Testosterone Therapy in Advanced Prostate Cancer.

Prostate cancer is an androgen driven cancer. Androgen deprivation therapy (ADT) has been the standard first line therapy for metastatic prostate cancer. Medical castration with Luteinizing hormone releasing hormone (LHRH) agonists and more recently LHRH antagonists has largely supplanted surgical castration. Key issues in optimizing ADT have been timing of ADT initiation in metastatic prostate cancer (early vs deferred), monotherapy with LHRH agonist alone vs combination therapy with an anti-androgen, and the schedule of medical castration (intermittent vs continuous). After numerous trials attempting to clarify the role of anti-androgens in initial therapy of metastatic prostate cancer with conflicting results on survival benefit with combination therapy, meta-analyses suggest a small but measurable prolongation in overall survival. The lower incidence of severe adverse events including cord compression in advanced prostate cancer with early ADT has established immediate initiation of ADT upon diagnosis of metastatic prostate cancer as standard clinical practice. The schedule of ADT has been the subject of extensive investigation spurred by early preclinical work suggesting continuous pressure of castration promoted development of castration resistance. Trials testing intermittent ADT in several clinical contexts including in patients with biochemical recurrence, suggested intermittent ADT is comparable to continuous ADT. However, except for the JPR7, trials had mixed patient populations and/or were not powered for overall survival (OS). The only OS powered large phase 3 trial in metastatic disease (INT-0162/SWOG-9346) demonstrated that survival with intermittent ADT is not comparable to that with continuous therapy. Continuous ADT therefore continues to be the standard; however, therapy should be tailored to a patient's individual needs with adequate counseling. Novel inhibitors of androgen synthesis including abiraterone and androgen receptor antagonists such as enzalutamide, and cytotoxic chemotherapy already proven to be effective in castration resistant prostate cancer are under investigation in hormone sensitive prostate cancer. If validated, they would represent a long overdue paradigm shift in advanced hormone sensitive prostate cancer management.

LONG-TERM OUTCOME FOR MEN WITH ANDROGEN INDEPENDENT PROSTATE CANCER TREATED WITH KETOCONAZOLE AND HYDROCORTISONE

Loss of TP53 and PTEN activity are frequent genetic events in CRPC that are often associated with poorly differentiated, treatment resistant tumors. Using the Pten/Tp53-null mouse prostate cancer (PCa) model (Pb-Cre; Ptenfl/fl Tp53 fl/fl) and organoid cultures we previously have shown that a high proportion of luminal progenitors are intrinsically resistant to androgen deprivation therapy (ADT). To identify mechanisms of ADT resistance in luminal progenitors, we performed RNAseq analysis of luminal progenitor organoids derived from wild-type(WT) and Pten/Tp53-null mice. Pathway analysis identified key signaling alterations in luminal tumor organoids (AR signaling, lipid metabolism, protein secretion, inflammation etc.) that also have been described in FACS-purified human prostate luminal (CD49flo) fractions. Interestingly, we found no difference in transcriptional profiles from intact and previously castrated tumor organoids, suggesting that Pten/Tp53 null luminal progenitors are intrinsically resistance to ADT. Of note, we observed most significant enrichment of interferon(IFN) signaling in luminal progenitor tumor organoids relative to wild type luminal organoids. In other cancers and contrary to the anti-proliferative IFN signaling, expression of a subset of IFN genes contributes to genotoxic therapy resistance. This subset, referred to as IRDS (IFN-related DNA damage signature), includes a group of unphosphorylated STAT1 (U-STAT1)-driven genes that has a pro-survival function and promotes cancer cell intrinsic drug resistance. We hypothesize that the IRDS contributes to survival of PCa cells following ADT or genotoxic therapies. RT-PCR, immunofluorescence, and western blot analysis of luminal progenitor organoids showed higher U-STAT1 levels in tumor- than WT organoids, whereas pSTAT1 (Y701) was undetectable. Similarly, U-STAT1 was upregulated in Pten/Tp53-null tumor tissue relative to normal prostate. Further, for tumor organoids, ADT resulted in higher U-STAT1 levels. STAT1 depletion in tumor organoids decreased the number of progeny organoids in subsequent passages, suggesting a role in self-renewal for luminal tumor stem cells. Altogether, U-STAT1 regulated signaling has pro-survival function in Pten/Tp53-null advanced PCa. Several PDXs originating from metastatic PCa (LuCaPs 23.1, 96 and 141) express high levels of U-STAT1 dependent IFN signaling. STAT1 depletion significantly reduced self-renewing ability of these PDX derived organoids, consistent with mouse luminal tumor organoids. Interestingly, in LuCaP 141, STAT1 depletion synergized with ADT to inhibit growth ex vivo. These findings suggest that U-STAT1 dependent IFN signaling may contribute to castration resistance. We subsequently analyzed human PCa datasets to determine clinical correlates of IRDS. Analysis of the TCGA primary PCa cohort revealed IRDS as a prognostic marker for progression (n= 500, p<0.05). Further, high IRDS-expressing samples in the CRPC dataset were enriched for low AR signaling (n = 150, r= -0.33, p< 0.05). CRPC patients expressing the highest IRDS levels (n=30 of 150) showed enrichment for genes associated with stem cell features and therapy resistance. Overall, our findings suggest U-STAT1 dependent IRDS expression is correlated with poorly differentiated PCa and may contribute to intrinsic therapy resistance. Citation Format: Supreet Agarwal, Kerry McGowen, Fathi Elloumi, Maggie Cam, Mike Beshiri, Keith Jansson, Eva Corey, Kathleen Kelly. Interferon signaling confers resistance to androgen deprivation therapy in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-050.

COMPLETE ANDROGEN BLOCKADE FOR PROSTATE CANCER: WHAT WENT WRONG?

Novel therapies for advanced prostate cancer: have we have widened the goal posts too far?

89Zr-MSTP2109A, A Novel Antibody Based Radiotracer to Evaluate and Guide the Clinical Translation of Antibody-Drug Conjugates Targeting STEAP1

Chemotherapy, not androgen receptor-targeted therapy should be used upfront for metastatic hormone-sensitive prostate cancer. PRO: docetaxel chemotherapy should be the default consideration in metastatic hormone-sensitive prostate cancer.

Background:Orally administrated agents play a key role in the management of prostate cancer, providing a convenient and cost-effective treatment option for patients. However, they are also associated with adherence issues which can compromise therapeutic outcomes. This scoping review identifies and summarizes data on adherence to oral hormonal therapy in advanced prostate cancer and discusses associated factors and strategies for improving adherence.Methods:PubMed (inception to 27 January 2022) and conference databases (2020–2021) were searched to identify English language reports of real-world and clinical trial data on adherence to oral hormonal therapy in prostate cancer using the key search terms ‘prostate cancer’ AND ‘adherence’ AND ‘oral therapy’ OR respective aliases.Results:Most adherence outcome data were based on the use of androgen receptor pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Self-reported and observer-reported adherence data were used. The most common observer-reported measure, medication possession ratio, showed that the vast majority of patients were in possession of their medication, although proportion of days covered and persistence rates were considerably lower, raising the question whether patients were consistently receiving their treatment. Study follow-up for adherence was generally around 6 months up to 1 year. Studies also indicate that persistence may drop further with longer follow-up, especially in the non-mCRPC setting, which may be a concern when years of therapy are required.Conclusions:Oral hormonal therapy plays an important role in the treatment of advanced prostate cancer. Data on adherence to oral hormonal therapies in prostate cancer were generally of low quality, with high heterogeneity and inconsistent reporting across studies. Short study follow-up for adherence and focus on medication possession rates may further limit relevance of available data, especially in settings that require long-term treatment. Additional research is required to comprehensively assess adherence.

Metastatic Burden in Hormone-Naive Prostate Cancer: A Tale of Two Subgroups

PurposeProstate-specific membrane antigen (PSMA) targeted positron emission tomography (PET) imaging significantly improved the detection of recurrent prostate cancer (PCa). However, the value of PSMA PET imaging in patients with advanced hormone-sensitive or hormone-resistant PCa is still largely unknown. The aim of this study was to analyze the detection rate and distribution of lesions using PSMA PET imaging in patients with advanced PCa and ongoing androgen deprivation therapy (ADT).MethodsA total of 84 patients diagnosed with hormone-sensitive or hormone-resistant PCa who underwent 68Ga-PSMA-11 PET/magnetic resonance imaging (MRI) or computer tomography (CT) under ongoing ADT were retrospectively analyzed. We assessed the detection of PSMA-positive lesions overall and for three PSA subgroups (0 to < 1 ng/mL, 1 to < 20 ng/mL and > 20 ng/mL). In addition, PSMA-positive findings were stratified by localization (prostatic fossa, pelvic, para-aortic, mediastinal/supraclavicular and axillary lymph nodes, bone lesions and visceral lesions) and hormone status (hormone-sensitive vs. hormone-resistant). Furthermore, we assessed how many patients would be classified as having oligometastatic disease (≤ 3 lesions) and theoretically qualify for metastasis-directed radiotherapy (MDRT) in a personalized patient management.ResultsWe detected PSMA-positive lesions in 94.0% (79 of 84) of all patients. In the three PSA subgroups detection rates of 85.2% (0 to < 1 ng/mL, n = 27), 97.3% (1 to < 20 ng/mL, n = 37) and 100% (> 20 ng/mL, n = 20) were observed, respectively. PSMA-positive visceral metastases were observed only in patients with a PSA > 1 ng/mL. Detection of PSMA-positive lesions did not significantly differ between patients with hormone-sensitive and hormone-resistant PCa. Oligometastatic PCa was detected in 19 of 84 patients (22.6%). Almost all patients, 94.7% (n = 18) would have been eligible for MDRT.ConclusionsIn this study, we observed an overall very high detection rate of 94% using PSMA PET imaging in patients with advanced PCa and ongoing ADT. Even in a majority of patients with very low PSA values < 1 ng/ml PSMA-positive lesions were found.

Introduction Androgen-deprivation therapy (ADT) is the main therapy for patients with advanced and metastatic prostate cancer (PCa) and, in combination with radiotherapy, for patients with localized high-risk PCa. Due to its favorable tolerability among different treatments available for ADT, leuprorelin acetate is well established as the leading luteinizing hormone-releasing hormone (LHRH) analog. The development of second-generation leuprorelin acetate (LA) depot formulation (Eligard®, Recordati S.p.A) allowed a consistent and controlled release of leuprorelin between injections and a more efficient reduction of testosterone levels with respect to conventional LHRH agonists. Areas covered This work provides a summary of the biological and clinical rationale for using LA to manage PCa and presents the current evidence about the therapeutic activity of the LA gel depot formulation, used as an advanced leuprorelin acetate delivery method. Expert opinion Results of the registration studies and post-marketing clinical trials demonstrate that the LA gel depot provides long-term efficacy in the clinical practice and a good degree of tolerability. Overall, collected data suggest that the LA gel depot can represent the ADT reference therapy in advanced PCa.

The Impact of Testosterone Therapy in Men on Cardiovascular Risk: Don’t Be Too Quick to Condemn

Introduction: Although prostate cancer (PCa) has long been considered an absolute contraindication for testosterone therapy (TTh), growing literature suggests TTh may be safely offered to men with localized PCa. We here present a single-center series of men treated with TTh for relief of symptoms, despite having more advanced disease, namely biochemical recurrence (BCR) or metastatic PCa (MET). Methods: We identified men treated with TTh with BCR, MET, or adjuvant androgen deprivation therapy (ADT). Consent included risks of rapid PCa progression and death. Laboratory and clinical results were analyzed. Results: Twenty-two men received TTh: 7 with BCR, 13 with MET, and 2 with adjuvant ADT. Median age was 70.5 years (range 58–94). Median TTh duration was 12 months (range 2–84) overall, including 20 months for BCR and 9.5 months for MET. Mean serum testosterone (T) increased from 210 to 1111 ng/dL. Median PSA (interquartile range) increased from 3.1 ng/mL (0.2–4.5) to 13.3 ng/mL (3.4–22) in the BCR group, 6.3 ng/mL (1.2–31) to 17.8 ng/mL (6.2–80.1) in the MET group, and <0.1 to 0.3 ng/mL in the ADT group. All patients reported symptom relief, especially improved vigor and well-being. Overall mortality was 13.6% and PCa-specific mortality was 4.5% during the period of TTh and 6 months after discontinuation. Seven of 10 with follow-up imaging within 12 months showed no progression. Five men have died: three during TTh and two succumbed at 2 years or longer after discontinuing TTh. One of the three deaths during TTh was PCa-specific. Three men developed significant bone pain at 7–41 months; two discontinued TTh and one continued, after focal radiation. There were no cases of rapid-onset complications, vertebral collapse, or pathological fracture. Conclusions: These initial observations indicate TTh was not associated with precipitous progression of PCa in men with BCR and MET, suggesting a possible role for TTh in selected men with advanced PCa whose desire for improved quality of life is paramount.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.