AAS & Prostate Cancer

[Michael Scally MD]

Huynh LM, Ahlering TE. Challenging beliefs of testosterone therapy and prostate cancer. Nature Reviews Urology 2019. https://doi.org/10.1038/s41585-019-0253-8

The relationship between testosterone therapy and prostate cancer continues to challenge historic and current beliefs. A new cohort analysis revealed a ~33% reduction in prostate cancer incidence in men with increased testosterone use. The mechanisms underlying this protective effect are unclear, but these findings challenge current paradigms and warrant further investigation.

Testosterone Deficiency, Metabolic Syndrome and Prostate Cancer.

Prostate physiology and pathology are sensitive to testosterone levels. Hypogonadal testosterone levels have been associated with incident and high-grade prostate cancer.

Early and intermediate prostate cancer progression is sensitive to obesity, diabetes mellitus and metabolic syndrome, which can be driven by low testosterone levels.

By contrast, in advanced and metastatic disease, castration-level testosterone via androgen deprivation therapy has a life-extending benefit.

Thus, before and at early disease stages, prostate cancer risk might be reduced by testosterone therapy via its effects on metabolic syndrome components, whereas suppression of androgen receptor signalling is required in patients with advanced disease.

PIN, prostatic intraepithelial neoplasia.

 

[Michael Scally MD]

Bipolar AR Therapy
SUO 2019: Bipolar AR Therapy

Since Huggins’ noble prize-winning work on the role of androgens in prostate cancer progression in 1940, hormonal suppression has been the mainstay of therapy for advanced malignancy. While a flurry of new targets have been discovered over the recent decade, with each sequential therapy, patients face diminishing response rates.

Additionally, these medications are associated with a host of side-effects, including decreased focus, fatigue, obesity, decreased bone mass, and sexual dysfunction. Dr. Samuel Denmeade from Johns Hopkins presented a novel approach to castrate-resistant prostate cancer using testosterone to re-sensitize patients to hormonal therapy.

Dr. Denmeade began his talk by exploring the 3 phases of androgen inhibitions: initial shock, adaptation and resistance. Essentially, as testosterone is suppressed, androgen receptor protein is overexpressed with gene amplification and eventual mutations which then leads to androgen synthesis.

Dr. Denmeade hypothesizes that by rapidly cycling of supraphysiologic and castrate testosterone levels (bipolar AR therapy—BAT) could disrupt the adaptive autoregulation of the androgen receptors and may re-sensitize castrate-resistant prostate cancer to androgen ablation.

To that end, Dr. Denmeade and colleagues are currently evaluating this strategy in the RESTORE study, a phase II study testing the ability to re-sensitize castrate-resistant men after ADT and 2nd line therapy with either abiraterone or enzalutamide.

The initial results for the post-enzalutamide arm has been published in Lancet Oncology, demonstrating an objective response rate of 43% after 3 cycles of BAT. Furthermore, 71% of patients experienced a >50% decrease in PSA following re-treatment with enzalutamide. Final results for the post abiraterone arm are still pending. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30906-3/fulltext

Given, these promising preliminary results, Dr. Denmeade and his team is currently evaluating BAT versus enzalutamide following progression on ADT with abiraterone in a phase II randomized control trial with a cross over design (TRANSFORMER trial, trial schema below).

Their initial results demonstrate that response rates were significantly higher when BAT was given prior to enzalutamide, as opposed to the medications given in the other order (8.1% vs 28.6%, p=0.045). Furthermore, BAT prior to 3rd line enzalutamide restored PSA responses and progression-free survival to the same rates seen when enzalutamide has been used as 2nd line therapy.

In conclusion, Dr. Denmeade provided an overview of an exciting new treatment strategy for men with advanced prostate cancer which has the potential to revolutionize classical thinking regarding androgens and prostate cancer. Final results of his group’s ongoing trials are eagerly anticipated.

 

[Michael Scally MD]

Bipolar Androgen Therapy for Men with Castration Resistant Prostate Cancer
SUO 2019: Bipolar Androgen Therapy for Men with Castration Resistant Prostate Cancer

As part of the SUO 2019 advanced prostate cancer session, Dr. Samuel Denmeade discussed his work with bipolar androgen therapy (BAT) for men with castration resistant prostate cancer (CRPC). Dr. Denmeade reminds us that metastatic prostate cancer remains an incurable disease, with a median overall survival in the CRPC state of three years. The mainstay of treatment is androgen deprivation therapy (ADT), however it is associated with many side effects:

· Depression
· Decreased muscle mass
· Breast enlargement
· No libido/sexual impotence
· Decreased bone mass
· Abdominal fat
· Fatigue
· Lack of focus

One of the main challenges of treating advanced prostate cancer is the development of resistance with each subsequent line of therapy. For example, enzalutamide in PREVAIL had a PSA progression-free survival of only 11.2 months. According to Dr. Denmeade, there are three phases of androgen inhibition: shock, adaptation, and resistance. The shock phase is when there is androgen receptor activity inhibition, which is followed by adaptation, namely androgen receptor overexpression, gene amplification, and development of ligand-independent androgen receptor variants.

The hypothesis for BAT is that men with CRPC could respond to rapid cycling between polar extremes of supraphysiologic and castrate testosterone levels, whereby rapid cycling disrupts adaptive autoregulation of the androgen receptor. Adaptive downregulation of the androgen receptor expression may re-sensitize CRPC to androgen ablative therapies.

…

Dr. Denmeade concluded with several take home points:

· Pharmacologic testosterone (BAT) can be given safely to asymptomatic men with castration-resistant prostate cancer
· Objective response and PSA response were observed in some men
· BAT may re-sensitize CRPC to androgen ablative therapies
· BAT improves quality of life in some men

 

[rambosmurf]

So

Bipolar Androgen Therapy for Men with Castration Resistant Prostate Cancer
SUO 2019: Bipolar Androgen Therapy for Men with Castration Resistant Prostate Cancer

As part of the SUO 2019 advanced prostate cancer session, Dr. Samuel Denmeade discussed his work with bipolar androgen therapy (BAT) for men with castration resistant prostate cancer (CRPC). Dr. Denmeade reminds us that metastatic prostate cancer remains an incurable disease, with a median overall survival in the CRPC state of three years. The mainstay of treatment is androgen deprivation therapy (ADT), however it is associated with many side effects:

· Depression
· Decreased muscle mass
· Breast enlargement
· No libido/sexual impotence
· Decreased bone mass
· Abdominal fat
· Fatigue
· Lack of focus

One of the main challenges of treating advanced prostate cancer is the development of resistance with each subsequent line of therapy. For example, enzalutamide in PREVAIL had a PSA progression-free survival of only 11.2 months. According to Dr. Denmeade, there are three phases of androgen inhibition: shock, adaptation, and resistance. The shock phase is when there is androgen receptor activity inhibition, which is followed by adaptation, namely androgen receptor overexpression, gene amplification, and development of ligand-independent androgen receptor variants.

The hypothesis for BAT is that men with CRPC could respond to rapid cycling between polar extremes of supraphysiologic and castrate testosterone levels, whereby rapid cycling disrupts adaptive autoregulation of the androgen receptor. Adaptive downregulation of the androgen receptor expression may re-sensitize CRPC to androgen ablative therapies.

…

Dr. Denmeade concluded with several take home points:

· Pharmacologic testosterone (BAT) can be given safely to asymptomatic men with castration-resistant prostate cancer
· Objective response and PSA response were observed in some men
· BAT may re-sensitize CRPC to androgen ablative therapies
· BAT improves quality of life in some men

it’s saying testosterone helped patients with certain types of prostate cancers?
Sorry my vocabulary is not advanced... 9 th grade education.. ged , then army, could you or anybody simplify it for me please?

 

[master.on]

Dr. Denmeade hypothesizes that by rapidly cycling of supraphysiologic and castrate testosterone levels (bipolar AR therapy—BAT) could disrupt the adaptive autoregulation of the androgen receptors and may re-sensitize castrate-resistant prostate cancer to androgen ablation.

Cycling supraphysiologic (high) and castrate (very low) testosterone levels?
That would be quite an emotional roller coaster ride.

 

[Wurst]

So

it’s saying testosterone helped patients with certain types of prostate cancers?
Sorry my vocabulary is not advanced... 9 th grade education.. ged , then army, could you or anybody simplify it for me please?

Yes, also new research indicates, that estrogen and inflammation is the leading cause of prostata growth!

 

[RoidmeDangerfield]

Yes, also new research indicates, that estrogen and inflammation is the leading cause of prostata growth!

I'm by no means an expert but this is what I've been saying all along for over twenty years. I always thought to myself, if prostate cancer were the result of unusually high testosterone levels then why do we see it typically in older men when their test levels are at their lowest in their lives? And that usually means that their testosterone to estrogen ratio favors estrogen.

 

[Michael Scally MD]

[OA] [Commentary] Mechanisms of High-Dose Testosterone

A new study describes the characterization of the mechanisms underlying responses to supraphysiological testosterone therapy (SPT) for men with castration-resistant prostate cancer (CRPC). The findings in patient-derived xenografts (PDXs) show that SPT results in sustained suppression of AR-V7 and E2F signalling and the DNA damage response (DDR) in responders, describing potential mechanisms of tumour growth inhibition by SPT.

Previous studies have shown that treatment of CRPC with SPT can be effective in some patients. “Despite preclinical results showing inhibition of prostate cell proliferation by SPT and positive results from clinical trials, use of SPT in advanced prostate cancer is still highly debated by clinicians,” explains senior author Eva Corey from the University of Washington. “However, patients failing enzalutamide have very limited treatment options, and SPT presents an option for durable response and improved quality of life for some of these men.” Thus, Corey’s team set out to study mechanisms of SPT action and to discover biomarkers to identify those patients who respond.

…

Thoma C. Mechanisms of high-dose testosterone. Nat Rev Urol. 2019;16(8):448. Mechanisms of high-dose testosterone

 

[Michael Scally MD]

Extreme Responses to Immune Checkpoint Blockade Following Bipolar Androgen Therapy and Enzalutamide in Patients with Metastatic Castration Resistant Prostate Cancer

Background: Immune checkpoint inhibition has been shown to have limited efficacy in patients with metastatic prostate cancer. Prostate cancers that harbor certain homologous recombination (HR) DNA repair gene mutations, inactivating CDK12 mutations or have underlying mismatch repair deficiency may be effectively treated with immunotherapy.

Combination therapy may improve clinical response rates to immune checkpoint blockade. We observed profound prostate-specific antigen (PSA) and/or objective responses to immune checkpoint blockade following prior treatment with bipolar androgen therapy (BAT) and enzalutamide.

Methods: We report three cases of patients with metastatic castration resistant prostate cancer (mCRPC) undergoing therapy with anti-PD-1 inhibitors. All patients underwent both somatic molecular testing and germline genetic testing.

Results: Two of the three patients with mCRPC harbored an inactivating mutation in an HR DNA repair gene (BRCA2, ATM). No patient demonstrated mismatch repair deficiency, nor were CDK12 alterations present. All three patients had been treated with BAT and enzalutamide before immune checkpoint blockade, a paradoxical approach for the treatment of mCRPC developed by our group.

Conclusions: These cases of mCRPC suggest that immune checkpoint blockade may have therapeutic potential in patients with prostate cancer, especially following immune activation ("priming") using BAT and enzalutamide.

Markowski MC, Shenderov E, Eisenberger MA, et al. Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer [published online ahead of print, 2020 Jan 23]. Prostate. 2020;10.1002/pros.23955. Error - Cookies Turned Off

 

[Michael Scally MD]

[OA] Serial Bipolar Androgen Therapy (sBAT) Using Cyclic Supraphysiologic Testosterone (STP) to Treat Metastatic Castration-Resistant Prostate Cancer (mCRPC)

During prostate carcinogenesis, molecular changes occur in prostate epithelial cells such that their Androgen Receptor (AR) protein expression increases significantly (i.e. >5 fold). This elevated AR expression perverts AR-dependent transcriptional programming from a growth suppressor to an oncogenic stimulator of malignant growth.

Due to this malignancy acquired addiction to AR transcriptional programming, androgen deprivation therapy (ADT), which lowers serum testosterone (T) from 600 to <100 ng/dL, not only inhibits prostate cancer cell proliferation, but also results in transcriptional reprogramming that induces cancer cell death. Unfortunately, metastatic prostate cancer patients eventually develop resistance to primary castration therapy in addition to secondary hormone-based therapies such as abiraterone and/or enzalutamide.

The most common mechanism for the development of resistance is via an adaptive “auto-regulation” that increases AR protein expression by >30-fold. This increase results in sufficient AR accumulation in the nuclei of castration-resistant prostate cancer (CRPC) cells to induce by mass action the AR-dependent transcriptional programming needed to both inhibit their death and stimulate their proliferation despite castrate levels of androgen.

...

Isaacs JT, Brennen WN, Denmeade SR. Serial bipolar androgen therapy (sBAT) using cyclic supraphysiologic testosterone (STP) to treat metastatic castration-resistant prostate cancer (mCRPC). Ann Transl Med. 2019;7(Suppl 8):S311. Serial bipolar androgen therapy (sBAT) using cyclic supraphysiologic testosterone (STP) to treat metastatic castration-resistant prostate cancer (mCRPC) - Isaacs - Annals of Translational Medicine

 

[Michael Scally MD]

Bipolar Androgen Therapy [Testosterone Administration] in Prostate Cancer (Update)

Over the past 20 years, there has been a paradigm shift in our understanding of testosterone and its impact on prostate cancer (PC). In 1941, Huggins and Hodges reported in their seminal article that androgen deprivation caused PC to regress while androgen stimulated PC growth. This finding was based on a single patient.

In 1965, Huggins later reported that both hormonal deprivation and hormonal excess (which he termed hormonal interference) might be used for therapeutic benefit. Other case reports from 1950 to 1980 reported therapeutic benefit of giving testosterone therapy (TTh) to men with advanced PC.

Just 13 years ago, the leading concern of most clinicians around the world with TTh was the fear of causing PC. However, a more recent survey of urologists in 2016 observed that 96% and 84% of urologists believed that it was safe to give men testosterone after radical prostatectomy and radiation, respectively. In fact, 63% of these urologists believed it was safe to give men testosterone while on active surveillance for PC.

This paradigm shift of TTh and PC risk over the past 20 years spawns from increased physician experience and comfort with using TTh among men with PC. One hypothesis, termed the prostate saturation hypothesis, provides an explanation on the effects of TTh in patients with PC.

The hypothesis postulates that at low levels of circulating androgens, androgen receptors (ARs) are unbound and consequently sensitive to fluctuations in testosterone levels. However, at physiologic levels of testosterone, the ARs are saturated, and further increases in testosterone levels do not affect the prostate.

Furthermore, data have emerged on the use of TTh as a protective agent against PC development and as a therapeutic agent for men with metastatic PC or with biochemical prostate-specific antigen (PSA) recurrence. The use of TTh as a therapeutic agent has been termed bipolar androgen therapy (BAT) and has changed our understanding of testosterone and its interaction with PC.

…

The question that arises is how can testosterone be therapeutic in men with metastatic PC or men with a biochemical recurrence? For decades, the belief was that ADT, not androgen therapy, was beneficial in men with metastatic PC or with biochemical PSA recurrence.

Although AR signaling plays a critical role in normal prostate development, ARs take on an oncogenic role in PC and lead to cell growth and proliferation. While ADT is one of the primary methods of treating PC, many patients develop CRPC after several months. In the low-androgen environment of ADT, many PC cells develop adaptive AR upregulation and subsequent increased androgen sensitivity. Studies have shown that supraphysiologic levels of testosterone (SPT) may lead to cell death and inhibited cancer growth in these hypersensitive cell lines.

…

Initial discoveries reporting the efficacy of androgen deprivation in the management of PC led to ADT as a primary treatment modality for PC. However, further research identified that SPT led to paradoxical inhibition of growth in the setting of CRPC. These findings resulted in the development of a treatment strategy termed BAT, in which testosterone levels are cycled between near-castration and supraphysiological levels. The foundation behind this strategy is that androgen deprivation primarily reduces PC growth.

While the PC cells that become resistant to androgen deprivation upregulate AR expression, supraphysiologic doses of androgen lead to cell death and inhibition of proliferation of these PC cell lines through a multimodal mechanism. Continuous cycling of testosterone levels in BAT is believed to repeatedly damage these PC cells and ultimately reduce proliferation and growth. Thus far, BAT appears safe in management of patients with metastatic CRPC. Nevertheless, further research on clinical outcomes, predictive biomarkers, and physiologic mechanisms is required.

Lo EM, Balasubramanian A, Pastuszak AW, Khera M. Bipolar Androgen Therapy in Prostate Cancer (Update). [published online ahead of print, 2020 Feb 4]. J Sex Med. 2020;S1743-6095(19)31884-3. https://www.jsm.jsexmed.org/article/S1743-6095(19)31884-3/abstract

 

[Michael Scally MD]

[OA] Late Onset Hypogonadism (LOH): Prostate Safety

Background: There have always been concerns regarding Testosterone Replacement Therapy (TRT) and prostate safety because of the central role of Testosterone (T) in prostate tissue. Even though there is a body of evidence supporting that the benefits of TRT outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among T prescribers.

Objectives: The aim of this article is to review the influence of T on prostate pathophysiology and discuss the potential impact of TRT on the most common prostate pathologies, including benign prostatic hyperplasia (BPH) and prostate cancer (PCa).

Materials and methods: We have performed an extensive PubMed review of the literature examining the effects of TRT on the prostate and its most common affections, especially in terms of safety.

Results: TRT has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of LUTS in patients with BPH. Studies evaluating the link between TRT and BPH/LUTS have mostly demonstrated no change in symptom scores and even some benefits.

There are a significant number of studies demonstrating the safety of TRT in individuals with LOH and a history of PCa. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non-high-risk disease.

Conclusion: TRT could be considered for most men with LOH regardless of their history of prostate disease. However, a discussion about the risks and benefits of TRT is always advised, especially in men with PCa. Appropriate monitoring is mandatory.

Miranda EP, Otávio Torres L. Late onset hypogonadism (LOH): Prostate safety [published online ahead of print, 2020 Feb 13]. Andrology. 2020;10.1111/andr.12772. Error - Cookies Turned Off

 

[Old]

Appropriate monitoring is mandatory

True of all medications

Even though there is a body of evidence supporting that the benefits of TRT outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among T prescribers.

However, a discussion about the risks and benefits of TRT is always advised, especially in men with PCa.

Discuss what? That they haven't a clue what is truly right or wrong in the matter? That they can't admit they've been wrong?

At this point it is little better than a pharmaceutical disclaimer that tells you every that can go wrong so that they are now free of liability in case something does actually go wrong.

 

[Michael Scally MD]

Evaluation of The Genomic Alterations in The Androgen Receptor Gene During Treatment with High-Dose Testosterone for Metastatic Castrate-Resistant Prostate Cancer

Introduction: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA).

Methods: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2–4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety.

Results: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6–5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone (n = 2) or enzalutamide (n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT (n = 9), yet no association between clinical outcomes and ctDNA findings was observed.

Conclusions: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed.

Moses M, Koksal U, Ledet E, et al. Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer. Oncotarget. 2020;11(1):15–21. Published 2020 Jan 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967778/

 

[Michael Scally MD]

[OA] [GMAFB] [RUFKM] [BOZO] Boosting Free Testosterone With OTC Natural Supplements: Be Careful What You Wish For

[Supplements causing prostate cancer!!!]

Gomella LG. Boosting Free Testosterone With OTC Natural Supplements: Be Careful What You Wish For. Can J Urol. 2020;27(1):10067. https://www.canjurol.com/html/free-articles/Cdn_JU27_I1_03_FREE_Editorial_Feb2020.pdf

 

[Michael Scally MD]

[OA] Late‐Onset Hypogonadism: Prostate Safety

Background - There have always been concerns regarding testosterone replacement therapy and prostate safety because of the central role of testosterone in prostate tissue. Even though there is a body of evidence supporting that the benefits of testosterone replacement therapy outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among testosterone prescribers.

Objectives - The aim of this article was to review the influence of testosterone on prostate pathophysiology and discuss the potential impact of testosterone replacement therapy on the most common prostate pathologies, including benign prostatic hyperplasia and prostate cancer.

Materials and Methods - We have performed an extensive PubMed review of the literature examining the effects of testosterone replacement therapy on the prostate and its most common affections, especially in terms of safety.

Results - Testosterone replacement therapy has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia.

Studies evaluating the link between testosterone replacement therapy and benign prostatic hyperplasia/LUTS have mostly demonstrated no change in symptom scores and even some benefits.

There are a significant number of studies demonstrating the safety of testosterone replacement therapy in individuals with late‐onset hypogonadism and a history of prostate cancer. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non–high‐risk disease.

Conclusion - Testosterone replacement therapy could be considered for most men with late‐onset hypogonadism regardless of their history of prostate disease. However, a discussion about the risks and benefits of testosterone replacement therapy is always advised, especially in men with prostate cancer. Appropriate monitoring is mandatory.

Miranda, EP, Torres, LO. Late‐onset hypogonadism: Prostate safety. Andrology. 2020; 00: 1– 8. https://doi.org/10.1111/andr.12772

 

[Old]

Boosting Free Testosterone With OTC Natural Supplements: Be Careful What You Wish For

[Supplements causing prostate cancer!!!]

Another turd trying to look smart by slamming both FT and supplements.

He states that "Recent clinical studies have demonstrated that for every increase of just 50 pmol/L of free testosterone there is a 10% increase in prostate cancer risk." and references https://www.europeanurology.com/article/S0302-2838(18)30546-3/fulltext

However that article says

• Our results indicate that men in the lowest study-specific tenth of calculated free testosterone concentration have a 23% reduced risk of prostate cancer compared with men with higher concentrations. Above this very low concentration, prostate cancer risk did not change with increasing free testosterone concentration
• Therefore, variation across the normal range of circulating free testosterone concentrations may not be associated with a prostate cancer risk. However, when circulating concentrations are very low, reduced androgen receptor signalling may lead to a reduction in prostate cancer risk

I invite correction in understanding this reference. But it seems that very low FT does reduce cancer risk. But having low normal verse high normal doesn't make much difference.

Who wants to live with very low FT? Might as well cut off genitals to eliminate cancer risk, just as some women have both breast removed as preventative care.

 

[Michael Scally MD]

Testosterone Replacement Therapy Reduces Biochemical Recurrence Post-Radical Prostatectomy

Background: To evaluate risk of prostate cancer biochemical recurrence following radical prostatectomy in men receiving versus not receiving testosterone therapy.

Patients and methods: 850 patients underwent radical prostatectomy by a single surgeon. All patients had preoperative testosterone and sex hormone binding globulin levels drawn; free testosterone was calculated prospectively.

152 (18%) patients with low preoperative calculated free testosterone levels and delayed post-operative sexual function recovery were placed on testosterone therapy and proportionately matched to 419 control patients by pathologic Gleason Grade Group and stage.

Rates and time to biochemical recurrence (two consecutive prostate specific antigen ≥ 0.2 ng/dl) were compared in univariate and multivariate regression; Cox regression was used to generate a survival function at the mean of covariates.

Results: Median follow-up was 3.5 years. There were no statistically significant differences in demographics or general health complications between groups. 11/152 (7.2%) and 53/419 (12.6%) patients experienced biochemical recurrence in the testosterone therapy versus control groups, respectively. In adjusted time to event analysis, testosterone therapy was an independent predictor of recurrence-free survival.

After accounting for Gleason Grade Group, pathologic stage, preoperative prostate specific antigen, and calculated free testosterone, patients on testosterone therapy were approximately 54% less likely to recur (HR:0.54, 95%CI:0.292-0.997). In men destined to recur, testosterone therapy delayed time to recurrence by an average of 1.5 years.

Conclusion: In our experience, testosterone replacement post-radical prostatectomy significantly reduced recurrence and delayed time to recurrence. There were no identifiable general health complications associated with testosterone therapy. These findings are hypothesis-generating and require confirmation with multi-centered, prospective randomized controlled trials.

Ahlering TE, Huynh LM, Towe M, et al. Testosterone replacement therapy reduces biochemical recurrence post-radical prostatectomy [published online ahead of print, 2020 Mar 2]. BJU Int. 2020;10.1111/bju.15042. doi:10.1111/bju.15042 Error - Cookies Turned Off

 

[Michael Scally MD]

Testosterone Replacement Therapy (TRT) and Prostate Cancer

Highlights

· Androgen therapy does not increase the risk of subsequent discovery of prostate cancer.

· Until more definitive data becomes available, clinicians wishing to treat their hypogonadal patients with localized prostate cancer (CaP) with testosterone replacement therapy should inform them of the lack of evidence regarding the safety of long-term treatment for the risk of CaP progression.

· Patient should not be treated with testosterone replacement therapy if they have CaP with

o High risk localized disease.

o Positive surgical margins.

o Positive lymph node.

o Metastatic disease.

Often contraindicated because of the theoretical risk of progression based on the dogma of hormone dependent prostate cancer (CaP), testosterone replacement therapy (TRT) is increasingly discussed and proposed for hypogonadal patients with localized CaP. To perform a systematic literature review to determine the relationship between TRT and the risk of CaP with a focus on the impact of TRT in the setting of previous or active localized CaP.

As of October 15, 2019, systematic review was performed via Medline Embase and Cochrane databases in accordance with the PRISMA guidelines. All full text articles in English published from January 1994 to February 2018 were included. Articles were considered if they reported about the relationship between total testosterone or bioavailable testosterone and CaP.

Emphasis was given to prospective studies, series with observational data and randomized controlled trials. Articles about the safety of the testosterone therapy were categorized by type of CaP management (active surveillance or curative treatment by radical prostatectomy, external radiotherapy or brachytherapy).

Until more definitive data becomes available, clinicians wishing to treat their hypogonadal patients with localized CaP with TRT should inform them of the lack of evidence regarding the safety of long-term treatment for the risk of CaP progression. However, in patients without known CaP, the evidence seems sufficient to think that androgen therapy does not increase the risk of subsequent discovery of CaP.

Lenfant L, Leon P, Cancel-Tassin G, et al. Testosterone replacement therapy (TRT) and prostate cancer: An updated systematic review with a focus on previous or active localized prostate cancer [published online ahead of print, 2020 May 11]. Urol Oncol. 2020;S1078-1439(20)30151-4. doi:10.1016/j.urolonc.2020.04.008 https://www.sciencedirect.com/science/article/abs/pii/S1078143920301514?via%3Dihub

 

[Michael Scally MD]

Bipolar Androgen Therapy in Prostate Cancer: Current Evidences and Future Perspectives

Highlights
· Testosterone at high levels can induce apoptosis in prostate cancer cells.
· Bipolar androgen therapy may prolong response in prostate cancer.
· Many mechanisms, including DNA damage, are involved in cells death.
· Clinical trials have shown some benefit from bipolar androgen therapy.
· Combinations with immunotherapy and PARP inhibitors are under investigation.

Testosterone suppression by androgen deprivation therapy is the cornerstone of prostate cancer treatment. New-generation hormone therapies improved overall survival in castration-resistant prostate cancer. More recent trials showed a further increase in overall survival when enzalutamide or abiraterone are associated with androgen deprivation therapy in hormone-sensitive disease.

However, a higher clonal pressure may lead to the upregulation of alternative pathways for cancer progression and to dedifferentiated diseases that would probably respond poorly to subsequent treatments. In this contest, new strategies that could be able to delay or even revert resistance are needed.

The bipolar androgen therapy is an under-investigation treatment that consists in periodical oscillation between castration levels and supraphysiological levels of testosterone in order to prevent the adaptation of prostate cancer cells to a low-androgen environment. This review aims to underline the biological rationale of bipolar androgen therapy and gather evidences from the most recent clinical trials.

Leone G, Buttigliero C, Pisano C, et al. Bipolar androgen therapy in prostate cancer: Current evidences and future perspectives [published online ahead of print, 2020 May 24]. Crit Rev Oncol Hematol. 2020;152:102994. doi:10.1016/j.critrevonc.2020.102994 Bipolar androgen therapy in prostate cancer: Current evidences and future perspectives - ScienceDirect