AAS & Prostate Cancer

Discussion in 'Steroid Forum' started by Michael Scally MD, Jul 25, 2013.

  1. MR10X

    MR10X Member

    I was on ADT prior to radiation and seed implants....its mot somethiong you want want to be on for a long time...I was on it for 3 months to shrink my prostrate (which the doc said was already small ). if i had to do it again i would skip the ADT and just do the seeds and radiation.......been 3 years since my treatment and my PSA is the lowest since treatments at 0.20 and this is while i was on testosterone.
     

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  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Teply BA, Kachhap S, Eisenberger MA, Denmeade SR. Extreme Response to High-dose testosterone in BRCA2- and ATM-mutated Prostate Cancer. Eur Urol. Elsevier: Article Locator

    Defects in DNA repair genes are now understood to be common in patients with metastatic castration-resistant prostate cancer (mCRPC) according to studies sequencing tumor samples and the germline. In a proof-of concept study to demonstrate that such defects could be exploited therapeutically, patients with mCRPC with mutations in DNA repair genes had responses when treated with olaparib.

    The mechanism by which PARP inhibition leads to cell death, is in part via induction of DNA double strand breaks, which go unrepaired in cells harboring defects in the homologous recombination repair pathway.

    We have previously reported on the therapeutic potential of high-dose testosterone in men with mCRPC. Preclinical studies demonstrated that rapid cycling between high and low levels of androgen, termed bipolar androgen therapy (BAT), could disrupt DNA relicensing and produce DNA double-strand breaks in CRPC cells.

    Given the emerging data on DNA repair defects in prostate cancer and the mechanism of BAT, we postulated that men with such defects may be particularly susceptible to BAT. Here we report a case of an exceptional responder to BAT and the underlying tumor mutations that possibly explain his susceptibility to the therapy.

    The patient is a 70-yr-old man with mCRPC. He initially presented with Gleason 9 disease for which he underwent radical prostatectomy followed by salvage radiation therapy. He was initiated on hormonal therapy 2 yr later because of rising prostate-specific antigen (PSA).

    He received bicalutamide, nilutamide, ketoconazole, and enzalutamide sequentially over 3 yr (Fig. 1). At the time of progression on enzalutamide, computed tomography (CT) imaging showed enlarging node-only disease (target lesion was 3.3 cm in the iliac node).

    He was enrolled in a clinical trial and received testosterone cypionate 400 mg intramuscularly every 28 d and continuous luteinizing hormone–releasing hormone agonist therapy. After two cycles, his PSA became unmeasurable and has remained so for 20 cycles of ongoing BAT (Fig. 1).

    He achieved a radiographic complete response after six cycles. At this point, the patient continues to have no evidence of disease on bone scan or CT scan, nondetectable PSA, and testosterone in the non-castrate range.

    To test whether this patient’s tumor had underlying DNA repair defects, we sequenced his archived primary prostate cancer tissue using a 203-gene panel (Personal Genome Diagnostics, Baltimore, MD, USA).

    The tumor was found to have an inactivating S1982Rfs*22 frame shift mutation in BRCA2 and an L2307F missense mutation in ATM. Both of these mutations were present in the germline.

    The results for this patient, who is experiencing a durable complete response to BAT, support the hypothesis that patients harboring mutations in DNA repair pathway genes may be particularly sensitive to BAT. Further testing of BAT in patients with DNA repair deficits or testing of BAT in combination with agents targeting the DNA repair pathway is warranted.

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  3. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Schweizer MT, Antonarakis ES, Denmeade SR. Bipolar Androgen Therapy: A Paradoxical Approach for the Treatment of Castration-resistant Prostate Cancer. Eur Urol. http://www.europeanurology.com/article/S0302-2838(17)30233-6/abstract

    Bipolar androgen therapy (BAT) is a paradoxical treatment for castrate-resistant prostate cancer whereby testosterone levels are rapidly alternated between supraphysiologic and near-castrate concentrations. Initial studies demonstrated that BAT is safe and produces clinical responses. A trial comparing enzalutamide against BAT is ongoing.
     
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  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Schweizer MT, Wang H, Luber B, et al. Bipolar Androgen Therapy for Men With Androgen Ablation Naive Prostate Cancer: Results From the Phase II BATMAN Study. Prostate 2016;76(13):1218-26. Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study

    BACKGROUND: We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT).

    Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in.

    METHODS: Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT.

    BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections.

    The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL).

    RESULTS: Twenty-nine of 33 patients received BAT following the ADT lead-in.

    The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys.

    CONCLUSIONS: BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT.
     
  5. Juced

    Juced Member

    pretty interesting
     
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Transient Exposure to Androgens Induces a Remarkable Self-Sustained Quiescent State in Dispersed Prostate Cancer Cells

    Our findings presented in this study may have potential therapeutic applications. It is known that more than 10% of patients treated with radical prostatectomy for prostate cancer will have a metastatic relapse of their cancer within the next 10 years, most likely due to an early metastatic spread of cancer cells that colonizes distant organs as solitary cancer cells.

    Therefore, transient treatments with androgens could enhance their transition toward a dormant state and/or stabilize their dormancy, thereby delaying the development of clinical metastases. This would be effective if the treatment is started just after radical prostatectomy, at a time when cancer cells are still dispersed and solitary, since, as indicated by our data, clusters of interacting cancer cells may become resistant to induction of dormancy.

    This therapy should be complementary to medical castration as androgen deprivation is likely to be a driving force which leads prostate cancer cells to become hypersensitive to androgens and to enter into dormancy in response to physiologic levels of androgens. Moreover, repeated cycles of androgen deprivation and supplementation could be envisioned, as AR antagonists does not destabilize dormancy once established.

    It is noteworthy that a similar paradigm of bipolar androgen therapy (BAT) was previously proposed to counteract the adaptative autoregulation of AR expression to the change of androgen concentration in CRPC cells.

    Our data suggest that BAT could also be of therapeutic value if applied earlier before biochemical relapse and at more distant intervals to inhibit proliferation of androgen-dependent disseminated cancer cells when they are still solitary.

    Thus, even if this treatment does not provide a complete protection from relapse it could be a welcomed therapeutic option since a reduction in the frequency of escape from dormancy should translate into a proportional extension of progression- free survival at a very limited cost.

    Bui AT, Huang ME, Havard M, Laurent-Tchenio F, Dautry F, Tchenio T. Transient exposure to androgens induces a remarkable self-sustained quiescent state in dispersed prostate cancer cells. Cell Cycle 2017;16(9):879-93. http://www.tandfonline.com/doi/abs/10.1080/15384101.2017.1310345?journalCode=kccy20

    Cellular quiescence is a reversible cell growth arrest that is often assumed to require a persistence of non-permissive external growth conditions for its maintenance.

    In this work, we showed that androgen could induce a quiescent state that is self-sustained in a cell-autonomous manner through a "hit and run" mechanism in androgen receptor-expressing prostate cancer cells.

    This phenomenon required the set-up of a sustained redox imbalance and TGFbeta/BMP signaling that were dependent on culturing cells at low density.

    At medium cell density, androgens failed to induce such a self-sustained quiescent state, which correlated with a lesser induction of cell redox imbalance and oxidative stress markers like CDKN1A. These effects of androgens could be mimicked by transient overexpression of CDKN1A that triggered its own expression and a sustained SMAD phosphorylation in cells cultured at low cell density.

    Overall, our data suggest that self-sustained but fully reversible quiescent states might constitute a general response of dispersed cancer cells to stress conditions.
     
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Rationale for Bipolar Androgen Therapy (BAT) for Metastatic Prostate Cancer

    Bui et al. report in Cell Cycle 2017; 16:879-893 that androgen can induce a quiescent dormant state that is self-sustained in a cell-autonomous manner through a “hit and run” mechanism in androgen receptor-expressing prostate cancer cells. Thus, these authors suggest that repeated cycles of androgen deprivation and supplementation [i.e. bipolar androgen therapy (BAT)] could be effective for inhibiting the very early phase of metastasis development by inducing and/or reinforcing a self-sustained quiescent state in disseminated solitary cancer cells.

    The results of Bui et al. thus complement our own rationale for on-going clinical trials of such BAT therapy in which castration resistant metastatic prostate cancer [mCRPC] patients continuously maintained on androgen ablation via luteinizing hormone releasing hormone agonist therapy are given intermittent cycles of pharmacologic levels of testosterone (T) via intramuscularly injection with 400mg of testosterone cypionate every 28 days to raises the serum T to > 1500 ng/dl by 2 days post-injection, with a decline to near castrate level (100 ng/dl) by 28 days post-injection.

    Our approach of bipolar cycling between pharmacological high followed by a rapid decline to castrate levels of T is based upon the coupled facts that during prostatic carcinogenesis, Androgen Receptor (AR) acquires an oncogene gain of function with regard to DNA replication licensing required for malignant cell proliferation and that during the subsequent progression during androgen ablation therapy to mCRPC, AR protein expression is greatly (>50-100 fold) increased.

    During early G1 of the cell cycle, nuclear AR in mCRPC cells binds to DNA at origins of replication sites (ORS) as part of the origin of replication complex (ORC) complex that is needed for licensing DNA replication during the S-phase, left panel in Figure. AR remains associated with the ORC during cell cycle progression until late mitosis when, as a DNA licensing factor, it must be removed via its degradation so that re-licensing can occur in the next cell cycle.

    In the presence of pharmacologic serum testosterone, increased ligand over-stabilizes ORC bound AR prevents its sufficient degradation. This lack of sufficient mitotic AR degradation due to ligand dependent over stabilization inhibits DNA relicensing, resulting in cell death in the subsequent cycle.

    An additional rationale for BAT is the observation that there are differences in the AR transcriptome when high-AR cell lines are exposed to either high or low androgen concentrations.

    Under high-androgen conditions, AR represses a number of genes, including AR and those involved in androgen synthesis, DNA synthesis, and proliferation. Therefore, high-dose T may lead castration-resistant cells to transition from a more oncogenic transcriptome associated with castrate T levels to a high-androgen transcriptome that does not support cancer proliferation.

    We hypothesized that such continuous rapidly cycling between the polar extremes from near-castrate to supraphysiologic (i.e. pharmacologic) serum T levels prevents adaptive changes in AR expression, prolonging the length of time during which patients respond to this therapy.

    Furthermore, because recent studies have shown that the double- strand DNA breaks and apoptosis induced by high doses of androgens are transient, rapid cycling of T could result in repeated rounds of DNA damage, enhancing antitumor effects.

    At present, BAT is being tested in a large (n = 180) randomized trial (NCT02286921; TRANSFORMER) in asymptomatic mCRPC patients who have failed on abiraterone. In this study, BAT is being compared to enzalutamide with a primary endpoint of progression-free survival

    (PFS). However, this trial will not allow to determine whether BAT is effective in inducing or reinforcing dormancy in disseminated solitary cancer cells and thus to decrease the frequency of metastatic recurrence. As suggested by Bui et al, this would require to test the effect of short duration BAT when started just after radical prostatectomy with a primary endpoint of metastasis-free survival.

    Isaacs JT, Brennen WN, Denmeade SR. Rationale for Bipolar Androgen Therapy (BAT) for Metastatic Prostate Cancer. Cell Cycle. http://www.tandfonline.com/doi/full/10.1080/15384101.2017.1360645
     
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  8. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Supraphysiologic testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions

    Since Huggins defined the androgen-sensitive nature of prostate cancer (PCa), suppression of systemic testosterone (T) has remained the most effective initial therapy for advanced disease although progression inevitably occurs.

    From the inception of clinical efforts to suppress androgen receptor (AR) signaling by reducing AR ligands, it was also recognized that administration of T in men with castration-resistant prostate cancer (CRPC) could result in substantial clinical responses.

    Data from preclinical models have reproducibly shown biphasic responses to T administration, with proliferation at low androgen concentrations and growth inhibition at supraphysiological T concentrations.

    Many questions regarding the biphasic response of PCa to androgen treatment remain, primarily regarding the mechanisms driving these responses and how best to exploit the biphasic phenomenon clinically.

    Here we review the preclinical and clinical data on high dose androgen growth repression and discuss cellular pathways and mechanisms likely to be involved in mediating this response.

    Although meaningful clinical responses have now been observed in men with PCa treated with high dose T, not all men respond, leading to questions regarding which tumor characteristics promote response or resistance, and highlighting the need for studies designed to determine the molecular mechanism(s) driving these responses and identify predictive biomarkers.

    Mohammad OS, Nyquist MD, Schweizer MT, et al. Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions. Cancers (Basel) 2017;9. Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions
     
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  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine

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    Potential mechanisms for repression of prostate cancer growth by high dose androgen.

    (A) AR activation in context of high dose androgen (denoted by light blue squares) may lead to transcriptional repression of myelocytomatosis oncogene cellular homolog (MYC) and its target gene S-phase kinase-associated protein 2 (SKP2), with loss of ubiquitin-mediated degradation of the G1 cyclin dependent kinase (CDK) inhibitors p21cip1 and p27kip1, leading to

    (B) G1 arrest. (AR can also directly induce expression of p21cip1 via an androgen response element (ARE) in its proximal promoter).

    (C) Ligand-dependent stabilization of AR during mitosis may inhibit AR degradation in M phase, preventing relicensing for DNA replication during G1 resulting in S phase arrest.

    (D) Androgen induced repression of genes that promote epithelial to mesenchymal transition (EMT) such as (sex determining region Y)-box 2 (SOX2), and expression of genes important in normal differentiation such as sister chromatid cohesion protein cohesion associated factor B (PDS5B (also known as androgen-induced proliferation inhibitor (APRIN)) and promyelocytic leukemia zinc finger protein (PLZF), may promote a more differentiated less aggressive cell state. Through recruitment of hypo-phosphorylated retinoblastoma protein (RB) to shared AR/RB/E2F binding sites, agonist-liganded AR represses genes involved in DNA replication, potentially leading to transcriptional reprogramming toward a less proliferative state.

    (E) Activated AR may act as a transcriptional repressor at certain AR binding sites (ARBS) via recruitment of lysine-specific histone demethylase 1 (LSD1) and demethylation of activating histone marks, resulting in decreased expression of full length AR and downstream generation of spliced variants.

    (F) AR-induced production of reactive oxygen species (ROS) leading to decreased RB phosphorylation and repression of E2F target genes may result in formation of senescence-associated heterochromatic foci (SAHFs).

    (G) Androgen signaling leads to co-recruitment of AR and topoisomerase II beta (TOP2B) and TOP2B-mediated DNA double stranded breaks (DSBs) in regulatory regions of AR target genes, potentially leading to DNA damage and apoptosis, particularly in the setting of DNA damage repair (DDR) deficiency (such as mutations in ataxia-telangiectasia mutated gene (ATM) or breast cancer 2 (BRCA2)). X: inhibition of gene expression; +: induction of gene expression.
     
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  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    A Prospective Audit of Intermittent Anti-Androgen verses Pituitary Blockade Suggests a Bipolar Androgen Type Strategy May Be Safe in Untreated Prostate Cancer

    OBJECTIVE: A locally advanced Gleason 4 + 4 prostate cancer patient who was on self-medication with intermittent anti-androgen monotherapy (iAAm) over 14 years suggested that raised testosterone was not dangerous and this suggestion needed investigating.

    PATIENTS: Others who were on AA continuously were recruited to ongoing audit of intermittent hormone therapy (IHT) and iAAm outcomes were compared with intermittent LHRH therapy (iLHRH or iMAB).

    RESULTS: Between 1994 and 2007, 111 patients sought IHT because of side effects of treatment. Forty-two M0 patients received IHT with iLHRHm or iMAB and 33 received iAAm (31 of these were M0). PSA nadir below 4 was necessary for entry. Overall survival was 87, 72 and 67% with iAAm and 73, 56 and 43% with iLHRH/MAB at 5, 8 and 10 years respectively. Overall survival was 61, 55 and 33% continued on iAAm and 56, 41, and 32% on iLHRH/MAB at 5, 8, and 10 years respectively. Multivariable analysis and matched case control analysis confirm that the maintenance of advantage for iAAm Testosterone levels in patients on iAAm compared to iLHRH therapy was more intense throughout treatment.

    CONCLUSION: These results complement recent progress in using bipolar androgen therapy to reverse castration resistance and add to the increasing acceptance that controlled testosterone exposure might be relevant in hormone-naive patients.

    Oliver T, Wilson P, Ansell W, et al. A Prospective Audit of Intermittent Anti-Androgen verses Pituitary Blockade Suggests a Bipolar Androgen Type Strategy May Be Safe in Untreated Prostate Cancer. Urologia Internationalis 2017. https://www.karger.com/Article/Abstract/485255
     
  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Gravina GL, Marampon F, Patrizia Sanità P, et al. Episode-like pulse testosterone supplementation induces tumor senescence and growth arrest down-modulating androgen receptor through modulation of p-ERK1/2, pARser81 and CDK1 signaling: biological implications for men treated with testosterone replacement therapy. Oncotarget. 2017; 8:113792-806. https://doi.org/10.18632/oncotarget.22776

    Despite the growing body of knowledge showing that testosterone (T) may not significantly affect tumor progression in hypogonadal patients treated for prostate cancer (Pca), the use of this hormone in this population still remains controversial. The effects of continuous or pulsed T stimulation were tested in vitro and in vivo on androgen-sensitive

    Pca cell lines in order to assess the differential biological properties of these two treatment modalities. Pulsed T treatment resulted in a greater inhibition than continuous T supplementation of tumor growth in vitro and in vivo. The effects of pulsed T treatment on tumor growth inhibition, G0/G1 cell cycle arrest, and tumor senescence was more pronounced than those obtained upon continuous T treatments.

    Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2. Pulsed, but not continuous, T supplementation decreased the expression levels of AR, p-ARser81 and CDK1 in both cellular models.

    The in vitro results were confirmed in an in vivo xenografts, providing evidence of a greater inhibitory activity of pulsed supraphysiological T supplementation than continuous treatment, both in terms of tumor volume and decreased AR, p-ARser81, PSA and CDK1 staining.

    The rapid cycling from hypogonadal to physiological or supra-physiological T intraprostatic concentrations results in cytostatic and senescence effects in preclinical models of androgen-sensitive Pca. Our preclinical evidence provides relevant new insights in the biology of Pca response to pulsed T supplementation.
     
  12. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Bipolar Androgen Therapy in Men with Metastatic Castration-Resistant Prostate Cancer After Progression on Enzalutamide

    BACKGROUND: Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide.

    METHODS: We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone.

    Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0-2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation.

    Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily.

    The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114.

    FINDINGS: Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15-49; p<0.0001) of 30 patients achieved a PSA50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33-71; p<0.0001) achieved a PSA50 response.

    During BAT, the only grade 3-4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3-4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment.

    INTERPRETATION: BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients.

    Teply BA, Wang H, Luber B, et al. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 2018;19(1):76-86. http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30906-3/abstract
     
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  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Opportunities in Supraphysiological testosterone Therapy as Treatment for Castration-Resistant Prostate Cancer

    Blocking androgen signaling has been the focus of treatment for advanced and metastatic prostate cancer (PC) for the past 70 years (1). First-line androgen deprivation therapy (ADT), either through surgical or medical castration (luteinizing hormone-releasing hormone agonists and antiandrogens), holds promise for PC patients; however, the disease inevitably progresses to castration resistance (2). Second-generation ADT, abiraterone acetate (AA) and enzalutamide (ENZ), have been effective for a subset of patients with castration-resistant PC (CRPC) with relatively short median survival benefits (~3 to 5 months) (3-5).

    Concerted effort in the field, including evidence from our group, clearly demonstrates a sustained AR activity in the CRPC tumors including

    (1) amplification of AR,

    (2) AR mutations,

    (3) expression of AR splice variants that are constitutively active,

    (4) altered milieu of AR coactivators and corepressors, and

    (5) intracrine synthesis of androgens to support CRPC progression (6, 7).

    The addiction of PC to the AR signaling paradoxically creates a therapeutic vulnerability that has recently attracted increasing attention. While ADT causes regression of PC, high level of androgen can also inhibit PC progression. The concept of cancer suppression using excessive hormone therapy was introduced by earlier work from Huggins in 1940: “malignant cells can regress from too little or too much hormone’’ (8).

    In relation to PC, AR regulates proliferation as well as differentiation of prostate epithelial and cancer cells but it has not been established what conditions support one over the other. Interestingly activation of AR with excessive hormone (i.e. supra-physiological levels of testosterone; SPT) was shown to inhibit growth of CRPC in vitro by negative effects on proliferation and increased expression of some of the AR-regulated genes that are expressed in differentiated luminal epithelium, e.g., prostate-specific antigen.

    Multiple preclinical studies demonstrated that SPT inhibits growth of PC cells that express AR (9-21), with evidence suggesting that higher levels of AR might lead to more pronounced SPT effects in certain phenotypes of CRPC (reviewed in (22)). However, AR by itself is not necessarily sufficient for the SPT-induced growth inhibition; cellular context (23) and AR-regulated transcriptome in its entirety will need to be assessed to delineate the molecular effect of SPT (24).

    Mechanistically, SPT-induced cell growth inhibition involves

    (1) cell cycle arrest,

    (2) disruption of AR-mediated DNA licensing,

    (3) DNA damage,

    (4) transcriptional repression of AR and its variants,

    (5) transcriptional reprogramming,

    (6) cellular quiescence or senescence, and

    (7) induction of apoptosis (reviewed in (22)).

    However, these effects were demonstrated exclusively in cell line models, and whether they play a significant biological role in SPT-induced tumor inhibition in patients remains to be determined.

    Clinical use of testosterone (T) supplementation in PC has been limited and provided controversial results. Two older National Prostatic Cancer Project trials that used T supplementation to normal levels with a goal to enhance the effectiveness of chemotherapy reported disappointing results (25, 26). Additional two phase I trials, which did not achieve consistent supra-physiological T levels, showed minimally reduced disease progression (27, 28).

    In contrast, several other studies showed that T-supplementation to normal-supraphysiological range (303-2637ng/dl), specifically in symptomatic hypogonadal PC patients, provided prolonged disease control (as measured by sustainably low PSA level) (29-31). In our opinion, the lack of favorable response in some of the clinical trials is, at least in part, due to the absence of a supraphysiological level of T as well as the unselected patient population.

    With advanced understanding of the biology and AR involvement in CRPC progression, leveraging the active AR signaling to explore therapeutic opportunity has recently received renewed attention in clinical settings. Dr. Denmeade’s group at John Hopkins University pioneered a therapy termed “Bipolar Androgen Therapy” (BAT) as a treatment for PC patients.

    With BAT treatment, PC patients receive intermittent T injections at doses shown to produce a spike in serum T to supraphysiological levels, followed by a decline to below normal at the end of a 28-day treatment cycle (32). This cycling strategy was developed based on the most common molecular hallmark of CRPC–overexpression of AR (33) and the potential growth inhibitory effect of SPT in AR-overexpressing PC.

    Rapidly cycling of T from SPT (~1500 ng/dl) to below normal T levels (~150 ng/dl) was expected to blunt the adaptive changes in AR expression, thereby delaying the emergence of resistance. In these proof-of-principle BAT trials, one in CRPC showed radiographic response rates of ~50% in men 32, and one in hormone-sensitive PC showed favorable PSA responses (34).

    Promising results of these trials led to a new clinical trial, in which asymptomatic CRPC patients that progressed on AA or ENZ receive BAT, and after progression on BAT the patients are re-challenged with AA or ENZ. This trial aims to evaluate the efficacy of BAT in patients who progressed on secondary ADT and assess whether BAT re-sensitizes CRPC to secondary ADT.

    Recent data from this trial showed a PSA50 response in 9/30 ENZ-resistant patients on BAT, and, importantly, 15/21 patients who progressed on BAT showed a PSA50 response upon ENZ re-challenge (35). These results are encouraging. However, additional analyses and larger number of patients are needed to correlate tumor/radiographic vs. PSA responses in individual patients.

    One of the reasons is that PSA changes do not necessarily associate with tumor regression in advanced CRPC. PSA, an AR regulated gene, is highly sensitive to AR activation/inhibition and can rise upon SPT and decline upon ADT, but might not faithfully reflect radiographic responses in advanced CRPC, which growth does not rely solely on AR signaling (e.g. FGF signaling (36)).

    BAT therapy shows great clinical promise in a subset of patients. However, universal to all cancer treatment modalities, not all patients respond to this treatment and resistance to BAT develops. Therefore, there is an opportunity to improve this therapy. It is notable that a critical step in drug development, determining the optimal dosing schedule, was bypassed in the clinical development of BAT.

    Despite the clinical efficacy of BAT, there were essentially no clinical data to support the hypotheses that cycling SPT (i.e. BAT) mitigates the development of resistance or that BAT represents the optimal mode for administering SPT. Notably, several preclinical studies have consistently demonstrated that SPT delivered on a continuous basis inhibits the growth of PC cells (13, 20, 21). While several small clinical trials of continuous T administration in men with CRPC have been carried out, they did not achieve SPT levels.

    Cycling or not cycling – that is the question.

    While we currently do not have sufficient evidence whether BAT results in better clinical outcome than continuous SPT, it is possible that long-term continuous SPT and BAT could alter AR signaling differently. One would anticipate that continuous SPT might trigger more pronounced differentiation, potentially causing a change from a “low-T” oncogenic AR transcriptome to that of a more differentiating SPT transcriptome (24). Meanwhile, BAT might provide better efficacy if cell-cycle relicensing effects and DNA damage are the critical mechanism of action (37, 38).

    While BAT was associated with improved quality of life (34, 35), this effect diminished over the course of a cycle of BAT, presumably due to T levels falling below normal range. It is possible that quality of life metrics will be better with continuous SPT but there also might be increase in negative side effects.

    While T therapy has been reported to be generally safe, with a small subset of patients experiencing severe cardiovascular-related complications (27-32, 39-42), continuous SPT has not been tested and monitoring will be essential. Careful evaluation of effects of BAT vs continuous SPT on tumor progression, as well as any potential health benefits or side effects will be required to make final decision.

    Interestingly, cycling of ADT, intermittent ADT, has been evaluated in PC extensively since its introduction in mid-1980s. However, intermittent ADT was not found to be inferior to continuous ADT with respect to the overall survival but it was shown to improve patients’ quality of life, and therefore it is thought to be a viable option for patients who experience significant adverse effects of continuous ADT (for review see (43),(44)).

    In addition, intermittent AA therapy has been recently shown to delay the development of resistance from 16.5 (continuous treatment) to 27 months (45). Whether the intermittent therapy diversifies the residual tumor clones or re-sensitize the residual clones that formerly failed remains scientifically and clinically important.

    In summary, we will need to seek answers to multiple important questions before unleashing the full potential of SPT therapy in CRPC:

    (1) which mode of SPT, BAT or continuous SPT, represents the optimal administration regimen for tumor growth inhibition;

    (2) what population of patients will benefit from SPT therapy;

    (3) is there a way to prolong the treatment response; and

    (4) what are the mechanisms of resistance, as these will be diverse in different tumor phenotypes.

    To address these questions, systematic pre-clinical trials will need to be performed, and pre-treatment and on-treatment clinical specimens will be essential to identify mechanisms of SPT action and biomarkers that predict SPT response.

    Lam, HM, Corey E. Opportunities in Supraphysiological Testosterone Therapy as Treatment for Castration-Resistant Prostate Cancer. Front. Oncol. 2018. https://www.frontiersin.org/articles/10.3389/fonc.2018.00167/full
     
  14. MR10X

    MR10X Member

    did ADT, radiation seed implants and 25 external radiation treatments in 2012...my PSA as of this month was 0.1
     
  15. Flathead Fred

    Flathead Fred Member

    Mr10x, what's your T level now? Any ED issues during or after your treatment?
     
  16. MR10X

    MR10X Member

    last time it was checked it was713 but goes up and down but always in normal range.i have to use cialis to keep errections but sure my problem is because of the seed implants and radiation treatments,i didnt have any problems before any treatments. i had to do a couple of pct cycles to get my test back to normal after the ADT treatments which had my test at 32..
     
  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Pharmacologic Dose testosterone to Treat Castration-Resistant Prostate Cancer: Mechanisms of Action and Drivers of Response
    http://www.dtic.mil/dtic/tr/fulltext/u2/1050397.pdf

    Schweizer, Michael [01 Oct 2017]

    Purpose: Single-arm studies have demonstrated preliminary signs of efficacy for intermittent pharmacologic dose testosterone (i.e. Bipolar Androgen Therapy; BAT) in treating advanced prostate cancer.

    In this project, we will conduct detailed molecular assessments on biospecimens (i.e. blood, metastatic tissue) from men receiving BAT to determine somatic and germline factors that predict for response/resistance.

    We will also evaluate additional PDT based regimens (e.g. combinatorial treatments) in preclinical models.

    Scope: This annual technical progress report details progress made during the first year of funding for this project (30 Sep 2016 1 Oct 2017).

    Major Findings: During Year 1 we have focused on biospecimen acquisition from men enrolled a Phase II study testing BAT vs. enzalutamide. Results from correlative and preclinical studies are not available at this time.
     
  18. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Denmeade SR. Bipolar androgen therapy in the treatment of prostate cancer. Clinical advances in hematology & oncology: H&O 2018;16:408-11. Bipolar Androgen Therapy in the Treatment of Prostate Cancer – Hematology & Oncology

    H&O - What is bipolar androgen therapy (BAT)?

    SD - BAT consists of the administration of a high dose of androgen—also called testosterone—in an effort to control prostate cancer in men whose tumors are progressing on androgen deprivation therapy (ADT). This causes the levels of testosterone in the blood to alternate between the polar extremes of very high and very low during a treatment cycle (Figure, see pdf).

    H&O - How can the intermittent administration of high-dose testosterone produce an antitumor effect?

    SD - We know that testosterone can initially stimulate the growth of prostate cancer when the cancer is still hormone-sensitive, which is why castration is used to inhibit prostate cancer growth. For many years, however, published research has described a paradox in which supraphysiologic levels of androgens also seem to inhibit prostate cancer growth—particularly in prostate cancer cells that have adapted to growing in low levels of testosterone—and cause the tumor cells to die. How can this be?

    The answer may lie with the androgen receptor. Prostate cancer cells are highly dependent on or perhaps even addicted to the activity of the androgen receptor—the cells must regulate and degrade the androgen receptor if they are to proliferate. As a strategy for survival in the low-testosterone environment of ADT, prostate cancer cells adapt to produce far more androgen receptor, which allows them to capture every possible molecule of testosterone. Androgen receptors also may mutate so that they function even the absence of testosterone. The result is that prostate cancer is highly responsive to ADT initially but over time becomes resistant and continues to grow.

    In BAT, a very high dose of testosterone saturates the androgen receptors, making them more resistant to degradation by the prostate cancer cells. This degradation is required for each cell to go through its normal cycle and produce daughter cells. In other words, we are taking advantage of the cell’s adaptive increase in androgen receptor, which makes it vulnerable to the shock of a high level of testosterone.

    The other beneficial aspect of this approach is that when the testosterone level drops again, some of the prostate cancer cells will be resensitized to the low level. This occurs in prostate cancer cells that were able to survive the spike in testosterone by downregulating their androgen receptor.

    We want to be able to target all the prostate cancer cells—the ones with very high levels of androgen receptor, which will be sensitive to high levels of testosterone, and the ones with very low levels of androgen receptor, which will be sensitive to the rapid return of low levels of testosterone.

     
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Investigational Therapies Targeting the Androgen Signaling Axis and The Androgen Receptor and In Prostate Cancer

    Introduction: Despite the heterogeneity of prostate cancer (PCa), androgen stimulation is fundamental to its development, growth and lethality. Therefore, the blockade of androgen receptor (AR) signaling is critical to controlling the disease, even after progression with castrate levels of androgens.

    Areas covered: We review the current understanding of new ways to block the AR, using novel antiandrogen inhibitors, which act on different parts of the AR signaling pathway in PCa. We also review new approaches, such as the use of poly (ADP-ribose) polymerase (PARP) inhibitors, targeting both the AR and the DNA repair pathway, potentially adding synergy and improving efficacy and the combination of AR inhibitors and immunotherapy.

    Bipolar androgen therapy (BAT), an innovative strategy to target the AR, has shown early evidence of efficacy in PCa is also discussed in detail. We highlight some of the key ongoing studies of greatest relevance to this topic.

    Expert commentary: Clinical trials investigating new AR targeted therapies should be encouraged in patients with PCa. While it is unlikely that one AR inhibitor will produce long-lasting responses in a substantial proportion of patients, there is evidence that some strategies, such as the BAT could resensitize the AR to antiandrogens, alternating therapies and delaying time to progression, maximizing benefit to patients.

    Isaacsson Velho P, Carducci MA. Investigational therapies targeting the androgen signaling axis and the androgen receptor and in prostate cancer - recent developments and future directions. Expert opinion on investigational drugs 2018. https://doi.org/10.1080/13543784.2018.1513490
     
  20. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Evans CP. Bipolar androgen therapy: an intriguing paradox. The Lancet Oncology 2018;19:8-10. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30907-5/fulltext

    In The Lancet Oncology, Benjamin A Teply and colleagues 1 report a phase 2 trial in men with metastatic castration-resistant prostate cancer with progression on an androgen receptor pathway inhibitor, enzalutamide, who were treated with bipolar androgen therapy (BAT). It is a novel and intriguing concept.