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Article

Evaluation and Effectiveness of Clinical Trials with Hormone Therapy in the Treatment of Prostate Cancer

by
Olga Ramos-Barriga
1,
Bárbara-Yolanda Padilla-Fernández
2,
Sebastián Valverde-Martínez
1,3,4,
Miguel Perán-Teruel
5,
Magaly-Teresa Márquez-Sánchez
3,
María-Carmen Flores-Fraile
1,
Javier Flores-Fraile
1,*,
Mario Martin-Hernández
3,4,
Edwin Grinard-de-León
4,
María-Begoña García-Cenador
1 and
María-Fernanda Lorenzo-Gómez
1,3,6
1
Department of Surgery, University of Salamanca, 37007 Salamanca, Spain
2
Section of Urology, Department of Surgery, University of La Laguna, 38200 Tenerife, Spain
3
Renal Urological Multidisciplinary Research Group (GRUMUR), The Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
4
Department of Urology, University Hospital of Ávila, 05004 Ávila, Spain
5
Department of Urology, University Hospital Arnau de Vilanova, 46015 Valencia, Spain
6
Department of Urology, University Hospital of Salamanca, 37007 Salamanca, Spain
*
Author to whom correspondence should be addressed.
Appl. Sci. 2022, 12(10), 5059; https://doi.org/10.3390/app12105059
Submission received: 1 March 2022 / Revised: 12 April 2022 / Accepted: 10 May 2022 / Published: 17 May 2022
Browse Figures
Versions Notes

Abstract

:
Background: Prostate cancer is currently the most common malignant tumour in men. Research on hormone therapy advances is necessary because, unfortunately, some tumours are not organ-confined. Objective: To review and analyse the current state of evidence regarding clinical trials with neoadjuvant or adjuvant hormone therapy for prostate cancer and determine the contribution of these trials to the clinical practice. Methods: A critical systematic analysis of hormone therapy clinical trials for prostate cancer in the American Society of Clinical Oncology (ASCO) 2022 official database was carried out and following the Cochrane Handbook for Systematic Reviews of Interventions, a meta-analysis of random effects and standard mean descriptive statistics were performed. Groups: Group A = Neoadjuvant (n = 53) clinical trials and Group B = Adjuvant (n = 73) clinical hormone therapy. Variables: Phase of the trial, modality of primary treatment, investigated intervention or drug, molecular targets, trial length, sponsors and collaborators, country/countries of trial development, estimated enrolment, assignment of patients, intervention and masking model, trial purpose, related articles, the average number of studied patients, and conclusive results in clinical practice. Results: A total of 7.15% of the studies were in phase I, 14.28% between phase I-phase II, 52.38% in phase II, 0.23% between phase II-phase III and 23.80% in phase III. In the neoadjuvant group, enzalutamide and abiraterone were more frequently used, the androgen receptor was more frequently investigated as a molecular target. In the adjuvant group, abiraterone and prednisone were more frequently used and the androgen receptor and cytochrome P450 were more frequently investigated. The mean number of articles related to each trial was 5.26 (SD 3.15, 1–10). In 47.27% of the published articles directly related to the trials, the investigated treatment was superior to the standard treatment. Adjuvant investigated drugs showed more superiority (52.22%) than neoadjuvant drugs (41.33%). Conclusions: Only 41.33% of neoadjuvant studies and 52.22% of adjuvant studies show conclusive results of superiority for the proposed therapeutic strategies. About a third of related scientific publications that transfer the results to clinical practice did not report conclusive results for either neoadjuvant (32%) or adjuvant (37.78%) therapy.

1. Introduction

Prostate cancer (International Classification of Diseases [ICD] 10 C61 Malignant tumour of the prostate) is the glandular epithelial cells’ abnormal and disordered growth that can spread [1,2].
Its incidence increases with age, and it is rarely diagnosed in patients under 50. It is estimated that around 200,000 new cases are diagnosed every year, and one in five has a fatal evolution [2]. Worldwide, there were an estimated 1.4 million diagnoses in 2020 [3,4]. Prostate cancer ranks second among the most frequent tumours in the Spanish population, both for incidence and fatality [5]. A total of 95% of these tumours are acinar adenocarcinomas, which tend to be multifocal. More than 50% are in the peripheral area, followed in frequency by the transition and central ones [6].
Research on hormone therapy advances in prostate cancer is very active: in the 2022 European Association of Urology Guidelines, a total of 193 new publications were added since 2021 [7]. This increase in the investigation is due to prostate cancer’s increasing prevalence with age, which increases 1.7 times every decade (on average), reaching numbers between 48% and 71% (59% on average) in men older than 79 years [8].
The prostate is a sexual organ that depends on testosterone to carry out the physiological function of producing fluid for seminal plasma. The effectiveness of hormone therapy for prostate cancer is based on stopping hormone-dependent activity by suppressing the hormones, and it depends on the degree of anaplasia or differentiation in the prostatic cancer cells. When these cells do not respond to the hormonal stimuli, they continue growing regardless of the suppression of these stimuli. On the other hand, hormone therapy never definitively cures prostate cancer, only stopping the progression. The effectiveness of this therapy is measured by the amount of time for the tumour to stop from growing [9].
The most significant discovery about the dramatic effects of castration and estrogen administration on prostate cancer cells was made by Huggins in 1941. Studies in dogs with prostate growth proved that castration or oestrogen administration caused a rapid shrinkage of dogs’ prostatic tumours [10,11,12]. Huggins and Scott subsequently proved that, in some cases, extragonadal androgen steroid withdrawal with bilateral adrenalectomy caused a further decrease in prostate cancer symptoms once castration effects had disappeared. This was the first discovery showing that cancer could be controlled by drugs [13,14].
Multiple variables that may have prognostic value in prostate cancer have been studied, but not all are equally important. They have allowed the development of prognostic nomograms useful when choosing the most suitable treatment for each specific case. The most widely used are the Memorial Sloan Kettering Center nomograms used before treatment, after radical prostatectomy, after cancer recurrence is observed and in hormone-refractory cancers [6].
Depending on staging, the patient is informed about the different treatment possibilities. Since it is a hormone-dependent tumour, hormone therapy has been indicated in organ-confined, locally advanced, metastatic or castration-resistant cases or even in men who had received curative treatment (prostatectomy, radiotherapy, or other), when it recurred [9].
Ciccarese et al. tried to understand the mechanisms that allow prostatic cells to become treatment-resistant. In their review, they address the resistance to abiraterone acetate and enzalutamide with special interest in androgen receptor (AR) splice variants (AR-Vs) such as AR-V7 [15]. They concluded that, given the available evidence, the study of these variants can be useful in predicting and treating metastatic castration-resistant prostate cancer (mCRPC) [2].
Another study by Vellky et al. studied androgen receptor expression in castration-resistant prostate cancer (CRPC). They concluded that there are signalling pathways through which ARs are downregulated epigenetically, post-transcriptionally, or posttranslationally, which results in types of CRPC that do not respond to androgen receptor-targeted therapies [16].
Hormonal therapy does not cure prostate cancer; it only stops the progression [9]. Therefore, when cancer becomes hormone-resistant or castration-resistant, new treatments (the new molecules) will be needed to act on those cancer cells that have learned to avoid the regulatory mechanisms of androgens [7,17,18]. Thus, it is essential to study this subject’s current state of evidence.
The objective of this study was to review and analyse the current state of evidence regarding clinical trials with neoadjuvant or adjuvant hormone therapy for prostate cancer and determine the contribution of these trials to clinical practice.

2. Objectives

  • Identify the stage of neoadjuvant and adjuvant clinical trials in hormone therapy for prostate cancer registered in the official databases of the American Society of Clinical Oncology (ASCO) website.
  • Find out the drugs and molecular targets most tested in hormone therapy in prostate cancer.
  • Establish which strategies have the most weight in clinical trials of hormone therapy for prostate cancer.
  • Determine the contribution to clinical practice regarding the management of prostate cancer based on clinical trials of hormone therapy and their scientific articles.

3. Methods

A critical systematic analysis of hormone therapy clinical trials for prostate cancer was conducted of the American Society of Clinical Oncology (ASCO) 2022 official database following the Cochrane Handbook for Systematic Reviews of Interventions [19]. Scheme 1 shows the flow chart diagram of the research strategy.
Terms such as “Prostate Cancer”, “Hormone Therapy”, and “Clinical Trial” were searched in PubMed, Medline and general search engines such as Google. After studying the items included in American, European and Asian databases on clinical trials for prostate cancer, it was decided to use the official webpage of the American Society of Clinical Oncology (ASCO) 2022 for the search, as shown in the flow chart diagram of the research strategy. Studies that included other types of cancer and those with only one group were excluded.
Therefore, the source to obtain information and abstracts was the official website for ASCO’s prostate cancer trials. Date of access: 1 April 2022 (American Society of Clinical Oncology (ASCO) 2022).
Although trials were selected using the ASCO’s trials list, the searches of published articles related to the trials were carried out to find clinical results in patients including those from other countries or continents.

3.1. Study Groups

Two study groups were established:
Group A (GA) (n = 31): clinical trials of neoadjuvant hormone therapy for prostate cancer.
Group B (GB) (n = 49): clinical trials of adjuvant hormone therapy for prostate cancer.

3.2. Analysed Variables

  • Trial phase: 1, 2, 3 or, when there was an intermediate phase between two phases, it was specified as 1.5 between 1 and 2, or 2.5 between 2 and 3.
  • Modality: Table 1 shows the type of therapy.
Types of therapy included several modalities: hormonal, surgery, radiation, chemotherapy, etc. We included all therapies received by patients. Each therapy received by patients was analysed. Many patients received combination therapy, but one of the therapies was the primary treatment. Depending on the primary treatment, hormone therapy could be neoadjuvant or adjuvant. These two types were separated into the two main study groups. The impact of each treatment in the combination therapy was analysed in the multivariate analysis carried out.
3.
Investigated Drug or Intervention
Table
Table 1. Primary treatment used for prostate cancer.
Table 1. Primary treatment used for prostate cancer.
Hormonal TherapySurgeryAnalgesic Agent
Radiation TherapyAntidiabetic TherapyProton Therapy
ChemotherapyImmunotherapyData Collection
PARP InhibitorMonoclonal AntibodyAntimicrobial Therapy
Signal Transduction InhibitorSupplement TherapyGenetic
Table 2 shows investigated drugs.
Hormonal deprivation therapies used in neoadjuvant trials were analysed (Table 3). A wide variety of ADTs was observed. In the multivariate analysis, no differences were found between the different modalities of ADT that could determine clinical results of superiority, equality, or inferiority over the standard treatments for prostate cancer.
Table 4 shows the hormonal deprivation therapies used in adjuvant trials. A wide variety of ADTs was also observed in the adjuvant trials, with a predominance of enzalutamide (n = 11), followed by the ADT chosen by the physician or institution with no specification of ADT (n = 22), abiraterone or enzalutamide (n = 11) and abiraterone (n = 8). In the multivariate analysis, no differences were found between the different modalities of ADT that could determine clinical results of superiority, equality, or inferiority over the standard treatments for prostate cancer.
4.
Molecular targets are listed in Table 5.
5.
Trial length (in months): length of time from the beginning of the study until 1st April 2022, if the study was still active, or total time if the trial had been completed.
6.
Sponsors and collaborators: Pharmaceutical company or Public Entity (hospital, university, institute).
7.
Country/countries: USA; Canada or multicentre.
8.
Estimated enrolment: number of patients included.
9.
Assignment of patients: randomised, successive assignment, or non-randomised.
10.
Intervention and masking model: none, double, triple, quadruple, or single.
11.
Trial purpose: treatment, diagnosis, or care.
12.
Publications or clinical evidence; the following were studied:
12.1.
Related articles in clinical practice: number of articles.
12.2.
Average number of patients investigated in the articles: mean, median, standard deviation and range.
12.3.
Conclusive results in clinical practice; three possible results:
-
Superiority of the investigated treatment over the standard treatment.
-
In process: the article reported that further studies were needed and there were no conclusive results.
-
No superiority of the investigated treatment over the standard treatment.

3.3. Statistical Analysis

Results were analysed by descriptive statistics, ANOVA analysis of variance, Student’s t-test and Fisher’s exact test were evaluated using the automatic statistical package SPSS V25, IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp [144]. For the meta-analysis of random effects odds ratios, the Review Manager software (Rev Man) [Computer program] Version 5.2. Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2012 was used [145]. Statistical significance was accepted for p < 0.05.

4. Results

4.1. Analysis of the Phase

We found that 8.73% of the studies were in phase I, 12.70% were between phases I- II, 52.38% were in phase II, 2.38% were between phases II-III, and 23.81% were in phase III. Significant differences were found (p = 0.0485). Phase II trials were the most frequent in both groups. In GA (neoadjuvant) [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72], 15.09% of the trials were in phase I and 58.49% in phase II. In GB (adjuvant) [73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143], 47.95% of the trials were in phase II.
Figure 1 and Supplementary Figures S1 and S2 show the findings in the random-effects meta-analysis with odds ratios between either neoadjuvant or adjuvant treatments and other treatments. In phase I (Figure 1), the distribution of the studies was homogeneous. In the neoadjuvant group, the total effect was OR = 1.03 with confidence intervals 0.90–1.18, p = 1.000. In the adjuvant group, the total effect was OR = 1.04 with confidence intervals 0.89–1.21, p = 1.000. There was the same distribution in both groups. In phase II (Supplementary Figures S1 and S2), the distribution of the studies was homogeneous; for the neoadjuvant group, the total effect was OR = 1.06 with confidence intervals 0.97–1.17 p = 1.000; in the adjuvant group, the total effect was OR = 1.04 with confidence intervals 0.96–1.13 p = 1.000. In phase III, the distribution of the studies was homogeneous, and the total effect was OR = 1.03 with confidence intervals 0.97–1.09 p = 0.76. Hormone therapy as primary adjuvant treatment in phase III was a protective factor and favoured the treatment of prostate cancer OR: 0.96 (95% CI 0.84–1.10). Both groups had the same distribution (Supplementary Figures S1 and S2).

4.2. Type of Treatment for Prostate Cancer

In the general sample, 91,27% of trials had hormonal therapy, 25.40% radiotherapy, 27.78% chemotherapy, 23.02% PARP inhibitors, 19.05% signal transduction inhibitor, and 10.32% surgery. There was no difference in treatment types between GA and GB (p= 0.8309) (Figure 2).

4.3. Investigated Drugs

The eight most frequently investigated drugs are shown in Table 6.
Differences were found in the proportion of the investigated drugs between GA and GB (p = 0.0019). In GA, enzalutamide (26.42%) and abiraterone/leuprolide (24.53%) were more frequently used. In GB, abiraterone, prednisone (43.84%) and enzalutamide (36.99%) were more frequently used.

4.4. Molecular Targets

Distribution of most frequent molecular targets in the study groups are shown in Table 7.
In GA and GB, the androgen receptor (p = 0.0051) was more frequently used as a molecular target.

4.5. Trial Length (Months)

The mean trial length was 42.54 months, standard deviation 25.32 months, median 40.50 months, and range 4–164 months. This means an average study length of 3.54 years, with a range from 4 months to 13.66 years. There were no differences between GA and GB (p = 0.324).
Supplementary Figure S3 shows the random-effects meta-analysis of the evolution time between studies with neoadjuvant and other treatments., Mean difference was −0.72 months (95% CI 0.92–0.53) p ≤ 0.0001, so there was a benefit in neoadjuvant treatment with hormone therapy over time. Mean total effect in adjuvant treatment was −0.52 months (95% CI 0.63 −0.40) p ≤ 0.0001, so there was a benefit in adjuvant treatment with hormonal therapy over time (Supplementary Figure S4).

4.6. Sponsors

Figure 3 shows Trial sponsors. Pharmaceutical companies funded 45.24% of trials and 57.14% were funded by a Public Entity. There was no difference between GA and GB (p = 0.2753).

4.7. Countries

Trials were geographically distributed as follows: 70.63% of the studies were performed in the U.S.A., 9.52% in Canada, and 22.22% were multicentre. No differences were found between GA and GB (p = 0.6923)

4.8. Number of Patients Included

The mean number of patients included was 275.71, SD 371.94, median 120.00 and a range of 11–2400 (Figure 4). No differences were found between GA and GB (p = 0.772).

4.9. Assignment

The selection of patients was randomised in 62.70% of the cases, successive in 25.40%, and non-randomised in 11.90% (Figure 5). Successive assignment was more common in GA, while randomised assignment was more common in GB (p = 0.2650).

4.10. Intervention and Masking Model

There was no masking in 102 trials (80.95%), single masking in one case (0.79%), double masking in 11 cases (8.73%), triple masking in 4 cases (3.17%) and quadruple masking in eight cases (6.35%). No differences were found between GA and GB (p = 0.7596).

4.11. Trial Purpose

The objective of one trial in GA was to investigate diagnosis; the objective of another one was to investigate care. The rest of the trials aimed to investigate treatment.

4.12. Evidence of Investigated Drugs’ Results in Clinical Practice: Publications Directly Related

The mean number of studied articles for each group was 5.26, the SD was 3.15, the median was 5, and the range was from 1 to 10. In GA, only 41.33% had conclusive superiority results, 52.22% in GB. 26.67% of GA studies and 10% of GB studies were still in process and did not have conclusive results (Figure 6). Superiority of the investigated drug could not be proven in 32% of cases in GA and 37.78% in GB (p = 0.0194) (Table 8).

5. Discussion

The last part of this study was an exhaustive search of the official databases of the American Society of Clinical Oncology for clinical trials of neoadjuvant and adjuvant therapy for prostate cancer to find the contribution of these trials to clinical practice regarding prostate cancer management [146]. Enzalutamide, abiraterone, and apalutamide were the most frequently investigated drugs in neoadjuvant conventional androgen deprivation therapy. Abiraterone and prednisone were the most studied drugs in adjuvant therapy.
This observation may mean that drugs whose efficacy has been proven are investigated in neoadjuvant therapy for cancers with a poor prognosis. However, effectiveness of these drugs was also examined in phase I trials. Therefore, using these drugs earlier may help manage the disease and increase the quality of life due to better control of symptoms or improving pathological outcomes of patients, as proven in another meta-analysis [147].
On the other hand, leuprolide was maintained in adjuvant therapies as a basal treatment in hormone therapy while abiraterone was the most investigated new drug in the adjuvant therapy group (43.84%). Another meta-analysis by Liu et al. [148] showed that adjuvant androgen hormone therapy improved overall survival and reduced recurrences and specific mortality. Whether or not this improvement was related to a particular molecule is unclear, given that more than one molecule was included in their analysis, much like our own research. Another meta-analysis compared the efficacy of these drugs concluding that there were no significant differences between these new molecules [149]. Target therapies were investigated in both fields (neoadjuvant and adjuvant). Still, we observed an interesting contrast in the type of drug used in each group. In neoadjuvant therapies, drugs targeting GnRH and LHRH receptors were more frequently investigated, while in adjuvant therapies the androgen receptor and CYP17 were the most frequent.
It should be highlighted that both phase I (trials to evaluate drug safety) and phase II (first efficacy evaluation) were more frequently found in neoadjuvant therapy trials. In contrast, phase III, which is used to compare efficacy with the standard treatment, was more frequently found in adjuvant trials. The average length of trials was 3.125 years, consistent with the established length of an average of 8 years for developing phases I, II and III within clinical trials [150].
As for the sponsors of clinical trials of this study, approximately half were funded by pharmaceutical companies and the other half by public entities, with a slight predominance of the latter. This is probably due to the lack of information, especially from clinical trials in the early stages, since the sponsor is usually a pharmaceutical company. Clinical trials were mainly carried out in the U.S.A., followed by Canada. This makes sense since our search was performed in the American Society for Clinical Oncology database [146].
The mean number of patients included was 178.68, ranging from 11 to 1273 patients. These data are consistent with those estimated for each phase: phase I (between 10–30 patients), phase II (less than 100 patients) and phase III (between hundreds and thousands of patients) [151].
Not having any masking was the most common in both groups; that is, all parties (both patients and professionals) were aware of the treatment received by patients [152].
In GA, successive assignment was the most frequent allocation technique used, whereas random assignment was most frequent in GB. This means that there were more risks using random assignment in GB, including trials with lower survival probability. There were studies with superior results in GB, but they were only half of them (52.22% in GB versus 41.33% in GA). It is essential to highlight that the patients involved in these studies are in worse and more desperate conditions. The percentage of trials where authors do not report superiority or no superiority in their results (37.78%) is very high. As mentioned above, these patients have a poorer prognosis and this could mean that worse conditions lead these patients to participate in more risky trials.

6. Future Lines of Research

Inclusion criteria were not specified in many clinical trials. Detailed descriptions of each patient’s degree of compromise that includes local spread of the illness, metastasis, and symptom severity were not available. In addition, serialised histopathological characterisation during follow-up is mostly impossible, since the nature of the aggressiveness or the immunohistopathological characterisation of the local and metastatic lesions is unknown in the patients. For this reason, despite the critical efforts in hormonal therapy research on prostate cancer, it is challenging to standardise inclusion criteria accurately. Thus, it would be essential to make a great effort in this sense in the future. In fact, in recent years, a large proportion of research on prostate cancer has focused on diagnostic characterisation other than prostate or metastatic lesions biopsy, since these are the current methods in usual clinical practice [5]. Therefore, it is essential to accurately define patients’ inclusion and stratification criteria according to the illness level.

7. Strength and Limitations

This meta-analysis included all types of hormone treatments found in the database used, allowing a large set of therapies to be analysed and compared.
Differences in clinical trials in terms of duration (range 11–152 months), inclusion criteria of patients, and the predominance of North American studies were limitations of this study.

8. Conclusions

The 41.33% of neoadjuvant studies and 52.22% of adjuvant studies showed conclusive results of superiority for the proposed therapeutic strategies. In almost half (47.27%) of the published articles directly related to the trials, the investigated treatment was superior to the standard treatment. About a third of related scientific publications that transferred their results to clinical practice did not report conclusive results for either neoadjuvant (32%) or adjuvant (37.78%) hormone therapy.
Clinical benefits regarding treatment response and prognosis from the scientific and economic effort invested in hormone therapy research for prostate cancer were observed in one-third of the treated patients.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/app12105059/s1, Figure S1: Forest plot neoadjuvant treatment vs other treatment, phase II and III trials; Figure S2: Forest plot adjuvant treatment vs other treatment, phase II and III trials; Figure S3: Forest plot time of treatment in the neoadjuvant group; Figure S4: Forest plot time of treatment in the adjuvant group.

Author Contributions

Conceptualisation, M.-F.L.-G. and M.-B.G.-C.; methodology, M.-F.L.-G.; formal analysis, M.-T.M.-S.; resources, O.R.-B.; B.-Y.P.-F.; and M.M.-H.; data curation, M.-T.M.-S.; writing—original draft preparation, J.F.-F.; writing—review and editing, J.F.-F. and M.-C.F.-F.; visualization, J.F.-F.; supervision, M.-F.L.-G. and M.P.-T.; project administration, S.V.-M. and E.G.-d.-L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Association for the Promotion of Training and Research in Surgical Specialties in Castilla y León (APFIEQ-CyL) (Asociación para la Promoción de la Formación y la Investigación en Especialidades Quirúrgicas en Castilla y León), Salamanca, Spain, grant number fl201901.

Institutional Review Board Statement

The study protocol with code 01072019-MLG-GRUMUR was conducted in accordance with the Declaration of Helsinki and approved by the Drug Research Ethics Committee of the Healthcare Area of Avila, Spain date of approval 30 January 2019.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The main researcher and the collaborators have no conflict of interest to report.

Abbreviations

AEMSPSSpanish Agency of Medicine and Sanitary Products
ARandrogen receptor
APFIEQ-CYLAssociation for the Promotion of Surgical Specialities Training and Research in Castilla y León (Asociación para la Promoción de la Formación e Investigación en Especialidades Quirúrgicas en Castilla y León)
CYP17Cytochrome 17
GAGroup A
GBGroup B
GnRHGonadotropin-releasing hormone
LHRHluteinizing hormone-releasing hormone
PARPpharmacological inhibitors of the enzyme poly ADP ribose polymerase
RTRadiotherapy
CTChemotherapy

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Scheme 1. Flow chart diagram of the research strategy. * This tool is provided by Us TOO International Prostate Cancer Education and Support Network. One can access information about prostate cancer-specific clinical trials through the phone or internet (accessed on 1 April 2022).
Scheme 1. Flow chart diagram of the research strategy. * This tool is provided by Us TOO International Prostate Cancer Education and Support Network. One can access information about prostate cancer-specific clinical trials through the phone or internet (accessed on 1 April 2022).
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Figure 1. Forest plot neoadjuvant or adjuvant treatment vs. other treatments, phase I.
Figure 1. Forest plot neoadjuvant or adjuvant treatment vs. other treatments, phase I.
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Figure 2. Type of treatment for prostate cancer in GA and GB.
Figure 2. Type of treatment for prostate cancer in GA and GB.
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Figure 3. Trial sponsors.
Figure 3. Trial sponsors.
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Figure 4. Box plot of number of patients included in the trials (p = 0.772). Circles represent studies with more than 2 standard deviations from the median and * represent atypical values.
Figure 4. Box plot of number of patients included in the trials (p = 0.772). Circles represent studies with more than 2 standard deviations from the median and * represent atypical values.
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Figure 5. Assignment of patients (p = 0.0320).
Figure 5. Assignment of patients (p = 0.0320).
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Figure 6. Number of published articles directly related to the trials (p = 0.3160).
Figure 6. Number of published articles directly related to the trials (p = 0.3160).
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Table
Table 2. Investigated drug or intervention in trials.
Table 2. Investigated drug or intervention in trials.
Androgen Deprivation Therapy (ADT)TriptorelinATRAPembrolizumabSamotolisib
Rucaparib.Testosterone enanthateAzacitidineSD-101Cisplatin
DocetaxelPDMX1001Filgrastim2-HydroxyflutamideEverolimus
EnzalutamideGalunisertibRibociclibAdavosertib (AZD-1775)Trastuzumab
AbirateroneCabazitaxelZEN003694Savolitinib/volitinib (AZD-6094)Doxorubicin
IpatasertibMetforminCarotuximabDarolutamideCyclophosphamide
PrednisoneIpilimumabIndomethacinADV/HSV-tkDexamethasone
ApalutamideCarboplatinTRC-253/JNJ-63576253ValacyclovirEribulin
DegarelixGonadotropinsCORT.125281Testosterone CypionateTopotecan
TalazoparibGnRH-based vaccineLHRH agonistsZuclomipheneSelinexor
Olaparib (AZD-2281)Radium223CPI-1205RifampinPaclitaxel
NilutamideGoserelinTAS-3681CrizotinibAcetaminophen
BicalutamideNivolumabRelugolixAbemaciclibDiphenhydramine
FlutamideRucaparib111 In-J591PemetrexedHLX07
Histrelin acetateMuscadine grape extract117 Lu-J591MidazolamOndansetron
LeuprolideOnvansertibHydrocortisoneFulvestrant
GoserelinIT-101/CRLX-101KetoconazoleLetrozole
ADT: Androgen deprivation therapy. ATRA: All-Trans Retinoic Acid.
Table
Table 3. Hormonal deprivation therapies used in neoadjuvant trials.
Table 3. Hormonal deprivation therapies used in neoadjuvant trials.
Neoadjuvant Hormone Deprivation TherapyReferencesNumber of Trials Where It Was Used (n)
Abiraterone[20,21,22,23,24,25,26,27,28,29] 10
Abiraterone or leuprolide[30]1
Abiraterone, apalutamide or leuprolide[31,32,33,34]4
Apalutamide[35,36,37,38,39,40]6
Bicalutamide[41]1
Bicalutamide and leuprorelin[42,43,44]3
Bicalutamide, Degarelix, goserelin, leuprorelin, triptorelin[24]1
Bilateral orchiectomy or LHRH agonist or LHRH antagonist[30,31,32,42,43,45,46,47,48,49,50]11
Darolutamide[23,50,51,52]4
Degarelix or goserelin or leuprolide[24,47]2
Docetaxel, Enzalutamide[53,54]2
Flutamide[55,56]2
Goserelin[49,54]2
Goserelin or Degarelix or leuprolide or triptorelin[47]1
Ketoconazole[57,58]1
Leuprolide[47,59]2
Letrozole[60,61]2
Relugolix[45]1
Talazoparib, Enzalutamida[62]1
Testosterone[24,63,64]3
The choice of the physician or institution/Non specified[20,21,23,24,25,26,27,32,36,37,43,52,61,63,65,66,67,68,69,70,71,72]22
Table
Table 4. Hormonal deprivation therapies used in adjuvant trials.
Table 4. Hormonal deprivation therapies used in adjuvant trials.
Adjuvant Hormonal Deprivation TherapyReferencesNumber of Trials Where It Was Used (n)
Abiraterone[73,74,75,76,77,78,79,80,81,82,83]11
Abiraterone or apalutamide[80,84,85,86,87,88,89]7
Abiraterone or apalutamide or leuprolide[90]1
Abiraterone or apalutamide or degarelix[91]1
Abiraterone or bicalutamide or leuprorelin[92,93]2
Abiraterone or enzalutamide[90,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109]17
Abiraterone or enzalutamide or testosterone[74,105,110,111,112,113,114]7
Abiraterone or leuprorelin[115]1
Apalutamide or leuprorelin[79,81,90,116,117]5
Bicalutamide[107]1
Cabazitaxel[82,112]2
Docetaxel[88,93,117,118]4
Enzalutamide[90,98,102,104,105,108,109,119,120,121,122,123,124,125,126,127,128,129,130]19
Leuprorelin[131,132]2
Leuprorelin or testosterone[74,105,110,111]4
TCR253[133]1
The choice of the physician or institution[92,129,134,135,136,137,138,139]8
Non specified[140,141,142,143]4
Table
Table 5. Molecular targets on which investigated drugs act.
Table 5. Molecular targets on which investigated drugs act.
ARALKPD1ENG
CYP17TGFBRPDCD1COX
PARP.TubulinHIF1 alphaEZH2
AKTNADPHTOP1CYPx
PKBCTLA4CDKNR3C1
GnRHGlucocorticoid receptorCSFRMET
LHRHCDBETWEE1
Table
Table 6. Most frequently investigated drugs. ADT: see specific section for ADT.
Table 6. Most frequently investigated drugs. ADT: see specific section for ADT.
Investigated DrugsGA, n = 53%GB, n = 73%Totalp-Value
Androgen deprivation therapy59.431115.07160.4237
Docetaxel611.321926.03250.0449
Enzalutamide1426.422736.99410.2503
Abiraterone1324.533243.84450.0377
Prednisone916.983243.84410.0019
Apalutamide1120.751621.92271.0000
Bicalutamide59.4379.59121.0000
Leuprolide1324.531317.81260.3802
Table
Table 7. Distribution of most frequent molecular targets in the study groups.
Table 7. Distribution of most frequent molecular targets in the study groups.
Molecular TargetsGA, n = 53%GB, n = 73%Total%p-Value
AR2649.065473.978063.490.0051
CYP171222.642736.993930.950.1181
GnRH1324.531216.442519.840.2691
LHRH1222.64912.332116.670.1497
AR = androgen receptor; CYP17 = Cytochrome P450 17alpha-hydroxylase/17,20-lyase; GnRH = gonadotropin-releasing hormone; LHRH = luteinizing hormone-releasing hormone.
Table
Table 8. Proportion of published articles related to clinical trials: conclusive results of superiority of the investigated or proposed drug over the standard treatment.
Table 8. Proportion of published articles related to clinical trials: conclusive results of superiority of the investigated or proposed drug over the standard treatment.
Conclusive Results for Clinical PracticeGAGB
Superiority of the investigated drug over the standard treatment41.3352.22
In process, without conclusive results26.6710.00
Not specified whether the investigated drug is superior or not to the standard treatment32.0037.78
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Ramos-Barriga, O.; Padilla-Fernández, B.-Y.; Valverde-Martínez, S.; Perán-Teruel, M.; Márquez-Sánchez, M.-T.; Flores-Fraile, M.-C.; Flores-Fraile, J.; Martin-Hernández, M.; Grinard-de-León, E.; García-Cenador, M.-B.; et al. Evaluation and Effectiveness of Clinical Trials with Hormone Therapy in the Treatment of Prostate Cancer. Appl. Sci. 2022, 12, 5059. https://doi.org/10.3390/app12105059

AMA Style

Ramos-Barriga O, Padilla-Fernández B-Y, Valverde-Martínez S, Perán-Teruel M, Márquez-Sánchez M-T, Flores-Fraile M-C, Flores-Fraile J, Martin-Hernández M, Grinard-de-León E, García-Cenador M-B, et al. Evaluation and Effectiveness of Clinical Trials with Hormone Therapy in the Treatment of Prostate Cancer. Applied Sciences. 2022; 12(10):5059. https://doi.org/10.3390/app12105059

Chicago/Turabian Style

Ramos-Barriga, Olga, Bárbara-Yolanda Padilla-Fernández, Sebastián Valverde-Martínez, Miguel Perán-Teruel, Magaly-Teresa Márquez-Sánchez, María-Carmen Flores-Fraile, Javier Flores-Fraile, Mario Martin-Hernández, Edwin Grinard-de-León, María-Begoña García-Cenador, and et al. 2022. "Evaluation and Effectiveness of Clinical Trials with Hormone Therapy in the Treatment of Prostate Cancer" Applied Sciences 12, no. 10: 5059. https://doi.org/10.3390/app12105059

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