Castrate Levels Research Articles

Late administration of luteinizing hormone-releasing hormone (LHRH) agonists and the impact on testosterone suppression in the real-world management of prostate cancer.

149 Background: LHRH agonists are standard for androgen deprivation therapy (ADT) for advanced prostate cancer (PCa). Increasing evidence suggests maintaining very low testosterone (T) levels is desirable and correlate with disease-specific survival. However, T levels may rise above castrate level between administrations, especially if the next dose is delayed. A previous publication showed that subcutaneously-administered leuprolide acetate (LA) provided a longer duration of action than intramuscularly-administered LA past the dosing interval. This study evaluated the timeliness of LHRH agonist administrations and subsequent rate of T breakthroughs in PCa patients. Methods: A retrospective review of electronic medical records from 1/1/07-6/30/16 of 85,030 LHRH agonist administrations for PCa treatment was conducted to evaluate the percentage of late subsequent administrations and T tests with T > 50 ng/dL. A late administration was defined as occurring on or after day 33 (1 mo formulation), 98 (3 mo), 129 (4 mo), or 195 (6 mo). Descriptive statistics were used. Results: 26.9% of all subsequent LHRH agonist administrations were late: 14.4% were ≤ 1 week late, 3.1% were between 1 and 2 weeks late, and 9.4% were > 2 weeks late. 21% of T tests demonstrated T > 50 ng/dL when administrations were late, in contrast to only 4% of measured T levels exceeded 50 ng/dL when LHRH agonists were administered early or on time. Conclusions: Across LHRH agonists, greater than a quarter of subsequent administrations were defined as late. Among late administrations, about half were > 1 week late, and more than a third were > 2 weeks late. Late administrations were correlated with inadequate castration over 20% of the time. Considering the clinical benefits of maintaining effective T suppression during ADT, clinicians should administer treatments within approved dosing instructions, include routine monitoring of T levels, and consider prescribing treatments with proven prolonged effect through the dosing period to achieve T suppression to castrate levels.

Early 18F-FDHT PET/CT as a predictor of treatment response in mCRPC treated with enzalutamide.

232 Background: Androgen deprivation is the mainstay in the treatment of metastatic prostate cancer. During treatment, the majority of patients will develop progressive disease despite castrate levels of testosterone; castration-resistant prostate cancer (CRPC). In vivo determination of androgen receptor status by 18F-FDHT PET/CT could be of use to predict treatment response timely and objectively. The objective of this study is to assess the value of early 18F-FDHT PET/CT to predict treatment response of enzalutamide in mCRPC. Methods: This pilot study was performed in 18 chemotherapy naïve men with mCRPC. 18F-FDHT PET/CT was performed at baseline and after 4 weeks of treatment with enzalutamide. Standard Uptake Value (SUV)max and SUVpeak of the 5 most intense and/or all bone, pleura and lymph node metastases were determined per patient. Area under the curve (AUC), sensitivity (Se) and specificity (Sp) of different characteristics of 18F-FDHT PET/CT were performed by ROC analysis. Response was determined at 12 weeks of treatment according to PCCTWG. Results: A total of 477 lesions (411 bone, 3 pleura and 63 lymph node) were found. At 12 weeks, response was seen in 16 patients, whereas 2 patients showed no response. The characteristics of 18F-FDHT PET/CT are shown in table 1. Baseline median SUVpeak of all metastatic lesions showed an AUC of 0.79 to predict response. AUC values using the 5 most intense lesions only or using the delta between baseline and 5 weeks were less accurate. Clinical trial information: NTR4086. Conclusions: Baseline 18F-FDHT PET/CT using SUVpeak of all metastatic lesions predicts treatment response in mCRPC treated with enzalutamide with an AUC of 0.79.[Table: see text]

Safety and Therapeutic Profile of a GnRH-Based Vaccine Candidate Directed to Prostate Cancer. A 10-Year Follow-Up of Patients Vaccinated With Heberprovac.

Heberprovac is a GnRH based vaccine candidate containing 2.4 mg of the GnRHm1-TT peptide as the main active principle; 245 μg of the very small size proteoliposomes adjuvant (VSSP); and 350 μL of Montanide ISA 51 VG oil adjuvant. The aim of this study was to assess the safety and tolerance of the Heberprovac in advanced prostate cancer patients as well as its capacity to induce anti-GnRH antibodies, the subsequent effects on serum levels of testosterone and PSA and the patient overall survival. The study included eight patients with histologically-proven advanced prostate cancer with indication for hormonal therapy, who received seven intramuscular immunizations with Heberprovac within 18 weeks. Anti-GnRH antibody titers, testosterone and PSA levels, as well as clinical parameters were recorded and evaluated. The vaccine was well tolerated. Significant reductions in serum levels of testosterone and PSA were seen after four immunizations. Castrate levels of testosterone were observed in all patients at the end of the immunization schedule, which remained at the lowest level for at least 20 months. In a 10-year follow-up three out of six patients who completed the entire trial survived. In contrast only one out eight patients survived in the same period in a matched randomly selected group receiving standard anti-hormonal treatment. Heberprovac vaccination showed a good security profile, as well as immunological, biochemical and, most importantly, clinical benefit. The vaccinated group displayed survival advantage compared with the reference group that received standard treatment. These results warrant further clinical trials with Heberprovac involving a larger cohort.

A New Sustained-release, 3-Month Leuprolide Acetate Formulation Achieves and Maintains Castrate Concentrations of Testosterone in Patients With Prostate Cancer

PurposeThis clinical trial investigated the effectiveness, pharmacokinetic properties, and safety profile of leuprolide acetate 22.5-mg depot, a new 3-month leuprolide depot formulation, as androgen deprivation therapy for patients with prostate cancer. MethodsA Phase III, open-label, multicenter study design for patients with prostate cancer, with patient inclusion assessed by the investigative site as patient's appropriate for androgen deprivation therapy. Patients received 2 separate intramuscular injections of leuprolide acetate 22.5-mg depot for a 3-month depot interval of therapeutic effect. Plasma testosterone concentrations were determined throughout the study. The primary efficacy analysis was the percentage of patients who achieve and maintain castrate testosterone levels (≤50 ng/mL) from days 28–168. Secondary end points included luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen, and safety assessments. A pharmacokinetic study was also conducted in a subset of 30 patients. FindingsAll 163 patients enrolled in the study received at least 1 dose of study drug; 162 of them were fully evaluable and 151 completed the study. Castrate levels of testosterone were achieved and maintained from days 28–168 in 96.8% (95% CI, 92.5%–98.7%) of patients. Five patients presented with sporadic testosterone levels >50 ng/dL. By day 28, of the 161 patients, 150 (99.4%) had achieved castrate levels, and 127 (78.9%) had achieved testosterone concentrations ≤20 ng/dL. At study end, 149 of 151 patients (98.7%) patients achieved castrate testosterone levels, with 142 of 151 (94.0%) having testosterone levels ≤20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating hormone concentrations had decreased from baseline to below the lower limit of quantitation and below baseline levels, respectively, whereas mean serum prostate-specific antigen was reduced by 94.7% from baseline. Most patients (>96%) had no change in their World Health Organization/Eastern Cooperative Oncology Group score, whereby 84.0% of patients had a baseline score of 0. Bone pain, urinary pain, and urinary symptoms were infrequent and remained so throughout the study. After administration, leuprolide concentrations increased rapidly. The peak was followed by a decline up to day 28, maintaining sustained drug levels until the following dose on day 84. The most common related treatment-emergent adverse events, detected in >5% of patients, were hot flushes, fatigue, and injection site pain reported by 77.3%, 9.8%, and 9.2% of patients, respectively. ImplicationsLeuprolide acetate 22.5-mg depot was effective in achieving and maintaining testosterone suppression. Safety and tolerability profiles were consistent with established profiles of androgen deprivation therapy. Clinical Trials.gov identifier: NCT01415960.

Discordance between testosterone measurement methods in castrated prostate cancer patients.

Failure to suppress testosterone below 0.7 nM in castrated prostate cancer patients is associated with poor clinical outcomes. Testosterone levels in castrated patients are therefore routinely measured. Although mass spectrometry is the gold standard used to measure testosterone, most hospitals use an immunoassay method. In this study, we sought to evaluate the accuracy of an immunoassay method to measure castrate testosterone levels, with mass spectrometry as the reference standard. We retrospectively evaluated a cohort of 435 serum samples retrieved from castrated prostate cancer patients from April to September 2017. No follow-up of clinical outcomes was performed. Serum testosterone levels were measured in the same sample using liquid chromatography coupled with tandem mass spectrometry and electrochemiluminescent immunoassay methods. The mean testosterone levels were significantly higher with immunoassay than with mass spectrometry (0.672 ± 0.359 vs 0.461 ± 0.541 nM; P < 0.0001). Half of the samples with testosterone ≥0.7 nM assessed by immunoassay were measured <0.7 nM using mass spectrometry. However, we observed that only 2.95% of the samples with testosterone <0.7 nM measured by immunoassay were quantified ≥0.7 nM using mass spectrometry. The percentage of serum samples experiencing testosterone breakthrough at >0.7 nM was significantly higher with immunoassay (22.1%) than with mass spectrometry (13.1%; P < 0.0001). Quantitative measurement of serum testosterone levels >0.7 nM by immunoassay can result in an inaccurately identified castration status. Suboptimal testosterone levels in castrated patients should be confirmed by either mass spectrometry or an immunoassay method validated at low testosterone levels and interpreted with caution before any changes are made to treatment management.

Measuring testosterone and testosterone replacement therapy in men receiving androgen deprivation therapy for prostate cancer: A survey of UK uro-oncologists' opinions and practice.

To explore the practice and attitudes of uro-oncologists in the UK regarding monitoring testosterone levels and the use of testosterone replacement therapy (TRT) in their prostate cancer patients treated with androgen deprivation therapy (ADT). An expert-devised online questionnaire was completed by the members of the British Uro-oncology Group (BUG). Of 160 uro-oncologists invited, 84 completed the questionnaire. Before initiating ADT in patients with non-metastatic prostate cancer, only 45% of respondents measured testosterone levels and 61% did not measure testosterone at all during ADT in the adjuvant or neoadjuvant setting. However, in men with metastatic prostate cancer, 71% of the uro-oncologists measured testosterone before starting ADT and the majority continued testing during treatment. Approximately two-thirds of respondents did not prescribe TRT for their patients who were in remission following neo(adjuvant) ADT and who had castration levels of testosterone. Among UK uro-oncologists, the measurement of testosterone levels before and during ADT was not typically part of routine practice in the management of patients with prostate cancer. However, testosterone levels were checked more frequently for patients with metastatic disease than disease at an earlier stage. Testing could be conducted in parallel with PSA measurement as testosterone levels are linked to biochemical failure. The majority of specialists participating in the survey did not prescribe TRT for their patients in remission following ADT. Uro-oncologists in the UK do not generally measure testosterone as part of their patient management and they remain cautious about the possible benefits of TRT in men with prostate cancer.

The STAT3 Inhibitor Galiellalactone Reduces IL6-Mediated AR Activity in Benign and Malignant Prostate Models.

IL6/STAT3 signaling is associated with endocrine therapy resistance in prostate cancer, but therapies targeting this pathway in prostate cancer were unsuccessful in clinical trials so far. The mechanistic explanation for this phenomenon is currently unclear; however, IL6 has pleiotropic effects on a number of signaling pathways, including the androgen receptor (AR). Therefore, we investigated IL6-mediated AR activation in prostate cancer cell lines and ex vivo primary prostate tissue cultures in order to gain a better understanding on how to inhibit this process for future clinical trials. IL6 significantly increased androgen-dependent AR activity in LNCaP cells but importantly did not influence AR activity at castrate androgen levels. To identify the underlying mechanism, we investigated several signaling pathways but only found IL6-dependent changes in STAT3 signaling. Biochemical inhibition of STAT3 with the small-molecule inhibitor galiellalactone significantly reduced AR activity in several prostate and breast cancer cell lines. We confirmed the efficacy of galiellalactone in primary tissue slice cultures from radical prostatectomy samples. Galiellalactone significantly reduced the expression of the AR target genes PSA (P < 0.001), TMPRSS2 (P < 0.001), and FKBP5 (P = 0.003) in benign tissue cultures (n = 24). However, a high heterogeneity in the response of the malignant samples was discovered, and only a subset of tissue samples (4 out of 10) had decreased PSA expression upon galiellalactone treatment. Taken together, this finding demonstrates that targeting the IL6/STAT3 pathway with galiellalactone is a viable option to decrease AR activity in prostate tissue that may be applied in a personalized medicine approach.

Role of Androgen Receptor in Prostate Cancer: A Review.

Androgen receptor (AR) is a steroid receptor transcriptional factor for testosterone and dihydrotestosterone consisting of four main domains, the N-terminal domain, DNA-binding domain, hinge region, and ligand-binding domain. AR plays pivotal roles in prostate cancer, especially castration-resistant prostate cancer (CRPC). Androgen deprivation therapy can suppress hormone-naïve prostate cancer, but prostate cancer changes AR and adapts to survive under castration levels of androgen. These mechanisms include AR point mutations, AR overexpression, changes of androgen biosynthesis, constitutively active AR splice variants without ligand binding, and changes of androgen cofactors. Studies of AR in CRPC revealed that AR was still active in CRPC, and it remains as a potential target to treat CRPC. Enzalutamide is a second-generation antiandrogen effective in patients with CRPC before and after taxane-based chemotherapy. However, CRPC is still incurable and can develop drug resistance. Understanding the mechanisms of this resistance can enable new-generation therapies for CRPC. Several promising new AR-targeted therapies have been developed. Apalutamide is a new Food and Drug Administration-approved androgen agonist binding to the ligand-binding domain, and clinical trials of other new AR-targeted agents binding to the ligand-binding domain or N-terminal domain are underway. This review focuses on the functions of AR in prostate cancer and the development of CRPC and promising new agents against CRPC.

Combined abiraterone acetate plus prednisone, salvage prostate bed radiotherapy and LH-RH agonists (CARLHA-GEP12) in biochemically-relapsing prostate cancer patients following prostatectomy: A phase I study of the GETUG/GEP.

BackgroundTo establish the maximum tolerated dose of abiraterone acetate plus prednisone (AA) combined with salvage radiotherapy (SRT) and goserelin in a phase 1 study in men with rising PSA following radical prostatectomy.MethodsAA was given during one month before SRT at 1000 mg PO once daily, then 750 mg (Dose Level 1, DL1) or 1000 mg (DL2) during 5 months combined with 6-months goserelin by injection on the first day of irradiation (scheme NEO) or one month before starting SRT (scheme CONCO).ResultsIn scheme NEO at DL1, 2/9 patients did not achieve castration levels of testosterone. 4/9 patients (44%) presented with grade 3 liver enzyme elevation. In scheme CONCO testosterone dropped to undetectable levels. At DL1, 6 patients were recruited, with no dose limiting toxicities. At DL2, 2/3 patients presented with grade 3 liver enzyme elevation occurring during SRT.ConclusionsWhen AA was administered without goserilin, only 78% achieved castration levels. AA combined with SRT and goserilin did not increase pelvic toxicity, but lead to an unsuspected high frequency of grade 3 liver toxicity. The phase II recommended dose of AA combined to goserelin and SRT is 750 mg.

A Retrospective Study of the Relationship Between Testicular Damage and Urinary Creatine Excretion: Possible Markers of Testicular Toxicity Induced by Drugs

ObjectivesCreatine and creatine phosphate act as a buffer system for the regeneration of ATP in tissues with high and fluctuating energy demands. Total creatine content of the rat testis is high compared to all other tissues except skeletal muscle and creatine excretion in rat urine has been shown to increase following testicular damage caused by toxicants. Because the use of biomarkers in toxicology is becoming increasingly important, we investigated whether urinary creatine might be a useful marker for testicular damage in human.MethodsIn a retrospective study, the records of 22 male patients with urological malignancies treated with cisplatin, leuprorelin or goserelin at 4‐week intervals between October 2005 and October 2015 were evaluated. Urinary creatine and serum follicle‐stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels were assessed in all patients. Single‐voided urine samples were collected to determine urinary creatine‐to‐creatinine ratios. Blood sample collection was done in the morning when serum testosterone levels are around their peak: such morning time sampling for testosterone measurements is recommended in the clinical setting and routinely used in epidemiological studies.ResultsSeven patients with urothelial carcinoma treated with cisplatin based chemotherapy (mean age, 64.1 years) showed no significant changes in urine creatine/creatinine ratio during treatment and had a significant increase in FSH and LH levels and a significant decrease in testosterone levels compared to those at baseline. Similarly, no significant changes in urine creatine/creatinine ratio occurred in patients with prostatic carcinoma treated with leuprorelin (n=8; mean age, 70.0 years) or goserelin (n=7; mean age, 70.4 years), both of whom had castrate levels of testosterone (≤0.5 ng/mL) and suppressed levels of FSH and LH during treatment.ConclusionsOur data demonstrate that testicular damage could not be detected by urinary creatine in patients treated with drugs showing testicular toxicity. Two major testicular functions, i.e., the production of testosterone and formation of haploid germ cells, are generally considered to be regulated by pituitary gonadotrophins, with LH acting on the testosterone‐producing Leydig cells located in the interstitium and FSH affecting Sertoli cells in the seminiferous tubules. Thus, our hormonal data may indicate the presence of cisplatin‐induced Sertoli cell dysfunction and inhibition of Leydig cell function by LH‐RH analogues.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Short-term effects of transdermal estradiol in men undergoing androgen deprivation therapy for prostate cancer: a randomized placebo-controlled trial.

There is increasing recognition that, in men, some biological actions attributed to testosterone (TS) are mediated by estradiol (E2). This study used two low doses of daily transdermal E2 gel to assess the effects on circulating E2 concentrations in men with prostate cancer with suppressed endogenous E2 production arising from androgen deprivation therapy (ADT). Secondarily, we aimed to assess short-term biological effects of E2 add-back without increasing circulating TS. 28-day randomised, placebo-controlled trial. 37 participants were randomised to either 0.9 or 1.8 mg of 0.1% E2 gel per day or matched placebo gel. Fasting morning serum hormones, quality of life questionnaires, and treatment side effects were evaluated at baseline, days 14 and 28. Hot flush diaries and other biochemical measurements were completed at baseline and study end. Transdermal E2 significantly raised serum E2 from baseline to day 28 compared to placebo in the 0.9 mg dose group (median: 208 pmol/L; interquartile range: 157-332) and in the 1.8 mg dose group (median: 220 pmol/L; interquartile range: 144-660). E2 treatment reduced hot flush frequency and severity as well as beta carboxyl-terminal type 1 collagen telopeptide. In men with castrate levels of E2 and TS, daily transdermal E2: 0.9-1.8 mg increased median serum E2 concentrations into the reference range reported for healthy men, but with substantial variability. E2 treatment reduced hot flushes and bone resorption. Larger studies will be required to test whether low-dose E2 treatment can mitigate ADT-associated adverse effects without E2-related toxicity.

Nadir testosterone (T) following in-situ polymer delivered, subcutaneously administered leuprolide acetate in men with prostate cancer (PCa).

204 Background: Achieving and maintaining T suppression to castration level is the cornerstone of androgen deprivation therapy (ADT) for advanced PCa. Modern assay methodology found median T level after surgical castration to be 15ng/dL; the 2016 European Association of Urology guidelines define castration as T &lt; 20ng/dL. Additionally, reaching nadir T &lt; 20ng/dL is correlated with improved duration of response to ADT, time to progression or disease-specific survival (Klotz 2015), and prognosis for overall survival (Kamada 2015). To examine the effectiveness of in-situ polymer-delivered, subcutaneously-administered leuprolide acetate (SC-LA) on T suppression, nadir T was evaluated in 4 pivotal trials. Methods: Eugonadal patients with advanced PCa were treated with either 7.5 (6 doses), 22.5, 30, or 45mg (2 doses each) SC-LA lasting 1, 3, 4, or 6 months, respectively in 4 open-label, fixed-dose, pivotal trials. Serum T levels were evaluated byradioimmunoassay. T was measured 2-4 times on day 0 and once on days 1, 3, 7, and every week until the next dose, and repeated until end of study. The 45mg group had an additional measurement on day 2. LA was measured on days 0, 4, 7, 14, 21, 28, 35, 42, 49, and 56 post-injection. Nadir T was the lowest value obtained in the entire trial. Results: Across the SC-LA formulations, median LA levels were consistently between 0.1-1ng/mL from week 2 until the end of study. When pooled, 90-96% of patients achieved T≤20ng/dL by week 6 and 90-97% maintained T≤20ng/dL from weeks 6-24. Pooled analysis (n = 437) showed 99%, 97%, 91%, and 80% of patients reached nadir T≤20ng/dL, ≤10ng/dL, ≤5ng/dL, and ≤3ng/dL respectively with a median nadir T≤3 ng/dL. When comparing across all doses, &gt; 88% of patients reached nadir T≤5ng/dL. Conclusions: Across all doses, SC-LA achieves consistent and prolonged serum LA drug delivery above 0.1ng/mL and provides favorable T suppression &lt; 20ng/dL, which may be attributed to the in-situ forming polymeric delivery system. Multiple T measurements throughout the study confirmed that 91% of PCa patients achieved low nadir T≤5ng/dL, which may have implications for extending progression-free survival and duration of response to ADT.

036 Testosterone Recovery Profiles after Cessation of Androgen Deprivation Therapy (ADT)

It has been demonstrated that the combination use of ADT improves overall and cancer-specific survival in men with unfavorable prostate cancer (PCa). After cessation of ADT, testosterone (T) levels are expected to recover from castrate to normal levels. However, very little is known about T recovery profiles in this population, and many patients remain on castrate levels indefinitely. The aim of this study was to evaluate T recovery after cessation of ADT in PCa patients. We reviewed our prospectively maintained database for PCa patients who received ADT therapy at our institution. Serum early morning total T (TT) levels were measured at baseline and periodically after ADT cessation. Multivariable time-to-event analysis (Cox proportional hazards) was performed to determine predictors of TT recovery after ADT cessation and included the following variables: patient age, baseline T level, and duration of ADT. 1641 men with a mean age of 66 (43-94) years were included. Primary treatment for PCa was RP in 36%, while the remainder had either RT or primary ADT. The majority received a GnRH agonist as mainstay for ADT. Mean duration of ADT was 28.8±39 months [0.5 to 324]. Distribution of ADT exposure was: <6 months (m) 33%, 6-12m 19%, 12-24m 16%, >24m 33%. Median follow-up was 47.5±45 months. Mean TT values were: baseline 358 ng/dl, 6-12m post ADT cessation 96 ng/dl, 12-18 174 ng/dl, 18-24m 228 ng/dl, >24m 273 ng/dl. At last follow-up: 77% men had TT level above castrate level, 45% had TT >300ng/dl and 39% returned to pre-treatment TT level. On multivariable analysis age over 65 years (HR 2.01, 95%CI 1.48-2.71, P<0.0001), ADT duration of 6 months or greater (HR 1.42, 95%CI 1.07-1.90, P=0.02), and baseline T of 400 ng/dl or more (HR 1.80, 95%CI 1.36-2.40, P<0.0001) were all significantly associated with a slower recovery time.

A systematic review of methods for quantifying serum testosterone in patients with prostate cancer who underwent castration

BackgroundThe clinical practice guidelines recommend measuring serum testosterone in patients with prostate cancer (PC) who undergo castration. The serum testosterone concentration should be <50ng/dL, a level established by using a radioimmunoassay method. The use of chemiluminescent immunoassays (IA) has become widespread, although their metrological characteristics do not seem appropriate for quantifying low testosterone concentrations. The objective of this review is to analyze the methods for quantifying testosterone and to establish whether there is scientific evidence that justifies measuring it in patients with PC who undergo castration, through liquid chromatography attached to a mass spectrometry in tandem (LC–MSMS). Material and methodsWe performed a search in PubMed with the following MeSH terms: measurement, testosterone, androgen suppression and prostate cancer. We selected 12 studies that compared the metrological characteristics of various methods for quantifying serum testosterone compared with MS detection methods. ResultsIAs are standard tools for measuring testosterone levels; however, there is evidence that IAs lack accuracy and precision for quantifying low concentrations. Most chemiluminescent IAs overestimate their concentration, especially below 100ng/dL. The procedures that use LC–MSMS have an adequate lower quantification limit and proper accuracy and precision. We found no specific evidence in patients with PC who underwent castration. ConclusionsLC–MSMS is the appropriate method for quantifying low serum testosterone concentrations. We need to define the level of castration with this method and the optimal level related to better progression of the disease.

Testosterone Diminishes Cabazitaxel Efficacy and Intratumoral Accumulation in a Prostate Cancer Xenograft Model

Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens. Thereby, maintaining its role even in castration resistant prostate cancer (CRPC). The recent STAMPEDE and CHAARTED trials showed that docetaxel in combination with ADT increased survival in hormone sensitive prostate cancer patients, suggesting cross-talk between AR signaling and chemotherapy efficacy. We hypothesized that a similar interaction may also apply for CRPC that is treated with cabazitaxel. We studied the impact of androgen status on the efficacy, pharmacodynamics and -kinetics of cabazitaxel in a unique and clinically relevant patient derived xenograft model of castration resistant disease. We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity. Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals. We confirmed that cabazitaxel pharmacokinetics were not affected by testosterone, suggesting that androgen status might influence cabazitaxel tumor uptake directly. This study reveals the impact of androgen status on cabazitaxel efficacy and supports the potential of combination of taxane chemotherapeutics with AR axis targeting agents.

Testosterone suppression in the treatment of recurrent or metastatic prostate cancer - A Canadian consensus statement.

Testosterone suppression, achieved through orchiectomy or medically induced androgen-deprivation therapy (ADT), is a standard treatment for men with recurrent and metastatic prostate cancer. Current assay methods demonstrate the capacity for testosterone suppression to <0.7 nmol/l, and clinical data support improved outcomes from ADT when lower levels are achieved. Practical clinical guidelines are warranted to facilitate adoption of 0.7 nmol/l as the new standard castrate testosterone level.A pan-Canadian group of experts, representing diverse clinical specialties, identified key clinical issues, searched and reviewed relevant literature, and developed consensus statements on testosterone suppression for the treatment of prostate cancer. The expert panel found that current evidence supports the clinical benefit of achieving low testosterone levels during ADT, and encourage adoption of ≤0.7 nmol/l as a new castrate level threshold. The panel recommends regular monitoring of testosterone (e.g., every 3-6 months) and prostate-specific antigen (PSA) levels as clinically appropriate (e.g., every 3-6 months) during ADT, with reassessment of therapeutic strategy if testosterone is not suppressed or if PSA rises regardless of adequate testosterone suppression. The panel also emphasizes the need for greater awareness and education regarding testosterone assay specifications, and strongly promotes the use of mass spectrometry-based assays to ensure accurate measurement of testosterone at castrate levels.

Transdermal Delivery of Luteinizing Hormone-releasing Hormone with Chitosan Microneedles: A Promising Tool for Androgen Deprivation Therapy.

Long-term administration of luteinizing hormone-releasing hormone analogs (LHRHa) is the main type of androgen-deprivation therapy (ADT) for lethal prostate cancer. A fully insertable microneedle system, composed of embeddable chitosan microneedles and a dissolvable polyvinyl alcohol/polyvinyl pyrrolidone supporting array, was developed for sustained delivery of LHRHa to the skin. A porcine cadaver skin test showed that chitosan microneedles can be fully embedded within the skin and microneedle-created micropores reseal within 7 days. The measured LHRHa loading amount was 73.3±2.8 μg per microneedle patch. After applying goserelin-containing microneedles to mice, serum LH levels increased initially and then declined below baseline at day 7. In contrast, serum testosterone levels increased to reach a peak at day 14 and then declined to a castration level at day 21. Additionally, such a castration level was maintained for 2 weeks. Therefore, transdermal delivery of goserelin with embeddable chitosan microneedles can produce a castrated state in mice. Such a system is a promising, feasible means of delivering ADT.

Health-Related Quality of Life in 536 Long-Term Prostate Cancer Survivors after Treatment with Leuprorelin Acetate: A Combined Retrospective and Prospective Analysis

Introduction: We investigated the health-related quality of life (HRQoL) of long-term prostate cancer patients who received leuprorelin acetate in microcapsules (LAM) for androgen-deprivation therapy (ADT). Methods: The observational study was carried out by 30 office-based German urologists in 536 prostate cancer (PCa) patients treated for ≥5 years with LAM and in 116 patients of an age-matched control group (CG). Data on HRQoL and health status was collected prospectively using validated questionnaires QLQ-C30, QLQ-PR25 and Karnofsky Index. Data on effectiveness (clinical response, prostate specific antigen [PSA], testosterone) and safety was collected retrospectively from patients' health records. We used descriptive statistics to analyze the data. Results: The mean treatment duration was 8.6 years (range 4.5-19.8 years). General health status (QLQ-C30) was comparable for both groups. Differences were observed regarding physical - and role functioning. ADT patients rated single items slightly worse than CG. Karnofsky-Index showed comparable high values (median of 90%). QLQ-PR25 revealed more PCa-related symptoms for ADT patients. Within 6 months, median PSA level declined >90% and median testosterone levels declined below castration level from 4.0 to 0.2 ng/mL. Clinical response (European Organisation for Research and Treatment of Cancer criteria) was observed in at least 90% of ADT patients. Conclusions: Long-term ADT with LAM is a well-accepted, tolerated, effective, and low-burden treatment option for patients with advanced, hormone-sensitive PCa.

Genomic Resistance Patterns to Second-Generation Androgen Blockade in Paired Tumor Biopsies of Metastatic Castration-Resistant Prostate Cancer

PurposePatients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy.Patients and MethodsWe analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgen-deprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor.ResultsWe observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A (CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade—palbociclib and ribociclib.ConclusionCDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamide-resistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.

Reactivation of androgen receptor-regulated lipid biosynthesis drives the progression of castration-resistant prostate cancer

Androgen receptor (AR) is a transcriptional activator that, in prostate cells, stimulates gene expression required for various cellular functions, including metabolisms and proliferation. AR signaling is also essential for the development of hormone-dependent prostate cancer (PCa) and its activity can be blocked by androgen-deprivation therapies (ADTs). Although PCa patients initially respond well to ADTs, the cancer inevitably relapses and progresses to lethal castration-resistant prostate cancer (CRPC). Although AR activity is generally restored in CRPC despite the castrate level of androgens, it is unclear whether AR signaling is significantly reprogrammed. In this study, we examined the AR cistrome in a PCa cell line-derived CRPC model using integrated bioinformatical analyses. Significantly, we found that the AR cistrome is largely retained in the CRPC stage. In particular, AR-mediated lipid biosynthesis is highly conserved and reactivated during the progression to CRPC, and increased level of lipid synthesis is associated with poor prognosis. The restoration of lipid biosynthetic pathways is partially due to the increased expression of AR splice variants. Blocking lipid/cholesterol synthesis in AR variants-expressing CRPC cell line and xenograft models markedly reduces tumor growth through inhibition of mTOR pathway. Silencing the expression of a fatty acid elongase, ELOVL7, also leads to the regression of CRPC xenograft tumors. These results demonstrate the importance of reactivation of AR-regulated lipid biosynthetic pathways in driving CRPC progression, and suggest that ADTs may be therapeutically enhanced by blocking lipid biosynthetic pathways.