AAS & Prostate Cancer

[Michael Scally MD]

Supraphysiological testosterone inhibits tumor growth and is associated with inhibition of ARV7 signaling and DNA damage response in preclinical models of enzalutamide-resistant prostate cancer
Program Planner

Background: Anti-androgen therapies suppress castration-resistant prostate cancer (CRPC) but CRPC cells develop resistance. One of the mechanisms of resistance is through overexpression of androgen receptor (AR) and AR splice variants.

In contrast to AR pathway inhibition therapies, recent clinical studies using bipolar androgen therapy demonstrated CRPC inhibition using supraphysiological levels of testosterone (SPT).

The objective of this study was to investigate the mechanisms driving SPT-mediated tumor growth inhibition using CRPC patient-derived xenografts (PDX).

Methods: PDXs were implanted in castrated SCID mice and randomized to control or SPT arms. For enzalutamide-resistant (ENZR) PDX studies, mice with established tumors were treated with enzalutamide and randomized to control or SPT upon development of resistance. Tumors were monitored for growth and collected for analyses.

Results: In a SPT preclinical trial using thirteen LuCaP CRPC PDX models, four PDXs responded to SPT treatment while nine demonstrated de novo resistance. Our analysis revealed that responding PDXs had intrinsically higher AR and ARV7 expression compared to non-responding PDXs. Moreover, ARV7 expression was negatively correlated with E2F signaling and proliferation only in responding PDXs, suggesting that the ARV7 program functions differently in responder and non-responder phenotypes.

Another PDX trial using ENZR PDXs determined that SPT inhibited the growth of LuCaP 35CR ENZR and LuCaP 96CR ENZR (responders), but not LuCaP 77CR ENZR (non-responder). Serum and intratumoral T were increased in both responders and the non-responder, suggesting that differential T delivery and tumoral retention were not the cause of differential tumor responses.

Tumor analyses determined that SPT decreased AR transcript levels, however, nuclear AR protein levels and canonical AR signaling remained high in both responders and the non-responder. Conversely, ARV7 transcript was consistently decreased but the ARV7 program was downregulated only in responders.

Additionally, an unbiased pathway analysis of RNASeq revealed that SPT drastically decreased genes associated with E2F-mediated cell cycle progression and proliferation and the DNA damage response (DDR) exclusively in responders. Further support for these pathways driving SPT-mediated tumor inhibition was demonstrated through the resolution of the suppressed ARV7/E2F1/DDR pathways in LuCaP 35CR ENZR upon acquiring SPT resistance, whereas the pathways remained suppressed in LuCaP 96CR ENZR, which exhibited a durable response to SPT.

Conclusion: Our data indicates that SPT therapy inhibits progression of a unique subset of ENZR CRPC and highlights critical roles for ARV7 signaling, DDR and E2F1-mediated proliferation in tumor inhibition.

 

[Michael Scally MD]

Supraphysiological androgens activate innate immune signaling in prostate cancer
Program Planner

Castration resistance prostate cancer (CRPC) first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of a functioning androgen receptor (AR) axis. This observation led to the development of “second-line” therapies aimed at further blocking androgen/AR signaling.

Unfortunately, resistance to these agents can also develop quickly. Paradoxically, several studies have suggested that the growth of AR-positive human CRPC cell lines may be inhibited by supraphysiologic levels of testosterone (SupT).

These studies suggested that the adaptive reliance on AR signaling by CRPC cells becomes a therapeutic liability that can be exploited through the administration of SupT, which we termed as bipolar androgen therapy (BAT). Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT with other agents to achieve increased efficacy and tumor responses.

Our data indicates that SupT induces DNA double strand breaks (DSBs) in prostate cancer (PCa) cells. Unrepaired DSBs induced by SupT are routed for specialized autophagic degradation, termed nucleophagy. We further show that SupT-induced autophagosomal DNA can activate cytoplasmic DNA sensing pathways and downstream innate immune signaling.

Based on our findings, we propose that BAT engages the immune system to inhibit tumor growth. Future combination of BAT with existing immunotherapeutics including immune checkpoint blockade may prove beneficial for treatment of CRPC.

 

[Michael Scally MD]

Is there a role for testosterone replacement therapy in reducing biochemical recurrence following radical prostatectomy?
Is there a role for testosterone replacement therapy in reducing biochemical recurrence following radical prostatectomy? | 2019 ASCO Annual Meeting Abstracts

Background: Historically, the use of testosterone replacement therapy (TRT) has not been recommended in men with a history of prostate cancer (PC). However, low testosterone levels are significantly associated with metabolic complications, decreased sexual function, and (more recently) high-grade PC.

In 2009, in hopes of improving sexual function outcomes in men following radical prostatectomy (RP), we began treating low-risk patients with TRT. The current study examines the impact of TRT on biochemical recurrence (BCR).

Methods: Between December 2009 and June 2018, a cohort of 850 patients underwent RP by a single surgeon. 152 (18%) men were postoperatively placed on TRT for recovery of sexual function. All data was prospectively collected and retrospectively analyzed. TRT patients were proportionately matched to 419 control patients by pathologic Gleason Grade Group (GGG) and stage. Univariate and multivariate comparisons were used to compare rates and time to BCR (two consecutive PSAs ≥ 0.2 ng/dl); Cox regression modeling was used to generate a survival function at the mean of covariates.

Results: There were no statistically significant differences in preoperative PSA, age, prostate weight, pathologic GGG and stage between the control versus TRT groups. Median follow-up time was 3 years in both groups.

7/152 (4.6%) and 39/419 (9.3%) patients experienced BCR in the TRT versus control groups, respectively (unadjusted, p=0.068). In adjusted time to-analysis, TRT was an independent predictor of recurrence-free survival, after controlling for GGG, p-stage, preoperative FT and PSA. A patient on TRT was approximately 53% less likely to experience a BCR (OR: 0.534, 95%CI: 0.288-0.993).

Conclusions: After accounting for pathologic GGG, stage, and other significant covariates, the use of TRT independently reduced recurrence post-RP. These results suggest the need for a multi-center randomized control trial.

 

[Michael Scally MD]

High dose testosterone in men with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD).
High dose testosterone in men with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD). | 2019 ASCO Annual Meeting Abstracts

Background: mCRPC progresses via adaptive mechanisms that allow ongoing androgen receptor (AR) signalling despite castrate levels of androgens. Bipolar androgen therapy (BAT), cycling between supraphysiologic and subphysiologic serum testosterone levels, aims to exploit these adaptations to induce tumor regression. Extensive clinical data demonstrate the safety and efficacy of BAT in men with asymptomatic mCRPC.

However, de novo resistance is still common and predictive biomarkers to refine patient selection are lacking. Pre-clinical data suggest that the induction of double-stranded DNA (dsDNA) breaks by BAT may be crucial to its mechanism of action. DNA repair defects, such as HRD, are particularly relevant in CRPC patients.

We hypothesize that CRPC patients with DNA repair deficits such as HRD, may be particularly responsive to BAT.

Methods: This is a phase II prospective single arm interventional trial (NCT03522064). Up to 30 patients will be recruited based on a Simon two-stage design with a power of 90% to detect an increase in response rate from 20% to 40%.

Key inclusion criteria include
i) asymptomatic or minimally symptomatic mCRPC,
ii) rising PSA despite a castrate serum testosterone and
iii) HRD on germline, tumor and/or circulating tumor DNA (ctDNA) analysis.

Key exclusion criteria include
i) ADT < 1 year,
ii) disease extent/sites that would cause significant risk if tumor flare occurs (e.g.: brain) and
iii) significant cardiac disease.

Previous PARP inhibitor therapy will be permitted in a subset.

Participants will receive IM testosterone enanthate 500mg q4w in combination with ongoing LHRH antagonist/agonist or orchidectomy. The primary endpoint is PSA response rate defined as PSA reduction ≥50% from baseline. Secondary endpoints include time to PSA progression, quality of life, radiologic response and safety and tolerability. Exploratory endpoints include changes in ctDNA and tumoral DNA alterations from baseline to progression. Accrual is ongoing.

 

[Michael Scally MD]

AR changes in circulating-tumor DNA (ctDNA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with high-dose testosterone.
AR changes in circulating-tumor DNA (ctDNA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with high-dose testosterone. | 2019 ASCO Annual Meeting Abstracts

Background: High-dose testosterone (HDT) is active in mCRPC pts and may allow successful re-sensitization to previously utilized androgen-axis targeted therapies. The relationship of genomic alterations in AR gene to HDT responsiveness is unclear.

Methods: Analysis of consecutive pts treated with ≥1 dose of HDT (testosterone cypionate q 2-4 weeks n = 29; continuous gel n = 4). Baseline characteristics, ctDNA data (Guardant360), and clinical outcomes were assessed. Presence of genomic AR alterations included amplifications (amps) and mutations (muts); all muts had allele fraction ≥0.3%. PSA response rates included PSA declines of > 30% or ≥50%. PSA-progression-free survival (PSA-PFS) was defined as HDT start date to PSA ≥ 25% over baseline after a second confirmed PSA rise.

Results: Between May 2016 and Feb 2018, 33 mCRPC pts had median age 73 (58-85), 39% Gleason 8-10, 100% bone mets, 24% nodes + bone, and median baseline PSA level 36.1 ng/mL (0.04-1290). HDT was given post-median of 2 (1-10) CRPC therapies. 73% (24/33) of pts previously received abiraterone (n = 14), enzalutamide (n = 4), or both sequentially (n = 6) prior to HDT for a median of 10.5 months (0.7-56.8). Baseline ctDNA showed 42% AR alterations (amps = 8, muts = 4, both = 2); 33% TP53, and 6% DNA repair (ATM n = 1; BRCA2 n = 1).

With median follow-up 4.4 months, HDT given for median of 4.2 months (95% CI, 3.6-4.8); 29% had PSA ≥50% response and 45% PSA ≥30% response. Median PSA-PFS is immature at 5.5 months (95% CI, 1.5-9.5); 14 pts still on HDT treatment. Grade ≥3 AEs were observed in 6% of pts (G4 thrombocytopenia = 1; G4 asthenia = 1). For pts with baseline AR alterations and HDT treatment, repeated ctDNA assays (n = 7) showed that 100% had decreased AR alterations. No relationship between PSA response and baseline ctDNA AR characteristics are discerned at this time.

Conclusions: HDT was safe and active in a subset of mCRPC. Responses were clearly noted for men receiving continuous daily testosterone gels, thus continuously high testosterone levels are active in addition to injection-induced bipolar changes. Further understanding of the genomic alterations predicting responsiveness to HDT in mCRPC is required.

 

[Michael Scally MD]

Supraphysiological Androgens Suppress Prostate Cancer Growth Through Androgen Receptor-Mediated DNA Damage

Prostate cancer (PC) is initially dependent on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition.

We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with anti-tumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks (DSBs), G0/G1 cell cycle arrest and cellular senescence.

SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA which was augmented by PARP1 inhibition. SPA-induced DSBs were accentuated in BRCA2-deficient PCs, and combining SPA with PARP or DNA-PKcs inhibition further repressed growth.

Next-generation sequencing was performed on biospecimens from PC patients receiving SPA as part of ongoing Phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA.

These results provide a mechanistic rationale for directing SPA therapy to PCs with AR amplification or DNA repair deficiency, and for combining SPA therapy with PARP inhibition.

Chatterjee P, Schweizer MT, Lucas JM, et al. Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage. J Clin Invest 2019;130. JCI - Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage

 

[Michael Scally MD]

Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts

Background Androgen deprivation therapy improves the survival of castration-resistant prostate cancer (CRPC) patients, yet ultimately fails with debilitating side effects.

Supraphysiological testosterone (SPT)-based therapy produces clinical responses with improved quality of life in a subset of patients. Currently, no information defines a durable response to SPT.

Objective To identify key molecular phenotypes underlying SPT response to improve patient selection and guide combination treatment to achieve a durable response.

Design, setting, and participants A patient-derived xenograft (PDX) preclinical trial was performed with 13 CRPC PDXs to identify molecular features associated with SPT response. Comprehensive intratumoral androgen, tumor growth, and integrated transcriptomic and protein analyses were performed in three PDXs resistant to the newer androgen receptor (AR) pathway inhibitor enzalutamide (ENZ) to define SPT response and resistance.

Intervention Testosterone cypionate.

Outcome measurements and statistical analysis SPT efficacy was evaluated by PDX growth, prostate-specific antigen (PSA) change, and survival. Intratumoral androgens were analyzed using mass spectrometry. Global transcriptome analysis was performed using RNA sequencing, and confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Log-rank and Mann-Whitney tests were used for survival and molecular analyses, respectively.

Results and limitations A durable SPT responder was identified, presenting robust repressions of ARv7 and E2F transcriptional outputs, and a DNA damage response (DDR) transcriptomic program that were altogether restored upon SPT resistance in the transient responder. ENZ rechallenge of SPT-relapsed PDXs resulted in PSA decreases but tumor progression.

Conclusions SPT produces a durable response in AR-pathway inhibitor ENZ CRPC that is associated with sustained suppression of ARv7 and E2F transcriptional outputs, and the DDR transcriptome, highlighting the potential of combination treatments that maintain suppression of these programs to drive a durable response to SPT.

Patient summary Patients with ENZ-resistant prostate cancer have very limited treatment options. Supraphysiological testosterone presents a prominent option for improved quality of life and a potential durable response in patients with sustained suppression on ARv7/E2F transcriptional outputs and DNA repair program.

Lam H-M, Nguyen HM, Labrecque MP, et al. Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts. European Urology 2019. https://www.sciencedirect.com/science/article/pii/S030228381930449X

 

[Michael Scally MD]

Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts

Background Androgen deprivation therapy improves the survival of castration-resistant prostate cancer (CRPC) patients, yet ultimately fails with debilitating side effects.

Supraphysiological testosterone (SPT)-based therapy produces clinical responses with improved quality of life in a subset of patients. Currently, no information defines a durable response to SPT.

Objective To identify key molecular phenotypes underlying SPT response to improve patient selection and guide combination treatment to achieve a durable response.

Design, setting, and participants A patient-derived xenograft (PDX) preclinical trial was performed with 13 CRPC PDXs to identify molecular features associated with SPT response. Comprehensive intratumoral androgen, tumor growth, and integrated transcriptomic and protein analyses were performed in three PDXs resistant to the newer androgen receptor (AR) pathway inhibitor enzalutamide (ENZ) to define SPT response and resistance.

Intervention Testosterone cypionate.

Outcome measurements and statistical analysis SPT efficacy was evaluated by PDX growth, prostate-specific antigen (PSA) change, and survival. Intratumoral androgens were analyzed using mass spectrometry. Global transcriptome analysis was performed using RNA sequencing, and confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Log-rank and Mann-Whitney tests were used for survival and molecular analyses, respectively.

Results and limitations A durable SPT responder was identified, presenting robust repressions of ARv7 and E2F transcriptional outputs, and a DNA damage response (DDR) transcriptomic program that were altogether restored upon SPT resistance in the transient responder. ENZ rechallenge of SPT-relapsed PDXs resulted in PSA decreases but tumor progression.

Conclusions SPT produces a durable response in AR-pathway inhibitor ENZ CRPC that is associated with sustained suppression of ARv7 and E2F transcriptional outputs, and the DDR transcriptome, highlighting the potential of combination treatments that maintain suppression of these programs to drive a durable response to SPT.

Patient summary Patients with ENZ-resistant prostate cancer have very limited treatment options. Supraphysiological testosterone presents a prominent option for improved quality of life and a potential durable response in patients with sustained suppression on ARv7/E2F transcriptional outputs and DNA repair program.

Lam H-M, Nguyen HM, Labrecque MP, et al. Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts. European Urology 2019. Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts - ScienceDirect

SUPRAPHYSIOLOGIC TESTOSTERONE Solutions For Enzalutamide-Resistant Prostate Cancer

In this issue of European Urology, Lam et al [1] report on their investigation of supraphysiologic testosterone (SPT) in castration-resistant prostate cancer (CRPC) patient-derived xenografts (PDXs).

The authors identified PDXs that demonstrate slow or suppressed growth when treated with SPT. They generated an enzalutamide-resistant model using these selected responders, and then treated them with either SPT or placebo.

Of their initial cohort of 13 PDXs, four were found to be SPT responders. Of these four, after induction of enzalutamide resistance, one durable responder, one transient responder, and one nonresponder to SPT were identified.

Before we review the data and conclusions, Lam et al should be congratulated on this significant undertaking. Working with PDXs is a laborious and resource- and time-consuming endeavor.

Furthermore, their comprehensive investigation and characterization of SPT response versus nonresponse are impressive.

Second, while the criticism of the work is fairly obvious (characterization based on one durable responder, one transient responder, and one nonresponder), it should be pointed out that important discoveries often arise from just one or two models. Thus, while the number of independent PDXs is a potential limitation, important insights may be gleaned for additional studies.

Third, it should be noted that enzalutamide resistant CRPC is a significant clinical problem. …

Overall, SPT for the treatment of CRPC has been an area of abundant interest. The study by Lam et al builds on prior work suggesting that ARv7 suppression and vulnerability to dsDNA breaks are related to responsiveness to SPT, and suggests possible early treatment biomarkers to assess responsiveness to SPT.

As noted above, the enzalutamide resistant population is a challenging group of patients to treat, particularly with hormonal manipulations. However, this work suggests that individualized genomic information and early treatment monitoring might identify a subset of enzalutamide-resistant patients who could benefit from SPT therapies.

We hope that Lam and colleagues will continue to build on this work and assess the relevance and validity of these findings in a patient-based study.

Thomas L, Baratchian M, Sharifi N. Supraphysiologic Testosterone Solutions for Enzalutamide-resistant Prostate Cancer. Eur Urol 2019. https://www.europeanurology.com/article/S0302-2838(19)30596-2/abstract

 

[Michael Scally MD]

Rapid Testosterone Cycling Reverses Castration Resistance

Bipolar androgen therapy (BAT) can induce clinical responses in men with metastatic castration-resistant prostate cancer (mCRPC) and can resensitize tumours to enzalutamide. Thus, BAT could be used in sequence with androgen-ablative treatments to improve outcomes for men with this disease.

Promising data from a pilot study indicated that BAT alone (in which levels of circulating androgens are rapidly cycled between supraphysiological and castration concentrations) induced clinical responses in men with mCRPC. This observation caused researchers to hypothesize that BAT could exploit the adaptive androgen receptor (AR) upregulation that occurs during antiandrogen therapy. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30906-3/fulltext

…

These results support the hypothesis that rapid cycling of androgens using BAT in the setting of prostate cancer progression could be clinically beneficial to men with mCRPC. Furthermore, BAT can resensitize resistant disease to enzalutamide therapy. Currently, two further studies on BAT in the post-abiraterone setting and for newly CRPC are ongoing and will add to our knowledge regarding the clinical utility of BAT.

Stone L. Rapid testosterone cycling reverses castration resistance. Nature Reviews Urology 2018;15:67. https://doi.org/10.1038/nrurol.2017.223

 

[Michael Scally MD]

[OA] New Horizons for Treating Castration Resistant Prostate Cancer: Bipolar Androgen Therapy

The treatment of metastatic prostate cancer has evolved over the decades focusing on manipulation of the androgen receptor pathway with or without chemotherapy. Despite new drugs discovered with incrementing survival benefits, the disease continues to be fatal after development of castration resistance and progression on abiraterone and enzalutamide.

In this context, attempts of androgen pathway manipulation have led to the development of the Bipolar Androgen Therapy (BAT), which consists of a rapid transition from a castration state to supraphysiologic levels of testosterone and then back to castration levels. Pilot studies have shown this strategy to be safe and supported the development of further clinical trials.

Phase II trials have demonstrated PSA response and disease control in a significant number of patients, including a resensitizing effect to enzalutamide. This promising strategy may become another available option for these patients.

Marchetti KR, Souza GP, Velho PI. New horizons for treating castration resistant prostate cancer: Bipolar Androgen Therapy. Braz J Oncol. 2018;14(48):1-10. http://www.brazilianjournalofoncology.com.br/details/46/en-US/new-horizons-for-treating-castration-resistant-prostate-cancer--bipolar-androgen-therapy

 

[Michael Scally MD]

From the Desk of Evan Yu: “Is Testosterone Such a Bad Thing for Prostate Cancer? Rationale for Using Supraphysiologic Testosterone to Treat Castration-Resistant Prostate Cancer.”
From the Desk of Evan Yu: “Is Testosterone Such a Bad Thing for Prostate Cancer? Rationale for Using Supraphysiologic Testosterone to Treat Castration-Resistant Prostate Cancer.”

We have known for decades that androgen deprivation offers remarkable efficacy and palliation for men with advanced prostate cancer. Yet, soon after Charles Huggins Nobel Prize-winning discovery, many case series started emerging, describing paradoxical benefits of testosterone supplementation for patients with prostate cancer. These clinical observations seem so counterintuitive given that androgen deprivation therapy is the hallmark of treatment for advanced prostate cancer. Yet, there may be supportive biological rationale to this surprising observation.

…

Although there is still limited data for the concept of supraphysiologic testosterone, there is increasing theoretical, pre-clinical and early clinical data that warrants further exploration in a well-controlled setting beyond anecdotal use. Only with properly well-designed trials will this field advance beyond haphazard use in the clinical setting. Fortunately, there are multiple ongoing trials (see below) that are actively accruing patients. Many patients are eager to enroll on these trials, as some have heard anecdotes that there may not only be potential for antitumor efficacy, but there may be some “good side effects” to being on supraphysiologic testosterone!

Ongoing Trials of Supraphysiologic Testosterone Therapy for Castration-resistant Prostate Cancer

· Transdermal Testosterone alternating with Enzalutamide (NCT03734653)

· COMBAT-CRPC: Combination of BAT with Nivolumab (NCT03554317)

· HiTeCH: BAT for metastatic castration-resistant prostate cancer patients with homologous recombination deficiency (NCT03522064)

· BAT-olaparib for an unselected metastatic castration-resistant prostate cancer population post-Abiraterone or -Enzalutamide (NCT03516812)

· RESTORE: Supraphysiologic Testosterone followed by Enzalutamide or Abiraterone (NCT02090114)

 

[Michael Scally MD]

[OA] Update on Systemic Prostate Cancer Therapies

3.1.3.1. Bipolar androgen therapy

PC cells can adapt to chronic androgen deprivation by autoregulatory increases in AR activity through alteration of the AR including amplification, deregulation, mutation, and post-translational modification [33]. However, a low-testosterone environment and AR overexpression induce vulnerability of CRPC cells to supraphysiological levels of androgens that can inhibit growth and promote cell death through inhibition of DNA relicensing and induction of double-strand DNA breaks.

Schweizer et al used testosterone injections and concurrent ADT (termed bipolar androgen therapy [BAT]) to obtain rapid cycling between extremes of high and low levels of testosterone [34], [35]. In combination with etoposide chemotherapy, this approach showed promising results in men with mCRPC. Several trials are currently investigating this paradoxical phenomenon with second-generation AR-targeted drugs, chemotherapy agents, or immunotherapeutics.

A phase II study (NCT02090114) of BAT in men with mCRPC and progression on enzalutamide recently met its primary endpoint, with 30% (n = 9) showing PSA decline and 36% (n = 5) with measurable disease (n = 15) objective radiological response. Patients (n = 30) received testosterone cypionate (400 mg intramuscularly) every 4 wk and continued ADT. Upon progression on BAT, patients were rechallenged with enzalutamide [36].

The phase III strategy (TRANSFORMER trial) will randomize abiraterone-refractory mCRPC patients to enzalutamide versus BAT and is powered to show an improvement in radiographic progression-free survival using BAT in this setting (NCT02286921).

Nuhn P, De Bono JS, Fizazi K, et al. Update on Systemic Prostate Cancer Therapies: Management of Metastatic Castration-resistant Prostate Cancer in the Era of Precision Oncology. European Urology 2019;75:88-99. http://www.sciencedirect.com/science/article/pii/S030228381830246X

 

[Michael Scally MD]

High-Dose Testosterone and Radium-223 Response in a Metastatic Castrate-Resistant Prostate Cancer

Radium-223 prolongs overall survival in bone-metastatic castrate-resistant prostate cancer (CRPC), but rarely is this therapy associated with PSA declines.

Clinical Practice Points

• Radium-223 prolongs overall survival in bone-metastatic castrate-resistant prostate cancer (CRPC), but rarely is this therapy associated with PSA declines.
• Preliminary data suggest that high-dose testosterone (HDT) therapy is a potential option for the treatment of CRPC.
• Herein we describe a unique case in which a patient exhibited a significant clinical and PSA response to a combination of HDT and radium-223.

Christensen BR, Barata PC, Ledet EM, Layton JL, Lewis BE, Sartor O. High-Dose Testosterone and Radium-223 Response in a Metastatic Castrate-Resistant Prostate Cancer. Clinical Genitourinary Cancer. https://www.clinical-genitourinary-cancer.com/article/S1558-7673(19)30249-6/abstract

 

[Michael Scally MD]

[None, Zip, Nada] Association of The Extent of Therapy with Prostate Cancer in Those Receiving Testosterone Therapy

Background - Conflicting evidence remains in the association of testosterone therapy (TTh) with prostate cancer (PCa). This inconsistency maybe due, in part, to the small sample sizes from previous studies and an incomplete assessment of comorbidities, particularly diabetes.

Objective - We investigated the association of PCa with TTh (injection or gel) and different TTh doses, and determined whether this association varies by presence of diabetes at baseline in a large, nationally representative, commercially insured cohort.

Design - We conducted a retrospective cohort study of 189,491 men aged 40‐60 years old in the IBM MarketScan® Commercial Database, which included 1,424 PCa cases diagnosed from 2011 to 2014. TTh was defined using CPT codes from inpatient and outpatient, and NDC codes from pharmacy claims. Multivariable adjusted Cox proportional hazards models were used to compute hazard ratios for patients with incident PCa.

Results - We found a 33% reduced association of PCa after comparing the highest category (>12) of TTh injections with the lowest (1‐2 injections) category (HR = 0.67, 95% CI: 0.54‐0.82). Similar statistical significant inverse association for PCa was observed for men who received TTh topical gels (>330 versus 1‐60 days' supply). Among non‐diabetics we found significant inverse association between TTh (injection and gel) and PCa, but a weak interaction between TTh injections and diabetes (P = 0.05).

Conclusion - Overall, increased use of TTh is inversely associated with PCa and this remained significant only among non‐diabetics. These findings warrant further investigation in large randomized placebo‐controlled trials to infer any health benefit by TTh.

Lopez DS, Huang D, Tsilidis KK, et al. Association of the extent of therapy with prostate cancer in those receiving testosterone therapy in a US commercial insurance claims database. Clinical Endocrinology 2019;0. Error - Cookies Turned Off

 

[Michael Scally MD]

Morgentaler A, Caliber M. Safety of testosterone therapy in men with prostate cancer. Expert opinion on drug safety 2019. https://www.tandfonline.com/doi/abs/10.1080/14740338.2019.1666103?journalCode=ieds20

Introduction: The use of testosterone therapy (TTh) in men with prostate cancer (PCa) is relatively new, and controversial, due to the longstanding maxim that TTh is contraindicated in men with PCa. Scientific advances have prompted a reevaluation of the potential role for TTh in men with PCa, particularly as TTh has been shown to provide important symptomatic and general health benefits to men with testosterone deficiency (TD), including many men with PCa who may expect to live 30-50 years after diagnosis.

Areas covered: This review outlines the historical underpinnings of the historical belief that TTh "fuels" PCa and the experimental and clinical studies that have radically altered this view, including description of the saturation model. The authors review studies of TTh in men with PCa following radical prostatectomy and radiation therapy, in men on active surveillance, and in men with advanced or metastatic PCa.

Expert opinion: TTh provides important symptomatic and overall health benefits for men with PCa who have TD. Although more safety studies are needed, TTh is a reasonable therapeutic option for men with low-risk PCa after surgery or radiation. Data in men on active surveillance are limited, but initial reports are reassuring.

 

[Michael Scally MD]

Can Testosterone Therapy Lower Prostate Cancer Risk?
Can Testosterone Therapy Lower Prostate Cancer Risk? - Renal and Urology News

Greater use of testosterone therapy (TTh) is associated with a lower risk for prostate cancer (PCa) in men without diabetes, according to study findings published in Clinical Endocrinology. Error - Cookies Turned Off

Of 189,491 men ages 40 to 60 years in the IBM MarketScan Commercial Database who received testosterone therapy, 1424 were diagnosed with PCa. Among men without diabetes, those who received more than 12 testosterone injections had a 33% lower risk for PCa than men who received only 1 to 2 injections, in adjusted analyses, David Lopez, DrPh, MPH, MS, of University of Texas Medical Branch at Galveston, and colleagues reported. Likewise, men with more than a 330-day supply of testosterone gel had 45% lower risks for PCa than men with a 60-day supply or less. The investigators found no significant association between testosterone use and PCa in men with diabetes.

Since their results showed a significant inverse relationship between TTh and PCa only among non-diabetics, “we could hypothesize that diabetes has a stronger effect on increasing probability of PCa than the beneficial effects of TTh,” Dr Lopez’s team wrote. “Therefore, diabetes overwhelmed the beneficial effects provided by TTh use on reducing the association with PCa among diabetics and thus no statistical association was found in this group. Yet, this latter statement is only hypothetical.”

 

[Michael Scally MD]

Prostate Specific Antigen Levels during Testosterone Treatment of Hypogonadal Older Men

CONTEXT: Prostate specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated. The Endocrine Society Guidelines recommendation of urological referral for a confirmed increase in PSA >1.4 ng/mL is not based on PSA changes in testosterone-treated men.

DESIGN: Double-blinded, placebo-controlled trial.

SETTING: Twelve United States academic medical centers.

PARTICIPANTS: 790 hypogonadal men >/=65 years with average testosterone levels </=275 ng/dL. Men at high risk for prostate cancer were excluded.

INTERVENTIONS: Testosterone or placebo gel for 12 months.

MAIN OUTCOMES: Percentile changes in PSA during testosterone treatment for 12 months.

RESULTS: Testosterone treatment that increased testosterone levels from 232 +/- 63 ng/dL to mid-normal was associated with a small but significantly greater increase (p<0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14+/-0.86 ng/mL (mean +/-SD) at baseline by 0.47+/-1.1 ng/mL at 12 months in the testosterone group and from 1.25+/-0.86 ng/mL by 0.06+/-0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase >/=1.7 ng/mL and 2.5% of men had an increase of >/=3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8.

CONCLUSIONS: When hypogonadal, older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA >/=1.7 ng/mL, and 2.5% had an increase >/=3.4 ng/mL.

Cunningham GR, Ellenberg SS, Bhasin S, et al. Prostate Specific Antigen Levels during Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial. The Journal of clinical endocrinology and metabolism 2019. Prostate Specific Antigen Levels during Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial

 

[Michael Scally MD]

Molecular Determinants of Response to High Dose Androgen Therapy in Prostate Cancer

Clinical trials of high-dose androgen therapy for prostate cancer have shown promising efficacy but are limited by lack of criteria to identify likely responders.

To elucidate factors that govern the growth-repressive effects of high-dose androgens we applied an unbiased integrative approach utilizing genetic screens and transcriptional profiling of prostate cancer cells with or without demonstrated phenotypic sensitivity to androgen-mediated growth repression.

Through this comprehensive analysis, we identified genetic events and related signaling networks that determine the response to both high-dose androgen and androgen withdrawal.

We applied these findings to develop a gene signature that may serve as an early indicator of treatment response and identify men with tumors amenable to high dose androgen therapy.

Nyquist MD, Corella A, Mohamad O, et al. Molecular determinants of response to high dose androgen therapy in prostate cancer. JCI insight 2019. https://insight.jci.org/articles/view/129715

 

[Michael Scally MD]

Safety of Testosterone Therapy in Men with Prostate Cancer

Introduction: The use of testosterone therapy (TTh) in men with prostate cancer (PCa) is relatively new, and controversial, due to the longstanding maxim that TTh is contraindicated in men with PCa.

Scientific advances have prompted a reevaluation of the potential role for TTh in men with PCa, particularly as TTh has been shown to provide important symptomatic and general health benefits to men with testosterone deficiency (TD), including many men with PCa who may expect to live 30–50 years after diagnosis.

Areas covered: This review outlines the historical underpinnings of the historical belief that TTh ‘fuels’ PCa and the experimental and clinical studies that have radically altered this view, including description of the saturation model. The authors review studies of TTh in men with PCa following radical prostatectomy and radiation therapy, in men on active surveillance, and in men with advanced or metastatic PCa.

Expert opinion: TTh provides important symptomatic and overall health benefits for men with PCa who have TD. Although more safety studies are needed, TTh is a reasonable therapeutic option for men with low-risk PCa after surgery or radiation. Data in men on active surveillance are limited, but initial reports are reassuring.

Morgentaler A, Caliber M. Safety of testosterone therapy in men with prostate cancer. Expert opinion on drug safety 2019:1-12. https://doi.org/10.1080/14740338.2019.1666103

 

[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.