Systematic Evaluation of Studies in the Fields of Diagnosis and Management of Prostate Cancer in Coronavirus Disease 2019 Era

Background: Prostate cancer is one of the most common cancers worldwide. The proper management of this cancer during the coronavirus disease 2019 (COVID-19) or similar outbreaks could be a serious challenge. Proper timing of surgery, radiotherapy, and other medical modalities are essential in providing the most effective treatment. Objective(s): This systematic review aimed at evaluating the proper management of prostate cancer during the COVID-19 outbreak. Method(s): This study was conducted from 2019 to 2022. An internet search was conducted using the keywords: Diagnosis, man-agement, radical prostatectomy, radiotherapy, hormone ablation therapy, chemotherapy and prostate cancer, and COVID-19. The visited databases included PubMed, Scopus, Web of Sciences, Google Scholar, and Scientific Information Database. The review was performed based on the preferred reporting items for a systematic review and meta-analyses (PRISMA) guidelines. Result(s): Postponing the biopsy for up to three months and adopting of non-invasive diagnostic methods were likely reasonable during the COVID-19 pandemic. Patients with cancer were more prone to severe injuries and were more likely to have serious compli-cations. Surgery, radiation therapy, brachytherapy, palliative radiation, hormone ablation therapy, and chemotherapy were among the pre-institutional treatments that had to be performed according to medical protocols as well as health and professional guide-lines. Conclusion(s): It was recommended that the prostate cancer screening should not be performed for asymptomatic men during the COVID-19 outbreak. It was also suggested that the treatment should be performed in the shortest possible time and in the safest way.Copyright © 2023, Author(s).

Impacts of androgen deprivation therapy on the risks and outcomes of SARS-CoV-2 infection in patients with prostate cancer.

Studies have investigated the effects of androgen deprivation therapy (ADT) use on the incidence and clinical outcomes of coronavirus disease 2019 (COVID-19); however, the results have been inconsistent. We searched the PubMed, Medline, Cochrane, Scopus, and Web of Science databases from inception to March 2022; 13 studies covering 84 003 prostate cancer (PCa) patients with or without ADT met the eligibility criteria and were included in the meta-analysis. We calculated the pooled risk ratios (RRs) with 95% confidence intervals (CIs) to explore the association between ADT use and the infection risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severity of COVID-19. After synthesizing the evidence, the pooled RR in the SARS-CoV-2 positive group was equal to 1.17, and the SARS-CoV-2 positive risk in PCa patients using ADT was not significantly different from that in those not using ADT (P = 0.544). Moreover, no significant results concerning the beneficial effect of ADT on the rate of intensive care unit admission (RR = 1.04, P = 0.872) or death risk (RR = 1.23, P = 0.53) were found. However, PCa patients with a history of ADT use had a markedly higher COVID-19 hospitalization rate (RR = 1.31, P = 0.015) than those with no history of ADT use. These findings indicate that ADT use by PCa patients is associated with a high risk of hospitalization during infection with SARS-CoV-2. A large number of high quality studies are needed to confirm these results.

Androgen deprivation therapy and hormonal status in men with COVID-19.

Severe course of cOVID-19 among men compared to the female led to a detailed study of the hormonal status of men with cOVID-19. The earliest works about this focused on the incidence and severity of cOVID-19 depending on the intake of androgen deprivation therapy. At the same time, different classes of androgen deprivation therapy have different effects on androgen concentration that was not always considered in the analysis. In this regard, we conducted a review of the available literature data with a targeted study of works that included androgen deprivation therapy with a unidirectional effect on the concentration of male sex hormones. In addition, we conducted a review of studies focused on the relationship between cOVID-19 and androgens (testosterone and dihydrotestosterone).Copyright © 2022 Authors. All rights reserved.

A cohort analysis of patients receiving neoadjuvant androgen deprivation therapy prior to robot-assisted laparoscopic prostatectomy during the Covid-19 pandemic.

Objectives: The purpose of this study was to investigate localised prostate cancer treated with or without neoadjuvant androgen deprivation therapy prior to robot-assisted laparoscopic prostatectomy, and the impact of Covid-19 treatment disruption, on clinico-pathologic outcomes. Patients and methods: Data was retrospectively collected from 124 consecutive patients treated with robot-assisted laparoscopic prostatectomy between November 2019-September 2020. Sixty-two patients were treated before 13 March 2020 (historic cohort) and 62 afterwards (covid cohort). Thirty-seven patients in the covid cohort additionally received neoadjuvant androgen deprivation therapy (mean duration of 3 months) consisting of bicalutamide 150 mg once a day for 4 weeks, with leuprolide 3.75 mg monthly injections commencing after week 1, up until the date of surgery. Results: Statistical analysis found no difference in peri-operative measures and length of stay for patients treated with or without neoadjuvant androgen deprivation therapy. Patients with delayed surgical treatment offered neoadjuvant androgen deprivation therapy showed a trend towards a reduction in positive surgical margins (p=0.134), N1 disease (p=0.424) and pathological down-staging (50% patients with pT2 disease). Patients within the covid cohort experienced significantly increased detectable prostate-specific antigen levels (p<0.007). Conclusion: Our study demonstrated that a three-month duration of neoadjuvant androgen deprivation therapy prior to robot-assisted laparoscopic prostatectomy may improve pathological outcomes but this time-frame is inadequate to influence detectable prostate-specific antigen levels. Covid-19-related treatment delays led to significantly increased detectable prostate-specific antigen levels. Level of evidence: 2b.

Androgen deprivation therapy and hormonal status in men with COVID-19

Severe course of cOVID-19 among men compared to the female led to a detailed study of the hormonal status of men with cOVID-19. The earliest works about this focused on the incidence and severity of cOVID-19 depending on the intake of androgen deprivation therapy. At the same time, different classes of androgen deprivation therapy have different effects on androgen concentration that was not always considered in the analysis. In this regard, we conducted a review of the available literature data with a targeted study of works that included androgen deprivation therapy with a unidirectional effect on the concentration of male sex hormones. In addition, we conducted a review of studies focused on the relationship between cOVID-19 and androgens (testosterone and dihydrotestosterone).

Androgen deprivation therapy duration is significantly associated with Testosterone recovery in Japanese patients with prostate cancer.

OBJECTIVE: Due to the fear generated by COVID-19 in Spring 2020, many patients postponed their scheduled outpatient visits. To differentiate those patients with prostate cancer (PCa) whose androgen deprivation therapy (ADT) injection treatment can be postponed, we investigated the characteristics of testosterone (T) recovery in Japanese patients after they received combined ADT and radiation therapy (RT). METHODS: We included 81 patients with PCa treated with ADT and RT at Keio University Hospital from January 2013 to December 2018. T-recovery was defined as the time interval between the last ADT injection and 3-6 months after T-normalization. The Kaplan-Meier method was used to estimate time to T-recovery. Cox proportional hazards models identified T-recovery predictors. RESULTS: The 50% cumulative incidence of T-recovery was 7.0 months for the 6-short-term group (defined as patients having ≤6 months of ADT therapy) versus 13.0 months for the 6-long-term group (>6 months of therapy) (p < 0.001). The incidence was 7.0 months for the 12 short-term-ADT (ST) group versus 18.0 months for the 12 long-term-ADT (LT) group (p < 0.001). Multivariate analysis revealed that a shorter duration of ADT was associated with a shorter time to T-recovery (hazard ratio, 0.253; 95% CI, 0.138-0.465; p < 0.001). No other factors were significant predictors of T-recovery. CONCLUSION: Androgen deprivation therapy duration is significantly associated with T-recovery in Japanese patients with PCa. If a patient undergoes ADT for more than 6 or 12 months, it is possible to postpone their outpatient visits for 13 and 18 months, respectively.

Effect of Androgen-Androgen Receptor Directed Therapy on COVID-19 Outcome in Prostate Cancer Patients.

TMPRSS2 is utilized by SARS-CoV-2 for cellular entry. Androgen-Androgen receptor directed therapy (A/ARDT) downregulates expression of TMPRSS2. We hypothesized A/ARDT might protect prostate cancer (PCa) patients from poor COVID-19 outcome. A retrospective analysis of PCa patients with COVID-19 infection was performed. 146 PCa cases were identified, 17% were on A/ARDT. Hospitalization rates were same 52% (OR = 0.99, 0.41-2.24). Mean hospitalization was 9.2 (Range: 1-25) and 14.9 (Range: 2-47) days in A/ARDT and non-A/ARDT groups, respectively. While definitive conclusions cannot be made regarding outcome differences between groups due to lack of statistical significance, these data generate hypothesis that A/ARDT might shorten hospitalization stay.

Androgen deprivation therapy in men with prostate cancer is not associated with COVID-2019 infection.

BACKGROUND: Androgens may play a role in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and host responses as the virus is dependent on the androgen-regulated protein transmembrane serine protease 2 for cell entry. Studies have indicated that prostate cancer patients receiving androgen deprivation therapy (ADT) are at reduced risk of SARS-CoV-2 infection and serious complications compared with patients without ADT, but data are inconsistent. METHODS: A total of 655 prostate cancer patients who were under surveillance at two urology departments in Sweden on April 1, 2020 were included in the study as well as 240 patients with benign prostatic hyperplasia (BPH). At follow-up early in 2021, the participants completed a questionnaire containing information about symptoms compatible with coronavirus disease 2019 (COVID-19). Blood samples were also collected for the assessment of SARS-CoV-2 IgG antibodies (SARS-CoV-2 Total; Siemens). We used multivariable logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between ADT and the risk of SARS-CoV-2 infection. RESULTS: The cumulative incidence of SARS-CoV-2 seropositivity was 13.4% among patients receiving ADT and 10.4% among patients without ADT. After adjusting for potential confounders, we observed no differences in symptoms or risk of SARS-CoV-2 infection between patients with and without ADT (OR: 0.98; 95% CI: 0.52-1.85). Higher body mass index, Type 1 diabetes, and prostate cancer severity, defined by high Gleason score (8-10; OR: 2.06; 95% CI: 1.04-4.09) or elevated levels of prostate-specific antigen (>20 µg/l; OR: 2.15; 95% CI: 1.13-4.07) were associated with increased risk of SARS-CoV-2 infection. Overall, the risk of SARS-CoV-2 infection was not higher among men with prostate cancer than among men with BPH. CONCLUSIONS: Our results do not support the hypothesis that ADT use in prostate cancer patients reduces the risk or symptom severity of SARS-CoV-2 infection or that prostate cancer patients are at increased risk of COVID-19 compared with men without prostate cancer.

Testosterone suppression combined with high dose estrogen as potential treatment of SARS-CoV-2. A mini review.

Compared to females, males experience severe acute respiratory syndrome due to COVID-19 (SARS-CoV-2) more often, and also die more frequently from COVID-19. Testosterone has inhibitory and estrogens have favorable effects on the immune system. Both ACE2 and TMPRSS2 are specific host-cellular proteins stimulating viral entry in cells and SARS-CoV-2. Both proteins can be suppressed by inhibition of testosterone levels and by stimulation of estrogen levels. Therefore, both androgen-deprivation therapy (ADT) and estrogen therapy (ET) may decrease COVID-19 virus cell entry. Literature was searched for evidence of COVID-19 treatment benefits with estrogens, progesterone, androgen deprivation, and anti-androgens. Data supporting the effect of ADT on SARS-CoV-2 are sparse and inconsistent. The benefit of anti-androgen therapy is inconsistent. Data on the effect of ET were not found. Indirect estrogen data related to menopausal hormone therapy and hormonal contraception are favorable. In a small study, progesterone had some beneficial effects. The combination of ADT and ET (ADET) has never been studied as a treatment option for SARS-CoV-2. Based on the mode of action of the combination, it is hypothesized that ADET may be an effective and safe treatment of SARS-CoV-2, to be confirmed in a clinical trial.

Comparison of abiraterone acetate and prednisolone (AAP) or combination enzalutamide (ENZ) + AAP for metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy (ADT): Overall survival (OS) results of 2 randomised phase III trials from the STAMPEDE protocol

Background: AAP or ENZ added to ADT improves outcomes for mHSPC. Any benefit of combining ENZ & AAP in this disease setting is uncertain. Methods: STAMPEDE is a multi-arm, multi-stage (MAMS), platform protocol conducted at 117 sites in the UK & Switzerland. 2 trials with no overlapping controls randomised mHSPC patients (pts) 1:1 to ADT +/- AAP (1000mg od AA + 5mg od P) or AAP + ENZ (160mg od). Treatment was continued to progression. From Jan 2016 docetaxel 75mg/m2 3-weekly with P 10mg od was permitted + ADT. Using meta-analysis methods, we tested for evidence of a difference in OS and secondary outcomes (as described previously: failure-free, metastatic progression-free, progression-free & prostate cancer specific survival) across the 2 trials using data frozen 3 Jul 2022. All confidence intervals (CI) 95%. Restricted mean survival times (RMST) restricted to 84 months (m). Results: Between Nov 2011 & Jan 2014, 1003 pts were randomised ADT +/- AAP & between Jul 2014 & Mar 2016, 916 pts were randomised ADT +/- AAP + ENZ. Randomised groups were well balanced across both trials. Pt cohort: age, median 68 years (yr), IQR 63, 72;PSA prior to ADT, median 95.7 ng/ml, IQR 26.5, 346;de novo 94%, relapsed after radical treatment, 6%. In AAP + ENZ trial, 9% had docetaxel + ADT. OS benefit in AAP + ENZ trial, HR 0.65 (CI 0.55‒0.77) p = 1.4×10-6;in AAP trial, HR 0.62 (0.53, 0.73) p = 1.6×10-9. No evidence of a difference in treatment effect (interaction HR 1.05 CI 0.83‒1.32, p = 0.71) or between-trial heterogeneity (I2 p = 0.70). Same for secondary end-points. % (CI) of pts reporting grade 3-5 toxicity in 1st 5 yr: AAP trial, ADT: 38.5 (34.2-42.8), + AAP: 54.4 (50.0-58.8);AAP + ENZ trial, ADT: 45.2 (40.6 – 49.8), + AAP + ENZ: 67.9 (63.5 – 72.2);most frequently increased with AAP or AAP + ENZ = liver derangement, hypertension. At 7 yr in AAP trial (median follow-up: 95.8m), % (CI) pts alive with ADT: 30 (26, 34) versus with ADT + AAP: 48 (43, 52);RMST: ADT: 50.4m, ADT + AAP: 60.6m, p = 6.6 x 10-9. Conclusions: ENZ + AAP need not be combined for mHSPC. Clinically important improvements in OS when adding AAP to ADT are maintained at 7 yr. Clinical trial identification: NCT00268476. Legal entity responsible for the study: Medical Research Council Clinical Trials Unit at University College London. Funding: Cancer Research UK, Medical Research Council, Janssen, Astellas. Disclosure: G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca;Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion;Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research;Financial Interests, Institutional, Research Grant: Janssen, Astellas;Non-Financial Interests, Principal Investigator: Janssen, Astellas;Non-Financial Interests, Advisory Role: Janssen, AstraZeneca. W.R. Cross: Financial Interests, Personal, Invited Speaker, Speaker fee: Myriad Genetics, Janssen, Astellas;Financial Interests, Personal, Advisory Board, Advisory Board fee: Bayer;Financial Interests, Institutional, Research Grant, Research grant: Myriad Genetics. S. Gillessen: Financial Interests, Personal, Advisory Board, 2018: Sanofi, Roche;Financial Interests, Personal, Advisory Board, 2018, 2019: Orion;Financial Interests, Personal, Invited Speaker, 2019 Speaker's Bureau: Janssen Cilag;Financial Interests, Personal, Advisory Board, 2020: Amgen;Financial Interests, Personal, Invited Speaker, 2020: ESMO;Financial Interests, Personal, Other, Travel Grant 2020: ProteoMEdiX;Financial Interests, Institutional, Advisory Board, 2018, 2019, 2022: Bayer;Financial Interests, Institutional, Advisory Board, 2020: Janssen Cilag, Roche, MSD Merck Sharp & Dohme, Pfizer;Financial Interests, Institutional, Advisory Board, 2018: AAA International, Menarini Silicon Biosystems;Financial Interests, Institutional, Advisory Board, 2019, 2020: Astellas Pharma;Financial Interests, Institutional, Advisory B ard, 2019: Tolero Pharmaceuticals;Financial Interests, Personal, Invited Speaker, 2021, 2022: SAKK, DESO;Financial Interests, Institutional, Advisory Board, 2021: Telixpharma, BMS, AAA International, Novartis, Modra Pharmaceuticas Holding B.V.;Financial Interests, Institutional, Other, Steering Committee 2021: Amgen;Financial Interests, Institutional, Advisory Board, 2021, 2022: Orion, Bayer;Financial Interests, Personal, Invited Speaker, 2021: SAKK, SAKK, SAMO - IBCSG (Swiss Academy of Multidisciplinary oncology);Financial Interests, Personal, Advisory Board, 2021: MSD Merck Sharp & Dhome;Financial Interests, Personal, 2021: RSI (Televisione Svizzera Italiana);Financial Interests, Institutional, Invited Speaker, 2021: Silvio Grasso Consulting;Financial Interests, Institutional, Other, Faculty activity 2022: WebMD-Medscape;Financial Interests, Institutional, Advisory Board, 2022: Myriad genetics, AstraZeneca;Financial Interests, Institutional, Invited Speaker, 2022: TOLREMO;Financial Interests, Personal, Other, Travel support 2022: AstraZeneca;Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator: Astellas;Non-Financial Interests, Advisory Role, 2019: Menarini Silicon Biosystems, Aranda;Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. C. Pezaro: Financial Interests, Personal, Advisory Board, Ad board Dec 2020: Advanced Accelerator Applications;Financial Interests, Personal, Advisory Board, Aug 2021: Astellas;Financial Interests, Personal, Advisory Board, Oct 2021: Bayer;Financial Interests, Personal, Invited Speaker, Sept-Oct 2020: AstraZeneca;Financial Interests, Personal, Invited Speaker, Oct 2020: Janssen;Financial Interests, Personal, Advisory Board, July-Sept 2022: Pfizer. Z. Malik: Financial Interests, Personal, Advisory Board, advisry board for new hormonal therapy for breast cancer: sanofi;Financial Interests, Institutional, Invited Speaker, research grant for CHROME study: sanofi;Other, Other, support to attend meetings or advisory boards in the past: Astellas,Jaansen,Bayer;Other, Other, Sponsorship to attend ASCO meeting 2022: Bayer. M.R. Sydes: Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training sessions for clinicians (no discussion of particular drugs): Janssen;Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training session for clinicians (no discussion of particular drugs): Eli Lilly;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Astellas, Janssen, Novartis, Pfizer, Sanofi;Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial: Clovis Oncology. L.C. brown: Financial Interests, Institutional, Research Grant, £170k educational grant for the FOCUS4-C Trial from June 2017 to Dec 2021: AstraZeneca;Financial Interests, Institutional, Funding, Various grants awarded to my institution for work undertaken as part of the STAMPEDE Trial: janssen pharmaceuticals;Non-Financial Interests, Other, I am a member of the CRUK CERP funding advisory panel and my Institution also receive grant funding from CRUK for the STAMPEDE and FOCUS4 trials: Cancer Research UK. M.K. Parmar: Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL: Medical Research Council Clinical Trials Unit at UCL;Financial Interests, Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Clovis;Non-Financial Interests, Advisory Role, Euro Ewing Consortium: University College London;Non-Financial Interests, Advisory Role, rEECur: University of Birmingham;Non-Financial Interests, Advisory Role, CompARE Trial: University of Birmingham. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca;Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis;Financial Interests, Institutional, Expert Testimony, Assisted with submissions regarding licencing for abiraterone: Janssen;Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi;Financial Interests, Institutional, Expert Testimony, Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel: Sanofi;Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck;Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer;Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial: Janssen, Astellas;Financial Interests, Institutional, Invited Speaker, Funding for RADIO trial bladder cancer: AstraZeneca. All other authors have declared no conflicts of interest.

Patient preferences for treatment and outcomes in hormone-sensitive prostate cancer (HSPC)

Background: Treatment options for patients with HSPC have broadened, and data regarding patient preferences for therapies can aid in therapeutic decision-making. This study evaluated the impact of attributes associated with therapies for US patients with locally advanced prostate cancer (LAPC) or metastatic HSPC (mHSPC) from the perspective of patient preferences. Methods: An online discrete choice experiment (DCE) was developed for patients with LAPC or mHSPC. The DCE included 12 questions designed to systematically require tradeoffs between treatment attributes of efficacy (5-year overall survival [OS]), tolerability (fatigue, skin rash, neurotoxicity, and common chemotherapy-related toxicity), and convenience (administration factors [route, frequency, and setting], concomitant use of steroids, and monitoring requirements). Respondents could choose androgen deprivation therapy (ADT) alone or with hypothetical therapies that improved 5-year OS but had additional adverse events (AEs). Attribute-specific importance weights measuring their relative impact on treatment choices were estimated using a mixed-logit model, which also controlled for heterogeneity in preferences. Results: From September 3 to October 14, 2021, 82 respondents (mean age 61 years) completed the survey (LAPC, n = 40;mHSPC, n = 42), with 61 (74.4%) receiving ADT at the time of the survey. Respondents reported treatment efficacy (36% [95% confidence interval (CI) 22, 49]) as the most important aspect of treatment choice, followed by changes in chemotherapy-related toxicity (13% [95% CI 3, 22]) and the need for concomitant steroid use (12% [95% CI 5, 19]). Respondents considered monitoring requirements (8% [95% CI 5, 19]) to be more important than fatigue (5% [95% CI 2, 13]). Administration factors were comparable in importance to therapy AEs (Table). Respondents preferred, by at least 10 percentage points, adding therapies to ADT that could improve 5-year OS, at the detriment of additional AEs. Conclusions: After efficacy, convenience was considered to impact treatment choices at a rate comparable to tolerability issues, potentially influenced by perceived COVID-19 exposure risks. Patients with LAPC and mHSPC prioritize efficacy despite the detriment of additional AEs.

Utilisation of docetaxel combined with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer: updated Victorian registry data

INTRODUCTION AND OBJECTIVES: Docetaxel is now standard-of-care initial anti-cancer therapy for men with metastatic hormone-sensitive prostate cancer (mHSPC). Overseas data indicate that docetaxel is used in a minority of men with mHSPC. We aimed to determine docetaxel uptake and identify predictors of utilisation of docetaxel in an Australian real-world setting. METHODS: Men diagnosed with prostate cancer from June 2014 to December 2020 enrolled to the Victorian Prostate Cancer Outcomes Registry (PCOR-Vic) were included. Data collected included demographics, year of diagnosis, and anticancer treatments within 12 months of diagnosis. Wilcoxon rank-sum and chi-square were used to identify predictors of docetaxel utilisation versus ADT alone. All predictors were entered as covariates simultaneously into a multivariable logistic regression model. Statistical significance was set at 0.05 (twosided). RESULTS: 1570 men with mHSPC were included in analysis. 448 (29%) received docetaxel with androgen deprivation therapy (ADT) and 682 (43%) ADT alone. In 2020, for the first time, docetaxel + ADT was prescribed more frequently than ADT alone (52% vs 48%), though data collection is not yet complete. Predictors of combined docetaxel use versus ADT alone were later year of treatment, younger age, and diagnosis in a private institution;with all remaining significant after multivariable adjustment for residence and clinical M-stage. The proportion of men under 70 receiving docetaxel versus ADT alone increased from 55% in 2014-15 to 79% in 2019-20, while in men aged 70 and over, the uptake doubled from 15% to 32% over the same period. CONCLUSIONS: In 2020, docetaxel + ADT overtook ADT alone as the most common initial treatment of mHSPC in Australian men. We identified a continual increase in docetaxel use in younger men following publication of the CHAARTED and STAMPEDE trials in 2015. Ongoing monitoring of the impact of COVID19 on use of docetaxel is warranted.

Relationship Between Androgen Deprivation Therapy for Prostate Cancer and Risk of SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Several cohort studies have explored the relationship between androgen deprivation therapy (ADT) and the severity of coronavirus disease 2019 (COVID-19). This study aimed to characterize the relationship between ADT and the severity of COVID-19 in patients with prostate cancer. METHODS: A systematic search was conducted using PubMed, Embase, and Cochrane Library databases from the inception of each database until February 31, 2020. Patients with prostate cancer who were treated with ADT were assigned to treatment group while those patients who were not treated with ADT were assigned to the control group. Outcomes were severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) positivity, hospitalization, intensive care unit (ICU) admission, and death. The risk of bias was evaluated using ROBINS-I (Risk Of Bias In Non-randomized Studies of Interventions) tool. RESULTS: Three studies with qualitative synthesis were included. Finally, two studies with quantitative synthesis having a total of 44,213 patients were included for the present systematic review. There was no significant difference in SARS-CoV-2 positive rate (odds ratio [OR], 0.52; 95% confidence intervals [Cis], 0.13-2.09; P = 0.362), hospitalization (OR, 0.52; 95% CIs, 0.07-3.69; P = 0.514), ICU admission (OR, 0.93; 95% CIs, 0.39-2.23, P = 0.881), or death (OR, 0.88; 95% CIs, 0.06-12.06; P = 0.934) between ADT and non-ADT groups. CONCLUSION: Qualitative and quantitative analyses of previous studies revealed no significant effect of ADT on COVID-19. However, more studies with higher quality that explore biochemical and immunological factors involved are needed to confirm this finding in the future.

Response of local disease at magnetic resonance after salvage radiotherapy for prostate cancer

Purpose or Objective To assess the pattern of response on dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) of presumed local lesions in the setting of salvage radiotherapy (sRT) after radical prostatectomy (RP). Materials and Methods The present prospective study (NCT04703543) was conducted at a single Institution between August 2017 and June 2020. Eligibility criteria were: undetectable prostate specific antigen (PSA) after RP;biochemical recurrence (2 consecutive PSA rises to 0.2 ng/ml or greater);a presumed local failure at DCE-MRI (early/fast enhancing discrete lesion on DCE sequences);no distant metastases at choline-PET/CT;no previous history of androgen deprivation therapy and/or RT. Accrued patients underwent sRT as it follows: 66-69 Gy/30 fractions to the prostatic bed, 73.5 Gy/30 fractions to the local failure at DCE-MRI, 54 Gy/30 fractions to the pelvic nodes (when treated). All patients were offered DCE-MRI 3 months after sRT, and repeated at 3-month intervals until complete disappearance or a maximum of 4 scans. The endpoint of the study, complete response (CR), was defined as the complete disappearance of the target lesion at DCE-MRI. In case of misses before CR, the observation was considered as a persisting partial response (PR). Results 62 patients with 72 nodules at DCE-MRI were accrued. All patients underwent the 1st DCE-MRI at a median of 3.3 months (IQR: 3.1-4.1) after sRT, 33 patients (53.2%) presented a CR, 27 (43,5%) a PR, 2 (3.2%) no response. One patient, implanted with a cardiac device, did not undergo further MRI. Three more patients declined further testing after the 1st (N=2) or the 2nd (N=1) re-evaluation due to the COVID-19 pandemic. Twenty-eight patients underwent a 2nd DCE-MRI after a median of 6.8 months (IQR: 6.5-7.6) from sRT, 20 had a CR, 8 had a PR. After a median time of 10.7 months (IQR: 10.6-12.6), 6 patients were scanned for a 3nd DCE-MRI: 4 CR, 2 PR. The last patient reported a CR after 16.7 months. The majority (94.3%, 95%CI: 88.0-100.0%) of lesions had completely disappeared by the 3rd re-evaluation or a median time of 10.7 months from the end of sRT (Figure).(Figure Presented) Independent predictors of CR at 1st re-evaluation on multivariable analysis were: the volume of the lesion at pre-sRT DCEMRI (OR 0.076, 95%CI 0.009-0.667;p=0.02), the time of re-evaluation from treatment (OR 3.39, 95%CI 1.156-9.993;p=0.026) and the PSA percent decrease at the 5th week of sRT (OR 1.02, 95%CI 0.999-1.050;p= 0.058) (Table). (Table Presented) Receiver-operating characteristic curve (ROC) analysis identified the best cut-off on CR for baseline volume at 0.545 cc, AUC 0.683 (95%CI: 0.548-0.818, p=0.014). The probability of a CR for lesions larger than the cut-off identified at ROC analysis was only around 75% at 10.7 months. Conclusion The vast majority of local lesions disappears at DCE-MRI after sRT, though larger lesions may require more than 10 months from treatment end.

Androgen Deprivation Therapy and Risk of SARS-CoV-2 Infection in Men With Prostate Cancer: A University of California Health System Registry Study

Association of the Clinical Cell-Cycle Risk Score With Metastasis After Radiation Therapy and Identification of Men With Prostate Cancer Who Can Forgo Combined Androgen Deprivation Therapy Tward and colleagues examined the ability to identify individuals with localized prostate cancer with such a low risk for metastasis following dose-escalated radiation therapy that there is no benefit to adding ADT ( 195). A combined clinical cell-cycle risk score (CCR) combines the cell cycle progression score (CCP) with the UCSF Cancer of the Prostate Risk Assessment score (CAPRA). The CCR was found to be a significant predictor of metastasis (HR, 2.21;95% CI, 1.70-2.87;P=5.6×10–9). The CCR score continued to be highly predictive for metastasis in bivariate analyses when comparing ADT use vs none (HR, 2.19;95% CI, 1.68-2.84;P=1.0 × 10–8) or ADT duration as a continuous variable (HR, 2.11;95% CI, 1.59-2.79;P=3.0×10–7). Patients with CCR scores below the identified threshold of 2.112 had less than a 5% risk for 10-year metastasis regardless of ADT use (overall, sufficient ADT, radiation therapy with any duration of ADT, or radiation therapy alone with no ADT) or National Comprehensive Cancer Network risk group (favorable intermediate risk, unfavorable intermediate risk, or high/very high risk).

Susceptibility to SARS-Cov-2 infection and risk for severe COVID-19 in patients with prostate cancer on androgen deprivation therapy.

Androgen deprivation therapy (ADT) has been hypothesized to protect against COVID-19, but previous observational studies of men with prostate cancer on ADT have been inconsistent regarding mortality risk from coronavirus disease 2019 (COVID-19). Using data from the Prostate Cancer data Base Sweden (PCBaSe), we identified a cohort of 114 547 men with prevalent prostate cancer on the start of follow-up in February 2020, and followed them until 16 December 2020 to evaluate the association between ADT and time to test positive for COVID-19. Among men testing positive for COVID-19, we used regression analyses to estimate the association between ADT and risk of COVID-19-related hospital admission/death from any cause within 30 days of the positive test. In total, 1695 men with prostate cancer tested positive for COVID-19. In crude analyses, exposure to ADT was associated with a 3-fold increased risk of both testing positive for COVID-19 infection and subsequent hospital admission/death. Adjustment for age, comorbidity and prostate cancer risk category substantially attenuated the associations: HR 1.3 (95% CI: 1.1-1.5) for testing positive for COVID-19, and OR 1.4 (95% CI: 1.0-1.9) for risk of subsequent hospital admission/death. In conclusion, although these results suggest increased risks of a positive COVID-19 test, and COVID-19-related hospital admission/death in men on ADT, these findings are likely explained by confounding by old age, cancer-associated morbidity and other comorbidities being more prevalent in men on ADT, rather than a direct effect of the therapy.

A Population-Level Analysis of the Protective Effects of Androgen Deprivation Therapy Against COVID-19 Disease Incidence and Severity.

Background: The incidence and severity of coronavirus disease 19 (COVID-19) is substantially higher in men. Sex hormones may be a potential mechanism for differences in COVID-19 outcome in men and women. We hypothesized that men treated with androgen deprivation therapy (ADT) have lower incidence and severity of COVID-19. Methods: We conducted an observational study of male Veterans treated in the Veterans Health Administration from February 15th to July 15th, 2020. We developed a propensity score model to predict the likelihood to undergo Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing. We performed multivariable logistic regression modeling adjusted with inverse probability weighting to examine the relationship between ADT and COVID-19 incidence. We conducted logistic regression analysis among COVID-19 patients to test the association between ADT and COVID-19 severity. Results: We identified a large cohort of 246,087 VA male patients who had been tested for SARS-CoV-2, of whom 3,057 men were exposed to ADT, and 36,096 men with cancer without ADT. Of these, 295 ADT patients and 2,427 cancer patients not on ADT had severe COVID-19 illness. In the primary, propensity-weighted comparison of ADT patients to cancer patients not on ADT, ADT was associated with decreased likelihood of testing positive for SARS-CoV-2 (adjusted OR, 0.88 [95% CI, 0.81-0.95]; p = 0.001). Furthermore, ADT was associated with fewer severe COVID-19 outcomes (OR 0.72 [95% CI 0.53-0.96]; p = 0.03). Conclusion: ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Testosterone and androgen receptor signaling may confer increased risk for SARS-CoV-2 infection and contribute to severe COVID-19 pathophysiology in men.

ANDROGENS IN CORONAVIR SARS-COV-2 INFECTION

Recent finding from molecular biologyl have shown that for the penetration of the SARS-CoV-2 coronavirus into host cells, a key role is played by protease serine 2, the activity of which is dependent on androgens. The important role of androgens is also evidenced by clinical observations that men in some age categories are infected by this novel coronavirus up to two times more frequently than women. In addition, men with androgenic alopecia tend to have a more serious clinical course, while men with androgen deprivation as a result of prostate cancer treatments tend to have milder courses. This is in line with the fact that preadolescent children are only rarely sickened with a serious form of SARS-CoV-2 infections. Even though these observations may be explained by other factors, many authors have hypothesized that lowered androgen levels and blocking their activity using anti-androgen medication may moderate the course of the viral infection in intermediately to critically affected cases. Clearly, it would be important for androgen deprivation to block not just gonadal androgens, but also adrenal androgens. The secretion of adrenal androgens can be reduced with corticoids, so recommended treatments using dexamethasone to patients with more serious COVID-19 disease do not just inhibit the cytokine storm, but also hinder the secretion of adrenal androgens.

Switching Patients With Prostate Cancer from GnRH Antagonist to Long-acting LHRH Agonist for Androgen Deprivation: Reducing Hospital Visits During the Coronavirus Pandemic.

Aim: To reduce the frequency of the need for hospital visits for patients with prostate cancer (PCa) taking androgen-deprivation therapy during the SARS-CoV-2 (COVID-19) pandemic, we switched them from gonadotropin-releasing hormone (GnRH) antagonist to a long-acting luteinizing hormone-releasing hormone (LH-RH) agonist. Here, we confirmed the efficacy and safety profile of this switching. Patients and Methods: We analyzed the medical records of 32 patients with PCa who received ADT and switched from GnRH antagonist to a long-acting LH-RH agonist during the COVID-19 pandemic, evaluating hematological and serological variables, including serum testosterone and prostate-specific antigen. Results: Before and after the switching from GnRH antagonist to LH-RH agonist, the median serum testosterone levels were 0.22 and 0.18 ng/ml, respectively, and the median serum prostate-specific antigen levels were 0.18 and 0.11 ng/ml, respectively. No changes in the rates of flare-ups of conditions or adverse events were observed. Conclusion: Switching from GnRH antagonist to a long-acting LH-RH agonist appears to be a reasonable option that does not diminish efficacy or exacerbate adverse events.

Targeting the androgen receptor signaling pathway in advanced prostate cancer.

PURPOSE: This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). SUMMARY: PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. CONCLUSION: Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.