Lipidomic profiling in patients with metastatic castration-resistant prostate cancer (mCRPC)

Background: A 3-lipid signature has been recently proposed to predict for prognosis in pts with mCRPC. This study aimed at assessing the lipidomic profiles of pts with mCRPC to identify new prognostic and predictive biomarkers. Methods: Plasma samples were collected from pts with mCRPC starting a 1st-line (1L) (n=29) and pretreated with >2 lines (>2L) (n=19). Lipids were extracted and analyzed with an untargeted lipidomic approach. T-test was applied to identify lipids differentially expressed. ROC curves and X-Tile were used to identify lipids’ threshold and to test association with overall survival (OS). Kaplan-Meier curves were constructed and Cox regression was used to adjust for prognostic variables. Results: We identified and quantified a total of 789 plasma lipids. 75 lipid specieswere significantly dysregulated in >2L compared to 1L samples. 63 species were upregulated, and 12 were downregulated. >2L pts showed higher levels of acylcar-nitine, diacylglycerols, phosphatidylethanolamine, triacylglycerols and ceramides (Cer). We tested the effect on OS of lipids included in the 3-lipid signature: Cer(d18:1/24:1), sphingomyelin (d18:2/16:0) and phosphatidylcholine (16:0/16:0). Only Cer (d18:1/24:1) was associated with OS, but without statistical significance in the multivariate model. Among upregulated lipids in >2L cohort, Cer (d18:1/18:0) (C18), Cer (d18:1/16:0), Cer (d18:2/18:0), Cer (d18:1/24:1) and Cer (d20:1/24:1) all showed proportional relative risk of death and significant association with OS in univariate models. However, only C18 retained significant association with OS after adjustmentfor basal PSA and line of treatment (HR: 3.26 [95% CI 1.37-7.76]). The association of C18 with OS was consistent in both subgroups 1L and >2L, separately analyzed. Biochemical response was only seen in 4/14 (28.6%) evaluable pts with high levels of C18. Conclusions: Using a quantitative mass spectrometry approach, we characterized the lipidomic profile of highly pretreated mCRPC pts. We found that C18 is increased in these pts compared to therapy-naïve men, and significantly associated with OS, paving the way for further investigations on its prognostic and predictive value

To switch or not to switch? A real-life experience using dexamethasone in combination with abiraterone

The recently published phase II prospective SWITCH trial evaluated whether patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate could benefit from a 'steroid switch' from prednisone to dexamethasone. A total of 26 patients, both chemonaive (14 patients) or pretreated with docetaxel (12 patients), with biochemical and/or limited radiological progression, were enrolled in this trial. Primary endpoint was prostate specific antigen (PSA) 30 defined as the proportion of patients with a PSA level decline 30% or more after 6 weeks of treatment with abiraterone acetate + dexamethasone. Secondary endpoints were: a PSA50 rate (defined as the proportion of patients with PSA decline of 50% or more after 12 weeks on abiraterone acetate + dexamethasone), biochemical and radiological progression-free survival (bPFS and rPFS, respectively), benefit from subsequent treatment and identification of biomarkers of response. Primary endpoint was reached in 46.2% of patients (12 patients), and two patients had an objective partial response on computed tomography scan. Median bPFS and rPFS were 5.3 months and 11.8 months. We present a case series of 11 patients who were consecutively treated with a steroid switch at our institution from January 2016 to August 2018 to investigate if this strategy could be used in a 'real-life' setting. We observed a PSA30 response in two patients (18%), median bPFS was 4.77 months (95% confidence interval [CI] 2.5-14.6) and median rPFS was 7.2 months (95% CI 3.8-15.5). Seven patients had a radiological stable disease as best response to steroid switch. Three patients were being still treated with abiraterone acetate + dexamethasone at data cut-off time. Our case series confirms that switching from prednisone to dexamethasone during abiraterone acetate treatment produces biochemical and radiological responses in both a predocetaxel and a postdocetaxel setting, providing a clinical benefit in mCRPC patients. However, to date, there is no clear indication as to which patient could benefit most from this kind of strategy

Current Treatment Options for Metastatic Hormone-Sensitive Prostate Cancer

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-na\uefve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase 3 trials have been conducted in this setting, no direct comparison is currently available among the different strategies. Inadequate power, absence of preplanning and small sample size frequently affect the subgroup analyses according to disease volume or patient's risk. The choice between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide, apalutamide or radiotherapy to the primary tumor remains challenging. Factors that are related to the tumor, patient or drug side effects, currently guide these clinical decisions. This comprehensive review aims to indirectly compare the phase 3 trials in the mHSPC setting, in order to extrapolate data useful for treatment selection, providing also perspectives on future biomarkers

BRCA Mutations in Prostate Cancer: Prognostic and Predictive Implications

Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles

Role of Circulating Tumor Cells (CTC), Androgen Receptor Full Length (AR-FL) and Androgen Receptor Splice Variant 7 (AR-V7) in a Prospective Cohort of Castration-Resistant Metastatic Prostate Cancer Patients

Circulating tumor cells (CTC), androgen receptor full-length (AR-FL), and androgen receptor splice variant 7 (AR-V7) are prognostic in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). AR-V7 seems to predict resistance to androgen-receptor signaling inhibitors (ARSi)

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

SIMPLE SUMMARY: Several strategies have demonstrated the ability to improve the survival of patients with both metastatic and nonmetastatic prostate cancer. The old backbone of androgen-deprivation monotherapy has been disrupted in the hormone-sensitive setting, and several options have been introduced for the management of the castration-resistant disease. However, no optimal sequencing is still defined, and few randomized comparisons are currently available to identify the approach that maximizes the long-term benefit for these patients. This comprehensive review aims at resuming the current evidence on this topic to help physicians during the treatment choice for patients with advanced prostate cancer. ABSTRACT: The treatment landscape of advanced prostate cancer has completely changed during the last decades. Chemotherapy (docetaxel, cabazitaxel), androgen-receptor signaling inhibitors (ARSi) (abiraterone acetate, enzalutamide), and radium-223 have revolutionized the management of metastatic castration-resistant prostate cancer (mCRPC). Lutetium-177–PSMA-617 is also going to become another treatment option for these patients. In addition, docetaxel, abiraterone acetate, apalutamide, enzalutamide, and radiotherapy to primary tumor have demonstrated the ability to significantly prolong the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Finally, apalutamide, enzalutamide, and darolutamide have recently provided impactful data in patients with nonmetastatic castration-resistant disease (nmCRPC). However, which is the best treatment sequence for patients with advanced prostate cancer? This comprehensive review aims at discussing the available literature data to identify the optimal sequencing approaches in patients with prostate cancer at different disease stages. Our work also highlights the potential impact of predictive biomarkers in treatment sequencing and exploring the role of specific agents (i.e., olaparib, rucaparib, talazoparib, niraparib, and ipatasertib) in biomarker-selected populations of patients with prostate cancer (i.e., those harboring alterations in DNA damage and response genes or PTEN)