points showed PSA reduction higher than Unknown 1(1.76%) 80%. At the 25th week, all evaluable patients (50 cases) achieved Body Mass Index <25 8 (14.03%) PSA values of 0.2 ng/ml and PSA was under detectable levels 25–30 31 (54.38%) (<0.1 ng/ml) in 92% of all patients (Table 3). PSA values dropped >30 12 (21.05%) from pretreatment levels of 7.61 ± 2.82 (3.53–16.77) ng/ml to Unknown 6 (10.52%) 0.04 ± 0.04 (0.00–0.16) ng/ml at the 25th week and remained low Basal Hypertension 6 months after cessation of enzalutamide (Table 4). <140/90 19 (33.33%) >141/91 31 (54.38%) Unknown 7 (12.28%) Basal elevated Cholesterol/Triglicerides Hormone Levels No 23 (40.35%) Patients treated with enzalutamide showed a sharp increase in Yes 19 (33.33%) testosterone and estradiol after 4 weeks of enzalutamide Unknown 15 (26.32%) Basal elevated ALT/AST treatment (Table 4). LH and FSH levels were also increased at Yes 3 (5.27%) week 25. Testosterone and estradiol levels decreased to No 54 (94.73%) pretreatment levels, but LH and FSH levels remained elevated at 6 months (Figure 2). Anthropometric, bone, and metabolic changes at a pre- general, hormonally-related and gastrointestinal toxicity were also specified time point. mild and uncommon. At the time of last evaluation, there was no statistically Late toxicity was recorded 6 months after enzalutamide cessation. significant weight change after enzalutamide treatment, either Most of the urinary and hypertensive severe toxicity disappeared. in bone density as measured in densitometric analysis or the Toxicity was mainly related to hormonally derived symptoms such bone resorption marker, alkaline phosphatase. Metabolic as breast pain and gynecomastia. Severe grade 3 toxicity was present changes in fasting glucose, cholesterol, or triglyceride levels in 2 patients, one with urinary pain and retention, and the other were not present after enzalutamide treatment. There was a showing grade 3 proctitis. Grade 3 hypertension was observed in modest increase in HDL cholesterol at the last evaluation 5 patients (Table 2). (Table 5). Frontiers in Oncology | www.frontiersin.org 5 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer TABLE 2 | Maximum grade acute and late adverse effect after treatment in 56 evaluable patients. Acute Toxicity Late Toxicity G1 G2 G3 G1 G2 G3 General Symptoms Hypertension 10 (17.86%) 26 (46.43%) 19 (33.93%) 18 (45.0%) 17 (42.50%) 5 (12.50%) Asthenia 18 (32.14%) 3 (5.36%) 2 (3.57%) AST/ALT elevation 11 (19.64%) Somnolence/Insomnia 5 (8.93%) 3 (5.36%) Headache/loss of concentration 1 (1.79%) 1 (1.79%) 1 (1.79%) Dizzines/ortostasim 6 (10.71%) 1 (1.79%) 1 (1.79%) 1 (1.79%) Depression/Anxiety 1 (1.79%) 1 (1.79%) 3 (5.36%) Dry skin 3 (5.36%) 1 (1.79%) 2 (3.57%) Skin hyperpigmentation folliculitis 2 (3.57%) 1 (1.79%) Mialgia/leg discomfort 3 (5.36%) Arthralgia 3 (5.36%) 1 (1.79%) Symptoms related to hormonal changes Breast Pain 14 (25.00%) 3 (5.36%) 11 (19.64%) Nipple pain/discomfort 3 (5.36%) 1 (1.79%) Gynecomastia 13 (23.21%) 5 (8.93%) 8 (14.29%) Hot flashes 2 (3.57%) 1 (1.79%) Libido Decreased 7 (12.50%) 6 (10.71%) Retrograde ejaculation 2 (3.57%) 2 (3.57%) Hipogonadism 2 (3.57%) 1 (1.79%) Urinary symptoms Pain 12 (21.43%) 6 (10.71%) 1 (1.79%) 1 (1.79%) Urgency 13 (23.21%) 6 (10.71%) 3 (5.36%) 1 (1.79%) Incontinence 9 (16.07%) 1 (1.79%) Polaquiuria 4 (7.14%) 8 (14.81) 2 (3.57%) Retention/obstruction 2 (3.57%) 4 (7.14%) 1 (1.79%) 1 (1.79%) Non infectous cystitis 4 (7.14%) 1 (1.79%) Nicturia 1 (1.79%) Gastrointestinal Symptoms Abdominal Pain 4 (7.14%) 2 (3.57%) Rectal Pain 4 (7.14%) 1 (1.79%) 1 (1.79%) Proctitis 7 (12.50%) 2 (3.57%) 1 (1.79%) Anorexia/Hyporexia 5 (8.93%) 1 (1.79%) 1 (1.79%) Disgeusia 2 (3.57%) 1 (1.79%) Constipation/Diarrhea 8 (14.29%) Nausea/Vomitting 5 (8.93%) 1 (1.79%) Meteorism 2 (3.57%) Acute grade 4 was observed in 2 patients (one hypertensive crisis and one elevation of AST/ALT). No grade 4 late toxicity was observed. Patients Reported Outcomes (PROs) at and an increase in symptoms were observed at the 12th and 25th Pre-Specified Time Points weeks, recovering one month after cessation of the treatment. PROs were analyzed through the EORTC QLQC30 and EORTC Specific PRO analysis of symptoms related to prostate cancer QLQ-PR25 at pretreatment, the 12th week of treatment, at the treatment (EORTC-QLQ-PR25) showed a significant impact on 25th week, and one month after cessation of enzalutamide. A the urinary domain during the radiotherapy treatment period reduction in QoL scores as estimated by the EORTC QLQC30 (12th–25th week) that recovered one month after cessation of TABLE 3 | PSA decline values at pre-specified time points. 25th week (n = 50) 1 month after enzalutamide 3 months after enzalutamide 6 months after enzalutamide (n = 51) (n = 51) (n = 51) PSA decline ≥80% 50/50 (100%) 51/51 (100%) 51/51 (100%) 51/51 (100%) (95% CI: 92.89–100%) (95% CI: 93.02–100%) (95% CI: 93.02–100%) (95% CI: 93.02–100) PSA decline ≥90% 50/50 (100%) 51/51 (100%) 46/51 (90.2%) 45/51 (88,24%) (95% CI: 92.89–100%) (95% CI: 93.02–100%) (95% CI: 78.59–96.74%) (95% CI: 76.13–95.56%) PSA <0.2 ng/ml 50/50 (100%) 42/51 (82.3%) 29/51 (56.8%) 26/51 (50.98%) (95% CI: 92.89–100%) (95% CI: 69.13–91.6%) (95% CI: 42.25–70.65%) (95% CI: 36.6–65.25%) PSA <0.1 ng/ml 44/50 (88%) 37/51 (72.5%) 13/51 (25.5%) 9/51 (17.6%) (95% CI: 75.69–95.47%) (95% CI: 58.26–84.11%) (95% CI: 14.33–39.63) (95% CI: 8.4–30.87%) Frontiers in Oncology | www.frontiersin.org 6 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer TABLE 4 | PSA and hormone profile values at pre-specified time points. Pretreatment 4th week 25th week 1 monthafter enza 3 months after enza 6 months after enza P-value PSA (ng/ml) (n = 56) (n = 52) (n = 50) (n = 51) (n = 51) (n = 51) Pre vs 4th w: p <0.0001 Pre vs 25th w p <0.0001 Mean ± SD 7.61 ± 2.82 2.98 ± 2.37 0.04 ± 0.04 0.09 ± 0.12 0.28 ± 0.29 0.29 ± 0.28 Pre vs 1 m p <0.0001 (range) (3.53–16.77) (0.22–11.50) (0.00–0.16) (0.00–0.52) (0.01–1.21) (0.01–1.11) Pre vs 3 m p <0.0001 95% CI 6.87–8.35 2.33–3.62 0.03–0.05 0.06–0.12 0.20–0.36 0.21–0.36 Pre vs 6 m p <0.0001 Testosterone (ng/ (n = 53) (n = 48) (n = 48) (n = 48) (n = 49) (n = 46) Pre vs 4th w: p <0.0001 ml) Pre vs 25th w p <0.0001 Mean ± SD 5.41 ± 2.74 9.83 ± 4.18 9.16 ± 4.52 8.04 ± 4.25 7.49 ± 10.55 4.82 ± 3.633 Pre vs 1 m p <0.0001 (range) (2.20–18.19) (3.11–19.00) (1.70–21.10) (1.40–24.27) (1.70–69.35) (1.30–25.91) Pre vs 3 m p = 0.154 95% CI 4.68–6.15 8.65–11.02 7.88–10.44 6.84–9.25 4.53–10.44 3.77–5.87 Pre vs 6 m p = 0.285 Estradiol (pg/ml) (n = 48) (n = 44) (n = 45) (n = 44) (n = 41) (n = 39) Pre vs 4th w: p <0.0001 Pre vs 25th w p <0.0001 Mean ± SD 26.52 ± 9.59 44.40 ± 41.72 ± 40.37 ± 16.78 30.05 ± 10.61 30.59 ± 10.62 Pre vs 1 m p <0.0001 17.56 19.93 (range) (10.00–47.70) (14.00–87.00) (0.00–85.00) (0.00–72.00) (12.00–51.00) (10.00–54.00) Pre vs 3 m p = 0.015 95% CI 23.80–29.23 39.21–49.59 35.90–47.54 35.41–45.33 26.80–33.30 27.25–33.92 Pre vs 6 m p = 0.057 LH (mUl/ml) (n = 51) (n = 49) (n = 49) (n = 46) (n = 44) (n = 45) Pre vs 4th w: p <0.0001 Pre vs 25th w p <0.0001 Mean ± SD 6.99 ± 4.98 13.19 ± 6.69 19.24 ± 8.46 17.49 ± 8.47 12.56 ± 6.67 11.12 ± 5.43 Pre vs 1 m p <0.0001 (range) (2.08–30.72) (4.83–35.95) (7.34–39.20) (7.24–39.40) (5.50–32.60) (4.68–30.24) Pre vs 3m p <0.0001 95% CI 5.62–8.36 11.32–15.07 16.87–21.61 15.04–19.94 10.59–14.53 9.54–12.71 Pre vs 6m p <0.0001 FSH (mUl/ml) (n = 48) (n = 45) (n = 44) (n = 41) (n = 40) (n = 40) Pre vs 4th w: p = 0.055 Pre vs 25th w p <0.0001 Mean ± SD 13.73 ± 18.77 15.11 ± 28.86 ± 27.14 ± 13.95 27.49 ± 12.08 27.43 ± 12.70 Pre vs 1 m p <0.0001 18.68 15.51 (range) (2.20–126.24) (2.30–116.44) (9.20–81.17 (11.40–88.66) (10.68–79.05) (9.51–84.71) Pre vs 3m p <0.0001 95% CI 8.42–19.04 9.66–20.57 24.27–33.44 22.87–31.41 23.74–31.23 23.49–31.36 Pre vs 6m p <0.0001 treatment. Gastrointestinal and sexual domains did not change DISCUSSION significantly during treatment and completely recovered at the end of the study period. Changes in the hormonal domain Patients having localized intermediate prostate cancer are usually remained significantly present one month after enzalutamide treated with a combination of radiation therapy and 6 months of treatment (Table 6, Figure 3). ADT. Previous studies have shown an excellent toxicity profile of enzalutamide monotherapy compared with ADT (26). Furthermore, combined enzalutamide and conventionally fractionated radiotherapy has been shown to be well tolerated in this particular clinical situation (38). But little is known about the toxicity and PROs when enzalutamide monotherapy is discontinued. Our study was planned to assess the role of enzalutamide monotherapy combined with modern hypofractionated EBRT for treating patients with localized intermediate-risk prostate cancer. As previously described in other studies (24), our patients showed a better toxicity profile than that traditionally described in ADT trials, caused by the compensatory elevation of sexual hormones. No changes in body mass index, bone density mass, fasting glucose, cholesterol, or libido were found one month after the end of enzalutamide. Just after the end of enzalutamide treatment, modest changes in HDL-cholesterol were still evident. As expected, testosterone, estradiol, LH, and FSH levels sharply increase during enzalutamide treatment (24). Our data showed for the first time that testosterone and estradiol levels tend to return to basal levels 6 months after cessation of enzalutamide, although LH and FSH remain elevated. This fact, would be relevant when assessing the acute and FIGURE 2 | Graphical presentation of PSA and Hormonal profile at pre- long-term hormonal side effects analyzed either by the specified timepoints. Data in Y-axis represent number of units (type of units physicians, through the CTCAE4.0 toxicity scale [Physician for each parameter is displayed in the figure lines). Data in X- axis represent Reported Outcomes, (PhyROs)] or the patients, through the number of weeks after pretreatment assessment. EORTC QLQC30 and EORTC QLQ-PR25 (PROs). In fact, no Frontiers in Oncology | www.frontiersin.org 7 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer TABLE 5 | Antropometric, bone and metabolic changes at pre-specified time point. Pretreatment 12th week 25th week 1 month after enza P-value Body Mass Index (n = 50) (n = 46) (n = 40) (n = 40) Mean ± SD 28.30 ± 4.55 27.55 ± 4.83 27.30 ± 4.18 27.38 ± 4.11 Pre vs 12th w: p <0.0001 (range) (17.03–44.39) (16.78–44.46) (17.32–40.04) (20.57–40.57) Pre vs 25thw: p = 0.001 95% CI 27.04–29.56 26.16–28.95 26.01–28.60 26.11–28.66 Pre vs 1 m: p = 0.082 Bone Density Femoral Neck (g/cm2) (n = 45) (n = 45) Mean ± SD 0.85 ± 0.15 0.86 ± 0.15 Pre vs 25th w: p = 0.253 (range) (0.58–1.35) (0.61–1.25) 95% CI 0.80–0.89 0.82–0.91 Bone Density Lumbar Spine (g/cm2) (n = 48) (n = 48) Mean ± SD 1.13 ± 0.21 1.14 ± 0.21 Pre vs 25th w: p = 0.342 (range) (0.77–1.87) (0.77–1.92) 95% CI 1.07–1.19 1.08–1.20 Alkaline Phosphatase (U/L) (n = 49) (n = 44) (n = 49) Mean ± SD 72.61 ± 27.65 65.48 ± 17.63 76.59 ± 25.78 Pre vs 12thw: p = 0.033 Pre vs 25thw: p = 0.093 (range) (39.00–226.00) (38.00–139.00) (36.00–186.00) 95% CI 64.87–80.36 60.27–70.69 69.37–83.81 Fasting Glucose (mg/dl) (n = 54) (n = 46) (n = 50) (n = 50) Mean ± SD 113.67 ± 31.71 113.43 ± 28.76 115.68 ± 31.95 117.94 ± 32.22 Pre vs 12thw: p = 0.881 (range) (83.00–253.00) (70.00–253.00) (83.00–247.00) (80.00–263.00) Pre vs 25thw: p = 0.886 95% CI 105.21–122.12 105.12–121.75 106.82–124.53 108.01–125.87 Pre vs 1 m: p = 0.758 Fasting Cholesterol Total (mg/dl) (n = 38) (n = 24) (n = 37) Mean ± SD 185.58 ± 40.56 189.88 ± 34.69 198.44 ± 38.42 Pre vs 12thw: p = 0.218 (range) (114.00–277.00) (117.00–254.00) (102.00–269.00) Pre vs 25thw: p = 0.054 95% CI 172.69–198.48 176.00–203.75 186.06–210.82 Fasting Cholesterol HDL (mg/dl) (n = 33) (n = 21) (n = 32) Mean ± SD 54.19 ± 22.46 49.72 ± 10.30 58.37 ± 22.12 Pre vs 12thw: p = 0.382 (range) (34.00–162.00) (34.00–69.00) (41.00–162.00) Pre vs 25thw: p = 0.015 95% CI 46.52–61.85 45.31–54.12 50.71–66.03 Fasting Cholesterol LDL (mg/dl) (n=33) (n = 20) (n = 32) Mean ± SD 109.34±40.64 108.08 ± 30,33 116.37 ± 30.64 Pre vs 12thw: p = 0.409 (range) (16.00-197.00) (57.00–173.00) (70.00–174.00) Pre vs 25thw: p = 0.220 95% CI 95.47-123.20 94.79–121.37 105.75–126.98 Fasting Triglicerides (mg/dl) (n = 38) (n = 20) (n = 38) Mean ± SD 130.22 ± 55.97 142.78 ± 61.16 136.85 ± 56.90 Pre vs 12thw: p = 0.971 (range) (54.00–265.00) (54.00–313.00) (56.00–301.00) Pre vs 25thw: p = 0.165 95% CI 112.42–148.02 119.71–165.85 118.49–154.68 sexual toxicity was observed, but gynecomastia (CTCAE 4.0) and This conventionally fractionated radiotherapy scheme had a hormonal related symptoms (QLQPR25) remained a problem lower EQD2 (70 Gy) (6). for patients one month after the end of enzalutamide treatment. The study from Kaplan et al. (38) already analyzed this In contrast, the global health status, the functioning area, or possibility by combining standard escalated cEBRT with symptoms other than hormonally related, returned to enzalutamide monotherapy in intermediate-risk prostate pretreatment levels one month after cessation of enzalutamide. cancer patients. Patients received conventionally fractionated The use of Hypo-EBRT is also a novelty in our study. We EBRT to a total dose of 79.2 Gy at 1.8 Gy per fraction for 44 treated our patients according to the Hypo-EBRT protocol fractions (9 weeks), and enzalutamide was administered for 6 described by Kupelian et al. (34) and as the treatment arm in months. They reported only 6 cases out of 45 (13.33%) of ≧grade the RTOG 0415 trial (6). This schedule and others (39) provide 2 urinary frequency. We observed this particular toxicity in 9/56 the highest EQD2 (80 Gy) to the PTV, compared to other patients (16.06%). No data are available regarding the other GU hypofractionated schemes (5–7). Our acute GU toxicity was toxicity items described in our study. We must note that due to slightly higher than that observed in the hypofractionated arm the selected radiotherapy treatment in the Kaplan study (38) (1.8 of the RTOG 0415 (32.9% vs 27%), while GI toxicity was very Gy per fraction, 44 fractions to a total dose of 79.2), the EQD2 of similar (8.9% vs 10.7%). Our 80 Gy EQD2 PTV included the this cEBRT is 74.67 Gy. This equivalent dose is well below the 80 proximal seminal vesicles (the first 1 cm of the seminal vesicles). Gy administered in our study. This extra volume was not treated in the RTOG trial, as only low- The PROs recognized a temporary increase in urinary scores risk patients were included in that trial. This higher PTV volume in the evaluations performed in the 12th week (just after the end would be related to the slightly increased urinary toxicity found of Hypo-EBRT) that was rapidly recovered at the end of the in our study (6). In the RTOG 0415 study, the hypofractionated study period. However, no gastrointestinal or sexual symptom arm had a very similar toxicity profile to the conventional arm. scores were changed. Frontiers in Oncology | www.frontiersin.org 8 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer TABLE 6 | Quality of Life assessment at pre-specified time points. QLQ30 Pretreatment (n = 53) 12 th week (n = 50) 25th week (n = 47) 1 month after enzalutamide (n = 45) P-value Global Health Mean ± SD 82.55 ± 16.69 74.50 ± 19.30 80.50 ± 15.57 81.48 ± 18.02 Pre vs 12th w: p = 0.011 (range) (33.33–100.00) (16.67–100.00) (50.00–100.00) (33.33–100.00) Pre vs 25th w: p = 0.155 95% CI 78.05–87.04 69.15–79.85 76.05–84.95 76.22–86.75 Pre vs 1 month: p = 0.682 Functioning area Mean ± SD 94.12 ± 7.19 88.53 ± 14.00 92.17 ± 8.53 92.05 ± 10.66 Pre vs 12th w: p = 0.011 (range) (62.22–100.00) (31.11–100.00) (71.11–100.00) (57.78–100.00) Pre vs 25th w: p = 0.075 95% CI 92.18–96.05 84.65–92.41 89.73–94.61 88.97–95.13 Pre vs 1 month: p = 0.260 Symptoms Area Mean ± SD 2.95 ± 3.17 6.49 ± 6.45 4.71 ± 4.37 4.37 ± 4.75 Pre vs 12th w: p <0.001 (range) (0.00–11.54) (0.00–26.92) (0.00–20.51) (0.00–16.67) Pre vs 25th w: p = 0.005 95% CI 2.10–3.80 4.70–8.28 3.46–5.96 3.00–5.75 Pre vs 1 month: p = 0.088 QLQ-PR25 Pretreatment (n = 53) 12th week (n = 50) 25th week (n = 47) 1 month after enzalutamide (n = 47) P-value Urinary Symptoms Mean ± SD 84.04 ± 12.60 69.51 ± 21.86 79.61 ± 17.64 81.84 ± 19.57 Pre vs 12th w: p <0.0001 (range) (37.50–100.00) (0.00–100.00) (25.00–100.00) (16.67–100.00) Pre vs 25th w: p = 0.031 95% CI 80.65–87.43 63.45–75.57 75.57–84.65 76.39–87.29 Pre vs 1 month: p = 0.470 Gastrointestinal Symptoms Mean ± SD 97.01 ± 5.91 94.33 ± 9.44 96.45 ± 6.89 96.92 ± 5.92 Pre vs 12th w: p = 0.059 (range) (75.00–100.00) (50.00–100.00) (75.00–100.00) (75.00–100.00) Pre vs 25th w: p = 0.569 95% CI 95.42–98.60 91.72–96.95 94.48–98.43 95.21–98.63 Pre vs 1 month: p = 0.844 Hormonal related symptoms Mean ± SD 96.54 ± 5.99 87.22 ± 10.86 84.75 ± 12.40 85.93 ± 10.42 Pre vs 12th w: p <0.0001 (range) (72.22–100.00) (50.00–100.00) (55.56–100.00) (55.56–100.00) Pre vs 25th w: p <0.0001 95% CI 94.93–98.15 84.21–90.23 81.18–88.33 82.96–88.91 Pre vs 1 month: p <0.0001 Sexual activity Mean ± SD 77.04 ± 19.97 80.79 ± 25.00 72.86 ± 25.84 78.70 ± 25.84 Pre vs 12th w: p = 0.550 (range) (33.33–100.00) (5.56–100.00) (11.11–100.00) (16.67–100.00) Pre vs 25th w: p = 0.232 95% CI 71.67–82.42 73.71–87.86 65.47–80.25 71.86–85.54 Pre vs 1 month: p = 0.822 The primary endpoint of the study deals with the efficacy of showed PSA response, in compared with 51/51 (100%) in our the combination of enzalutamide monotherapy and modern series for the same response evaluator. No data on PSA response Hypo-EBRT, in terms of reduction of PSA levels, in patients was given after enzalutamide cessation in the Kaplan study, but with localized intermediate-risk prostate cancer, as used in 56.8% of our patients remained in the PSA response (<0.2 ng/ml) similar trials (24–26, 38). 6 months after enzalutamide cessation. Again, the lower EQD2 As stated earlier, activity analysis was performed with the radiation dose in this study (74.67 Gy) the the present one (80 intention of treating conditions. The PSA response was analyzed Gy) would explain the lower response rate observed. by the proportion of patients who showed a reduction of at least The effect of radiotherapy along with enzalutamide versus 80% of the initial values at the end of the 25 weeks of enzalutamide alone, would only be indirectly analyzed by enzalutamide treatment. The seminal study by Tombal et al. comparing the results from Tombal et al. (24) with those (24) showed a PSA response of 92.5% (95% CI 86.2–98.8), results from Kaplan and this study. Enzalutamide alone similar to the 100% observed in our study. We also analyzed provided a 45% rate of undetectable PSA (<0.1 ng/ml) the kinetics of PSA reduction at pre-specified time-points (1, 3, compared with 61.3% (38/62) for cEBRT and 88% for Hypo- and 6 months) after the cessation of enzalutamide. Our study EBRT. Although patient and tumor characteristics are of poorer showed that all patients remain in PSA response 6 months after prognosis in the enzalutamide alone trial (24), these data would the cessation of enzalutamide. Furthermore, 90% of the patients shed light on the effect of radiotherapy along with enzalutamide still showed a PSA decline of 90% of the pretreatment values, 6 in this particular setting. months after the enzalutamide cessation. Obviously, the effect of Although available results regarding the role of enzalutamide radiotherapy on this maintained PSA decline is to be taken and hypofractionated radiotherapy (38 and present series) are into account. limited by the short follow-up, recent evidence seems to confirm The study by Kaplan et al. (38) combined conventionally the role of this approach in prostate cancer patients. Long-term fractionated radiotherapy with enzalutamide monotherapy in evidence for the role of antiandrogen monotherapy as an intermediate-risk prostate cancer. They defined PSA response as alternative to ADT combined with hypofractionated PSA levels lower than 0.2 ng/ml at the end of 25 weeks of radiotherapy comes from the CHiiP trial (40). In a post hoc enzalutamide (39). Forty-nine out of 62 (79%) of their patients analysis, they compared the results of 2,700 patients who Frontiers in Oncology | www.frontiersin.org 9 July 2022 | Volume 12 | Article 891886 Lara et al. Enzalutamide & Hypofractionatedd-RT in Prostate Cancer during radiotherapy, achieving tumor repopulation during this very long treatment time and therefore, reducing tumor control A induced by radiation (41). Furthermore, conventionally fractionated radiotherapy probably does not take full advantage of the increased radiosensitation observed when enzalutamide is given in the presence of fractions higher than 2 Gy (hypofractionated radiotherapy) (38). We can conclude that the treatment schedule proposed here B for the first time is safe and very active in reducing the PSA levels. Our study also showed that such a PSA reduction is maintained 6 months after the cessation of enzalutamide treatment. Longer follow-up is needed to confirm the potential use of this combination in future randomized trials. C DATA AVAILABILITY STATEMENT The data presented in the study is available on request, further inquiries can be directed to the corresponding author/s. FIGURE 3 | PRO (A). QLQ30_Global Health Status/Functional Status. (B) ETHICS STATEMENT QLQ30_Symptoms Status. (C) QLQ_PR25. PROs score is displayed in the Y- axis. Weeks after pretreatment assessment are displayed in the X-axis. The studies involving human participants were reviewed and approved by the CEIm University Hospital Canarias. The patients/participants provided their written informed consent received LHRHa and those of 403 patients who received to participate in this study. bicalutamide (150 mg/day) as concomitant hormonal treatment. All characteristics of patient and tumor were similar among the two groups unless bicalutamide patients were significantly younger (median 67 vs 69 years LHRHa). After a AUTHOR CONTRIBUTIONS median follow-up of 9.3 years, there was no difference in All authors listed have made a substantial, direct, and intellectual biochemical or clinical failure. Late toxicity, as estimated by contribution to the work and approved it for publication. the LENT-SOMA, was more frequently reported in LHRHa patients compared to bicalutamide patients. The quality of life was similar in both arms. These mature results of a first-generation antiandrogen FUNDING (bicalutamide) in monotherapy combined with hypofractionated This is an independent academic study (Canarian Foundation of radiotherapy would probably be confirmed when using a more Health Investigations, FUNCANIS) supported by an unrestricted active second-generation antiandrogen like enzalutamide in a educational grant from Astellas. similar setting. The improvement in PSA response by adding radiotherapy to enzalutamide and the better response observed when using modern hypofractionated EBRT are related, in our opinion, SUPPLEMENTARY MATERIAL not only to the higher EQD2 administered but to the biological basis of the radiosensitizing effect of enzalutamide. If protracted The Supplementary Material for this article can be found online conventional radiotherapy schemes are used (daily fractions for at: https://www.frontiersin.org/articles/10.3389/fonc.2022. almost nine weeks), tumor proliferation would be relevant 891886/full#supplementary-material 3. Lee WR. Prostate Cancer and the Hypofractionation Hypothesis. J Clin Oncol REFERENCES (2013) 31:3849–51. doi: 10.1200/JCO.2013.52.4942 1. NCCN. Prostate Cancer. NCCN Guidelines Version 3 (2016). Available at: 4. Zietman AL. Making Radiation Therapy for Prostate Cancer More www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Economical and More Convenient. J Clin Oncol (2016) 34:2323–4. doi: 2. Gray PJ, Zietman AL. Dose-Escalated Radiotherapy for Prostate Cancer: Is 10.1200/JCO.2016.67.3764 the Sky the Limit? JAMA Oncol (2015) 1:883–4. doi: 10.1001/jamaoncol. 5. 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She is also the National Coordinator of the Efficacy and Side Effects of Bicalutamide Compared With Luteinizing Brachytherapy Group of the Spanish Society of Radiation Oncology (SEOR). Hormone-Releasing Hormone (LHRH) Analogs in Combination With AG-I received payment or honoraria for lectures, presentations, speakers bureaus, Radiation Therapy in the CHHiP Trial. Int J Radiat Oncol Biol Phys (2022) manuscript writing, or educational events from ASTELLAS, BAYER, JANSSEN, 113(2):305–15. doi: 10.1016/j.ijrobp.2021.12.160 IPSEN PHARMA & BOSTON SCIENTIFIC and declared participation on a Data 41. Pedicini P, Strigari L, Benassi M. Estimation of a Self-Consistent Set of Safety Monitoring Board or Advisory Board for BAYER, ELEKTA, JANSSEN & Radiobiological Parameters From Hypofractionated Versus Standard ASTELLAS. GS received payment or honoraria for lectures, presentations, Radiation Therapy of Prostate Cancer. Int J Radiat Oncol Biol Phys (2013) speakers bureaus, manuscript writing, or educational events from ASTELLAS, 85(5):e231–7. doi: 10.1016/j.ijrobp.2012.11.033 BAYER & JANSSEN and support for attending meetings and/or travel from ASTELLAS & IPSEN PHARMA. XM received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Conflict of Interest: PL received payment or honoraria for lectures, presentations, ASTELLAS & BAYER and support for attending meetings and/or travel from speakers bureaus, manuscript writing or educational events from Carl-Zeiss and ASTELLAS, IPSEN PHARMA & JANSSEN. He declared Participation on a Data support for attending meetings and/or travel from Carl-Zeiss. JR-M received Safety Monitoring Board or Advisory Board for BAYER &ASTELLAS. The payment or honoraria for lectures, presentations, speakers bureaus, manuscript remaining author declares that the research was conducted in the absence of writing or educational events from ASTELLAS, BAYER, JANSSEN, CASEN- any commercial or financial relationships that could be construed as a potential RECORDATI, IPSEN PHARMA & BOSTON SCIENTIFIC and support for conflict of interest. attending meetings and/or travel from ASTELLAS & JANSSEN. He also received equipment, materials, drugs, medical writing, gifts or other services Publisher’s Note: All claims expressed in this article are solely those of the authors from ASTELLAS, BAYER, JANSSEN, CASEN-RECORDATI, IPSEN PHARMA & and do not necessarily represent those of their affiliated organizations, or those of BOSTON SCIENTIFIC. AP-E received payment or honoraria for lectures, the publisher, the editors and the reviewers. Any product that may be evaluated in presentations, speakers bureaus, manuscript writing or educational events from this article, or claim that may be made by its manufacturer, is not guaranteed or ASTELLAS, JANSSEN & IPSEN PHARMA and support for attending meetings endorsed by the publisher. and/or travel from ASTELLAS & JANSSEN. AL declared payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational ́ Copyright © 2022 Lara, Rodrıguez-Melco ń , Palacios-Eito, Lozano, Hervaś -Moroń , events from ASTELLAS, JANSSEN & IPSEN PHARMA and declared Villafranca, Gom ́ ez-Iturriaga, Sancho and Maldonado. This is an open-access article participation on a Data Safety Monitoring Board or Advisory Board JANSSEN distributed under the terms of the Creative Commons Attribution License (CC BY). & ASTELLAS. EV received payment or honoraria for lectures, presentations, The use, distribution or reproduction in other forums is permitted, provided the speakers bureaus, manuscript writing or educational events from JANSSEN original author(s) and the copyright owner(s) are credited and that the original &IPSEN PHARMA, support for attending meetings and/or travel from publication in this journal is cited, in accordance with accepted academic practice. No ELEKTA, and declared participation on a Data Safety Monitoring Board or use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Oncology | www.frontiersin.org 12 July 2022 | Volume 12 | Article 891886