AAS & Prostate Cancer

[Michael Scally MD]

Testosterone Therapy Does Not Increase the Risks of Prostate Cancer Recurrence or Death After Definitive Treatment for Localized Disease

Background: The safety of testosterone therapy (TT) after definitive treatment for localized prostate cancer remains undefined. We analyzed the risks of biochemical recurrence and mortality in men receiving TT after treatment for localized prostate cancer.

Methods: Cohort analysis using the national US Veterans Affairs Informatics and Computing Infrastructure. We identified 69,984 patients with localized prostate cancer diagnosed from 2001 to 2015 treated with surgery or radiation.

We coded receipt of TT after treatment as a time-dependent covariate; used the National Death Index to identify cause of death; and defined biochemical recurrence as PSA > 0.2 ng/mL after surgery and nadir + 2 ng/mL after radiation.

We analyzed recurrence and mortality using cumulative incidence curves, Fine-Gray competing risk regression, and Cox regression.

Results: This cohort included 28,651 surgery patients and 41,333 radiation patients, of whom 469 (1.64%) and 543 (1.31%), respectively, received TT with a median follow-up of 6.95 years.

Comparing testosterone users to nonusers, there were no between-group differences in biochemical recurrence, prostate cancer-specific mortality, or overall mortality after surgery [hazard ratios (HR): 1.07; HR: 0.72 (p = 0.43); and HR: 1.11 (p = 0.43), respectively] or radiation [HR: 1.07; HR: 1.02 (p = 0.95); and HR: 1.02 (p = 0.86), respectively]. Limitations included lack of detailed data on TT duration and serum testosterone concentrations.

Conclusions: In this multi-ethnic national cohort, TT did not increase the risks of biochemical recurrence or prostate cancer-specific or overall mortality after surgery or radiation. These data suggest that TT is safe in appropriate men after definitive treatment of localized prostate cancer.

Sarkar RR, Patel SH, Parsons JK, et al. Testosterone therapy does not increase the risks of prostate cancer recurrence or death after definitive treatment for localized disease [published online ahead of print, 2020 Jun 8]. Prostate Cancer Prostatic Dis. 2020;10.1038/s41391-020-0241-3. doi:10.1038/s41391-020-0241-3 Testosterone therapy does not increase the risks of prostate cancer recurrence or death after definitive treatment for localized disease

 

[Michael Scally MD]

A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE)

Background: Cyclic high-dose testosterone injections, also known as bipolar androgen therapy (BAT), is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). BAT has shown clinical activity in prior studies enrolling men with mCRPC and may potentially restore sensitivity to prior androgen receptor (AR)-targeted agents.

Objective: To evaluate the clinical activity of BAT in patients progressing on AR-targeted therapy as well as responses to abiraterone or enzalutamide upon rechallenge after BAT.

Design, setting, and participants: RESTORE is a multicohort phase II study enrolling asymptomatic mCRPC patients after abiraterone or enzalutamide at Johns Hopkins Hospital (NCT02090114). Participants (29 after abiraterone and 30 after enzalutamide) received 400 mg testosterone cypionate intramuscularly every 28 days, with ongoing luteinizing hormone-releasing hormone agonist/antagonist treatment (ie, BAT). Following progression on BAT, patients were rechallenged with their most recent AR-targeted therapy.

Outcome measurements and statistical analysis: Coprimary endpoints were >50% decline in PSA from baseline (PSA50) responses to BAT and following AR-targeted therapy rechallenge. Outcomes in the post-abiraterone cohort are presented, as well as updated results from the post-enzalutamide cohort and an exploratory AR-V7 analysis.

Results and limitations: No statistically significant difference in PSA50 response rates to BAT was observed (30% [post-enzalutamide cohort] vs 17% [post-abiraterone cohort], p = 0.4). However, PSA50 responses to AR-targeted therapy rechallenge were higher in the post-enzalutamide cohort (68% vs 16%, p = 0.001). The median time from enrollment to progression following rechallenge with AR-targeted therapy (ie, progression-free survival 2; PFS2) was longer in the post-enzalutamide versus post-abiraterone patients (12.8 vs 8.1 mo, p = 0.04). Outcomes were worse in patients with detectable AR-V7 in circulating tumor cells (median PFS2: 10.3 vs 7.1 mo, p = 0.005).

Conclusions: BAT shows clinical activity in mCRPC patients and may be more effective at resensitizing to enzalutamide versus abiraterone.

Patient summary: BAT is well tolerated in metastatic castration-resistant prostate cancer patients. The type of prior AR-targeted therapy might affect response to BAT as well as AR-therapy rechallenge. BAT followed by AR-targeted therapy rechallenge did not improve outcomes in AR-V7-positive patients.

Markowski MC, Wang H, Sullivan R, et al. A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts [published online ahead of print, 2020 Jul 2]. Eur Urol. 2020;S0302-2838(20)30471-1. doi:10.1016/j.eururo.2020.06.042 https://www.europeanurology.com/article/S0302-2838(20)30471-1/abstract

 

[Michael Scally MD]

[OA] Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

The androgen receptor (AR) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different AR antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key cellular response for the treatment of PCa.

Surprisingly, while physiological levels of androgens promote growth, supraphysiological androgen levels (SAL) inhibit PCa growth in an AR-dependent manner by inducing cell senescence in cancer cells. Thus, oppositional acting ligands, AR antagonists, and agonists are able to induce cellular senescence in PCa cells, as shown in cell culture model as well as ex vivo in patient tumor samples.

This suggests a dual AR-signaling dependent on androgen levels that leads to the paradox of the rational to keep the AR constantly inactivated in order to treat PCa. These observations however opened the option to treat PCa patients with AR antagonists and/or with androgens at supraphysiological levels. The latter is currently used in clinical trials in so-called bipolar androgen therapy (BAT).

Notably, cellular senescence is induced by AR antagonists or agonist in both androgen-dependent and castration-resistant PCa (CRPC). Pathway analysis suggests a crosstalk between AR and the non-receptor tyrosine kinase Src-Akt/PKB and the PI3K-mTOR-autophagy signaling in mediating AR-induced cellular senescence in PCa.

In this review, we summarize the current knowledge of therapeutic induction and intracellular pathways of AR-mediated cellular senescence.

Kokal M, Mirzakhani K, Pungsrinont T, Baniahmad A. Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer. Cancers (Basel). 2020;12(7):E1833. Published 2020 Jul 8. doi:10.3390/cancers12071833 Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

 

[Michael Scally MD]

Testosterone and Prostate Health: Have the Paradigms Truly Shifted?

The concept that testosterone (T) promotes the growth of prostate cancer (PCa) was firmly established around the middle of the last century, based initially on animal and human studies entirely appropriate for the post-World War II state-of-the art.

Since then, a great deal of progress has been made in our appreciation of the relationships between T and prostate health. Original concepts have been revised and firmly held opinions have been challenged following clinical observations and discoveries in the fields of biochemistry, genetics, and immunology.

More recent developments in the understanding of the interactions between androgens and the androgen receptor and the concept of the prostate being an endocrine organ within the hypothalamus-pituitary-gonadal (HPG) axis domain has shed new insights on the relations and clinical significance of hormones and prostate health.

By a wide margin, urologists treat most men with a current or remote diagnosis of PCa and are consulted and increasingly asked to take primary responsibility for managing those who are also affected by testosterone deficiency (TD).

This brings into focus the need to provide a succinct view of the common situations faced by clinicians about the confusing and often controversial issues involving androgens and androgen administration to men.

Therefore, following a brief introduction on the fundamentals of T and prostate tissue interactions, we will discuss four scenarios that are of most relevance in clinical practice.

Morales A, Siemens DR. Testosterone and prostate health: Have the paradigms truly shifted?. Can Urol Assoc J. 2020;14(8):230-234. doi:10.5489/cuaj.6549 Testosterone and prostate health: Have the paradigms truly shifted? | Canadian Urological Association Journal

 

[Michael Scally MD]

[OA] Use of Hormones in Doping and Cancer Risk

Hormones with anabolic properties such as growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are commonly abused among professional and recreational athletes to enhance physical ability. Despite their adverse effects are well-documented, the use of GH and IGF-1 has recently grown.

This article highlights the anabolic activity related to mechanisms of cancer development and progression. GH/IGF-1 axis is able to activate cellular mechanisms that modulate every key stage of cancer formation and progression, such as inhibition of apoptosis, resistance to treatments, and induction of angiogenesis, metastatic process and cell proliferation.

Results from pre-clinical studies and epidemiological observations in patients with an excess of GH and IGF-1 production or treated with these hormones showed a positive association with the risk to develop several types of cancer.

In conclusion, athletes should be made aware that long-term treatment with doping agents might increase the risk of developing cancer, especially if associated with other licit or illicit drugs and/or high-protein diet.

De Santi M, Baldelli G, Brandi G; GSMS-SItI, Working Group on Movement Sciences for Health, Italian Society of Hygiene preventive Medicine and Public Health; WDPP, Working Group Doping Prevention Project. Use of hormones in doping and cancer risk. Ann Ig. 2019;31(6):590-594. doi:10.7416/ai.2019.2319 SEU - Annali di Igiene

 

[Michael Scally MD]

Oncological Safety and Functional Outcomes of Testosterone Replacement Therapy in Symptomatic Adult-Onset Hypogonadal Prostate Cancer Patients Following Robot-Assisted Radical Prostatectomy

Purpose - Testosterone replacement therapy (TRT) remains controversial in men with treated prostate cancer. We assessed its safety and functional impacts in patients after definitive surgical treatment with robotic-assisted radical prostatectomy (RARP).

Methods - We performed a retrospective analysis of 1303 patients who underwent RARP during the years 2006–2019. We identified men with symptoms of andropause and low serum testosterone who received TRT post-RARP; then we divided the cohort into two groups accordingly for comparison.

Biochemical recurrence (BCR) was the primary endpoint. Secondary endpoints included functional outcomes. Predictors of BCR, including the effect of TRT on BCR, were evaluated using univariable and multivariable logistic regression.

Results - Among the forty-seven men who received TRT, the mean age was 60.83 years with a median follow-up of 48 months. Three (6.4%) and 157 (12.56%) patients experienced BCR in TRT and non-TRT groups, respectively. Baseline characteristics were similar between both groups except for higher mean BMI in the TRT group (p = 0.03).

In the multivariate analysis (MVA), higher pre-RARP prostate-specific antigen (PSA) (p = 0.043), higher International Society of Urological Pathology score (p < 0.001), seminal vesical invasion (p = 0.018) and positive surgical margin (p < 0.001) were predictors of BCR.

However, TRT was not (p = 0.389). In addition, there was a significant change in the Sexual Health Inventory for Men (p = 0.022), and serum testosterone level (p < 0.001) before and 6 months after initiation of TRT.

Conclusion: Our findings suggest that TRT, in well-selected, closely followed, symptomatic men post-RARP is an oncologically safe and functionally effective treatment in prostate cancer patients post-RARP.

Shahine, H., Zanaty, M., Zakaria, A.S. et al. Oncological safety and functional outcomes of testosterone replacement therapy in symptomatic adult-onset hypogonadal prostate cancer patients following robot-assisted radical prostatectomy. World J Urol (2020). https://doi.org/10.1007/s00345-020-03475-7

 

[Michael Scally MD]

[OA] Strategies for Testosterone Therapy in Men with Metastatic Prostate Cancer in Clinical Practice: Introducing Modified Bipolar Androgen Therapy

Purpose: To investigate prostate-specific antigen (PSA) and clinical responses to a variety of treatment strategies involving testosterone therapy (TTh) in men with metastatic prostate cancer (mPCa).

Materials and Methods: Case records were reviewed for three men with advanced PCa treated with TTh for improved quality of life. Two had bone metastases and nephrostomies at baseline. The third had biochemical recurrence, and continued TTh after developing bone metastases. All rejected androgen deprivation therapy, desired improved quality of life with TTh, and accepted the risk of rapid PCa progression and death.

Results: All men experienced substantial symptomatic and health benefits during TTh, including improved strength, vigor, and sexuality. Two reversed substantial weight loss. A 94-year-old man with baseline PSA of 546 ng/mL survived 11 months with continuous TTh, with last PSA of 2493 ng/mL. Two men in their 60s received some form of TTh for 3.5 and 8 years, respectively, and are still alive. None experienced sudden major adverse events. Continuous TTh resulted in progressive rise in PSA to high values.

The combination of TTh and enzalutamide provided moderate protection against weakness and fatigue with PSA <10ng/mL for 6 months. PSA values fluctuated from <1.0 to >100 ng/mL within 1–2 months depending on recent androgen status.

The most promising strategy appears to be a modified bipolar androgen therapy consisting of repeating cycles of 8 weeks of high-dose TTh followed by 4 weeks of enzalutamide, allowing for prolonged periods of vigor while maintaining PSA control.

Conclusions: These pilot results support explorations of new hormonal strategies involving TTh for men with mPCa.

Morgentaler A. Strategies for Testosterone Therapy in Men with Metastatic Prostate Cancer in Clinical Practice: Introducing Modified Bipolar Androgen Therapy. Androgens: Clinical Research and Therapeutics. Oct 2020.76-84. http://doi.org/10.1089/andro.2020.0009

 

[Michael Scally MD]

Bipolar Androgen Therapy Sensitizes Castration-Resistant Prostate Cancer to Subsequent Androgen Receptor Ablative Therapy


Highlights

Prostate cancer (PCa) adapts to low testosterone by upregulating the androgen receptor (AR).

High AR is a therapeutic vulnerability to bipolar androgen therapy (BAT).

This is a trial of BAT as first-line hormonal therapy for patients with castration-resistant PCa (CRPC).

BAT produced prostate-specific antigen and objective responses in a subset of patients.

BAT appeared to sensitise CRPC to subsequent androgen ablative therapy.

Background: Cyclical, high-dose testosterone administration, termed bipolar androgen therapy (BAT), can induce clinical responses and restore sensitivity to androgen signalling inhibition in patients with previously treated castration-resistant prostate cancer (PCa) (CRPC). This trial evaluated whether BAT is a safe and effective first-line hormonal therapy for patients with CRPC.

Patients and methods: In cohort C of this single-centre, open-label, phase II, multi-cohort trial (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance study), 29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist. The primary end-point of the study was the PSA50 response rate to BAT treatment.

Results: After treatment with BAT, four of 29 patients (14%; 95% confidence interval [CI]: 4-32%) experienced a PSA50 response. The median radiographic progression-free survival to BAT was 8.5 months (95% CI: 6.9-15.1) for patients with metastatic CRPC. After progression on BAT, 17 of 18 patients (94%; 95% CI: 73-100%) achieved a PSA50 response and 15 of 18 patients (83%; 95% CI: 59-96) achieved a PSA90 response on abiraterone or enzalutamide. Twelve of 15 patients (80%; 95% CI: 52-96) with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months.

Conclusion: As first-line hormonal treatment for CRPC, BAT was well tolerated and resulted in prolonged disease stabilisation. After progression on BAT, patients had favourable responses to second-generation androgen receptor-targeted therapy.

Sena LA, Wang H, Lim ScM SJ, et al. Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy. Eur J Cancer. 2020 Dec 28;144:302-309. doi: 10.1016/j.ejca.2020.11.043. Epub ahead of print. PMID: 33383350. https://www.ejcancer.com/article/S0959-8049(20)31408-8/fulltext

 

[Michael Scally MD]

The Role of Androgen Therapy in Prostate Cancer: From Testosterone Replacement Therapy to Bipolar Androgen Therapy

Highlights

An overview of the re-evaluation of the relationship between androgen and prostate cancer.

The paradoxical androgen saturation model indicates that the effect of androgens on prostate cancer cell proliferation is biphasic.

Testosterone replacement therapy can improve symptoms of testosterone deficiency and confer significant health benefits in patients with non-cancer or early-stage prostate cancer without stimulating cancer progression or recurrence.

Clinical trials data suggest that there might be a therapeutic role for bipolar androgen therapy in men with advanced prostate cancer, and potential mechanisms are emphasized.

Testosterone replacement therapy (TRT) is the primary treatment for male testosterone deficiency. This therapy raises concerns over the risk of prostate cancer (PC), because testosterone has historically been considered the fuel for PC.

We discuss the re-evaluation of the relationship between androgen and PC, and highlight the safety of TRT in the treatment of symptomatic men with testosterone deficiency who have low-risk disease after treatment for localized PC with surgery or radiation.

Furthermore, we review the clinical application and potential mechanisms of bipolar androgen therapy (BAT) in the treatment of castration-resistant PC, emphasizing that much remains to be done before BAT can be broadly applied.

Xie T, Song XL, Wang C, Yu YZ, Wang JQ, Chen ZS, Zhao SC. The role of androgen therapy in prostate cancer: from testosterone replacement therapy to bipolar androgen therapy. Drug Discov Today. 2021 Feb 6:S1359-6446(21)00065-9. doi: 10.1016/j.drudis.2021.01.034. Epub ahead of print. PMID: 33561465. The role of androgen therapy in prostate cancer: from testosterone replacement therapy to bipolar androgen therapy

 

[Michael Scally MD]

TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer

Purpose: Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC).

Methods: The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101).

The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL).

Results: The PFS was 5.7 months for both arms (hazard ratio

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, 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT.

The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80).

OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT.

Conclusion: This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.

Denmeade SR, Wang H, Agarwal N, et al. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer. J Clin Oncol. 2021 Feb 22:JCO2002759. doi: 10.1200/JCO.20.02759. Epub ahead of print. PMID: 33617303. https://ascopubs.org/doi/10.1200/JCO.20.02759