Search

Background Intermittent androgen deprivation therapy (ADT) in biochemically recurrent castration-naive prostate cancer is non-inferior to continuous therapy. We hypothesised that finite-duration abiraterone acetate plus prednisone (Abi +P) added to ADT will further reduce the duration of treatment exposure by prolonging time to prostate-specific antigen (PSA) recurrence without impacting eugonad state recovery. Methods This phase II, randomised, open-label trial enrolled patients with rising PSA ≥ 0.2 ng/ml after radical prostatectomy and/or a PSA ≥ 1 following radiotherapy. Patients were randomised 1:1 to receive Abi (1 g PO daily) + P (5 mg PO daily) + ADT or ADT alone for 8 months. The primary end-point was PSA-free survival difference at 1 year following completion of therapy. Results Between February 2013 and July 2016, 200 patients were enrolled. Of 100 patients randomised to each arm, 99 in the Abi +P arm and 98 in the ADT arm were evaluable. Median follow-up was 64.4 months. Median PSA-free survival was 27.0 months for the Abi +P-treated group versus 19.9 months for the ADT-treated group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47–0.87). The PSA-free survival at 1 year post-treatment completion was 98% for the Abi +P group and 88% for the ADT group. Median time to eugonad state was 13.1 months for the abiraterone-treated group and 12.8 months for the ADT-treated group. Median eugonad PSA-free survival was 12.5 months for the abiraterone-treated group versus 9.0 for the ADT-treated group (HR 0.72, 95% CI 0.53–0.98). There were no significant between-group differences in androgen deprivation-related adverse events. Conclusions In men with biochemically recurrent prostate cancer following definitive treatment of the primary, finite duration treatment with ADT and Abi +P results in a significantly longer PSA relapse-free interval than treatment with ADT alone.

Novel androgen signaling inhibitors are currently standard of care in the treatment of patients with prostate cancer. Second-generation androgen receptor antagonists have demonstrated efficacy in earlier disease settings, fulfilling an unmet need in the treatment of patients with advanced prostate cancer.The present article focuses on the development and establishment of apalutamide among the available treatment options for prostate cancer. A literature search was performed in Pubmed/Medline for past studies and reviews of the drug. Ongoing clinical trials were also examined in the Clinicaltrials.gov online database.Apalutamide has demonstrated benefit for patients with non-metastatic castration resistant and metastatic hormone naive prostate cancer. It is an efficacious, tolerable, and convenient oral agent, thus a valuable addition in the armamentarium of prostate cancer therapeutics for both non-metastatic castrate resistant and metastatic hormone naïve prostate cancer. Ongoing trials are investigating the drug as monotherapy and in combinations in other disease settings. Results are expected to further expand the drug's indications and shape the future landscape of prostate cancer therapy.

BACKGROUND: The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signaling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signaling signature associated with response to androgen signaling inhibition. PATIENTS AND METHODS: We report on the outcome of the first module of a phase II trial on Abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMB) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. Endpoints included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR C-/N-terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumor markers also included v-ets avian erythroblastosis virus E26 oncogene homolog (ERG), splice variant ARV7 by IHC and steroids by Liquid chromatography-tandem mass spectrometry. RESULTS: Out of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. 48 patients had tumor infiltrated BMB at baseline. Pretreatment androgen signaling signature was linked to benefit from AA (p

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes. ispartof: NATURE BIOTECHNOLOGY vol:40 issue:11 pages:1624-+ ispartof: location:United States status: published

Knockout of ERβ in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERβ plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERβ agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR for 4 mo to 6 mo resulted in loss of ERβ and PTEN expression and increase in patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of increasing ERβ expression, but, on treatment longer than 8 mo, ERβ was lost and EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in PCa, addition of ERβ agonists together with abiraterone should be considered as a treatment that might sustain expression of ERβ and offer some benefit to patients.

135 Background: In pre-operative studies, a short duration of AA + LHRHa produced marked cytoreduction in a subset of men with high-risk prostate cancer (PCa). However, in M0HNPC, androgen signaling inhibition (ASI) is reserved for men with short PSA doubling time. We reasoned that the subset of men who experience cytoreduction with pre-operative AA + LHRHa would also benefit from a short duration of AA + LHRHa at PSA recurrence. This report is a one-year follow-up of our second analysis (ASCO Annual Meeting 2018; PMID 34536949). Methods: FINITE is a phase II trial that randomized (1:1) to two treatment groups, 8 months of LHRHa alone or LHRHa plus AA 1000 mg and prednisone 5 mg daily (NCT01786265). Eligible patients had a rising PSA after definitive therapy and no prior systemic therapy. At disease progression, men were eligible for crossover to 8 months of the alternative therapy. The primary endpoint was PSA-free survival at 12 months (≤ 0.1 ng/dL). Time to PSA progression was calculated from date of initial treatment to date of PSA progression, defined as first occurrence of a rising PSA, if PSA remained detectable after treatment, or when the PSA ≥ 1 ng/dL, if it was undetectable after treatment and confirmed 4 weeks thereafter. The probabilities of PSA progression were defined using the Kaplan-Meier method. Results: 199 men were randomized, and 197 received initial treatment (LHRHa = 99, LHRHa + AA = 98). Median age at enrollment was 65 years, median PSA was 0.95 ng/dL (range 0.1 – 33.3), and median testosterone was 342.5 ng/dL (10-986). At data cut-off (October 1, 2021), men who received LHRHa + AA were more likely to be PSA-free 12 months after completing treatment (34% vs. 19%, p = 0.02). 168 men (85%) had experienced PSA progression, and median time to PSA progression was 24.3 months for entire cohort. Receipt of LHRHa + AA was associated with longer time to PSA progression than LHRHa alone (27.2 vs. 19.9 months, p = 0.003). Conclusions: Our findings support that finite treatment with AA + LHRHa produces more durable disease-free survival than LHRHa. The finite duration of AA + LHRHa is a toxicity-sparing approach that may allow for a transition from a treatment to curative paradigm for a subset of men with M0HNPC. Further analyses will aim to link the subset of men who benefit from finite AA + LHRHa between localized high-risk PCa and M0HNPC. Clinical trial information: NCT01786265.

Simple Summary Prostate cancer may in some cases exhibit microscopic and molecular characteristics of a distinct subtype of disease which is referred to as neuroendocrine differentiation. This entity is rarely found in patients initially diagnosed with metastatic disease and most commonly occurs after treatment of prostate cancer in advanced stages with hormonal agents. This specific presentation of the disease is not effectively targeted by the hormonal therapies used in prostate cancer and exhibits an aggressive clinical course. Interestingly, some tumors may have molecular and clinical characteristics of a neuroendocrine tumor subtype, without however exhibiting the respective histomorphologic features. This aggressive-variant prostate cancer (AVPC) subtype is sensitive to platinum-based chemotherapy, without, however, an impressive long-term response. In this review article we provide an overview of neuroendocrine prostate cancer focusing on the AVPC subtype and we approach current treatment options as well as ongoing research efforts. Abstract In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies.

Cancers can vary greatly in their transcriptomes. In contrast to alterations in specific genes or pathways, the significance of differences in tumor cell total mRNA content is poorly understood. Studies using single-cell sequencing or model systems have suggested a role for total mRNA content in regulating cellular phenotypes. However, analytical challenges related to technical artifacts and cellular admixture have impeded examination of total mRNA expression at scale across cancers. To address this, we evaluated total mRNA expression using single cell sequencing, and developed a computational method for quantifying tumor-specific total mRNA expression (TmS) from bulk sequencing data. We systematically estimated TmS in 5,181 patients across 15 cancer types and observed close correlations with clinicopathologic characteristics and molecular features, where high TmS generally accompanies high-risk disease. At a pan-cancer level, high TmS is associated with increased risk of disease progression and death. Moreover, TmS captures tumor type-specific effects of somatic mutations, chromosomal instability, and hypoxia, as well as aspects of intratumor heterogeneity. Taken together, our results suggest that measuring total mRNA expression offers a broader perspective of tracking cancer transcriptomes, which has important clinical and biological implications.

Prostate cancer commonly affects older men, with one out of five patients being diagnosed at 75 years or older. Elderly patients are more likely to have reduced performance and nutritional status, increased comorbidities, polypharmacy, and altered host-dependent pharmacokinetics and pharmacodynamics. Moreover, elderly patients are often underrepresented in clinical trials, mainly because of comorbidities and decline in performance status. The International Society of Geriatric Oncology recommends management of elderly patients according to fitness and personal preference, rather than chronological age. Since androgen signaling has a nodal role in prostate cancer progression, androgen-targeting agents remain the mainstay of systemic therapy for this disease. However, the potential benefit of these treatments may be compromised by toxicity, especially in elderly patients. Hence, management decisions require evidence-based consideration of both potential benefits and risks on an individualized basis. Furthermore, especially elderly patients should undergo geriatric screening and must be actively monitored during treatment to detect adverse events early and prevent complications. A personalized and vigilant approach could provide the elderly patient with the optimal benefits of existing and emerging prostate cancer treatments, while sparing them the risks of excessive toxicity and avoiding overtreatment.

Background Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC. Patients and Methods In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety. Results From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years. Conclusion There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.

Background: Advanced androgen signaling inhibition, a prevailing therapy approach in advanced prostate cancer, incurs variable response Therapy selection guided by predictors is an unmet need Methods: We reviewed MDACC GU department and Hellenic Sister Institute records for Abiraterone Acetate (AA) treated mCRPC patients (pts) with extraordinary response (absence of radiographic/clinical progression for ≥3 years) We compared to reported findings for COU-AA-302 and real world experience to identify candidate predictors of outcome We applied a previously proposed COU-AA-302 response prognostic model Archived diagnostic and subsequent tumor specimens were retrieved for molecular characterization Results: Forty four of 430 reviewed mCRPC pts had extraordinary response Table depicts features Median time to AA discontinuation was 5 8 yr (range 3-12 5+) and 20 pts are on treatment Safety profile is acceptable with no overt increase in fractures or cardiovascular, metabolic morbidity All pts experienced >50% PSA decline with nadir ≤0 1 in 80%, occurring within 5mo (median) (range

5504 Background: Novel androgen signaling inhibitors (ASI) with medical castration may improve outcomes in LHRPC. We previously reported relapse free survival association with pathologic measures of tumor regression. However a wide range of persistent cancers was recorded. To build on our findings and test candidate predictors of outcome, we conducted a study examining APA effect in LHRPC. Methods: This is a phase II neoadjuvant study of 6 months APA+LHRHa +/- AA (randomized 1:1) in LHRPC (≥ cT2 + Gleason Score ≥ 8 or ≥ cT2b + Gleason ≥ 7 + PSA > 10 ng/mL) followed by radical prostatectomy (RP). We studied treatment effect by pathology measures [path. stage, tumor volume (TV), tumor cellularity % (TC), tumor epithelial volume (TEV: TC x TV)]. Tumor expression of candidate markers of outcome was assessed in the diagnostic biopsy by IHC [AR signaling (AR-N, ARC19, ARV7, PSA), PTEN, glucocorticoid receptor (GR), Ki67, p53, RB] and DNA/RNA seq. A previously identified candidate predictive molecular signature (AR-N overexpression, nARV7 absence, no GR overexpression, Ki67 ≤10%) was tested. Univariate (Fisher’s exact, Wilcoxon) and multivariate (logistic, linear models) analyses employed. Results: Sixty three -of 65 pts enrolled- had RP. PS-ECOG 0, median age 65 (43-77). Treatment was well tolerated with Grade 3 hypertension in 7 (2 APA + LHRHa). Presurgical PSA was ≤0.1 in 62/63 (98%). Organ confined disease (≤ypT2N0) found in 13/32(41%) APA+LHRHa vs. 12/31 (39%) APA+AA+LHRHa treated. 2 (3%) had pathologic complete remission (APA+AA+LHRHa), 6 (10%) minimal residual disease (5 on APA +LHRHa). Despite uniformity in PSA response, we recorded heterogeneity in measures of tumor viability: TV (0-11.5cc), TC (1-80%), TEV (0-6.1cc). ≤ypT2N0 associates with diagnostic biopsy positivity for the prespecified molecular signature (p