ABSTRACT
BACKGROUND: Therapeutic approach used for pancreatic ductal adenocarcinoma is usually translated also for the rarer acinar counterpart, which shows a different mutational landscape nevertheless. While dMMR/MSI-H status is rare in the ductal histotype, it appears to be more prevalent in pancreatic acinar cell carcinoma (PACC). CASE PRESENTATION: We report the case of a patient with locally advanced MSI-H PACC in whom the treatment with the anti-PD-1 pembrolizumab, administered as third line, made possible surgical resection, achieving even an exceptional pathological complete response. CONCLUSIONS: Treatment of PACC should be tailored based on the peculiar molecular features that distinguish PACC from ductal adenocarcinoma. Evaluation of potentially therapeutically targetable alterations should be mandatory in case of PACC diagnosis.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Acinar Cell , Pancreatic Neoplasms , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Carcinoma, Acinar Cell/drug therapy , Carcinoma, Acinar Cell/pathology , Male , Antineoplastic Agents, Immunological/therapeutic use , Middle Aged , AgedABSTRACT
Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug's efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.
Subject(s)
Abiraterone Acetate , Biomarkers, Tumor , MicroRNAs , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/diagnosis , Abiraterone Acetate/therapeutic use , Pilot Projects , Aged , MicroRNAs/blood , MicroRNAs/genetics , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Middle Aged , Gene Expression Regulation, Neoplastic/drug effects , PTEN Phosphohydrolase/genetics , Circulating MicroRNA/blood , Neoplasm Metastasis , Homeodomain Proteins/genetics , Homeodomain Proteins/blood , Aged, 80 and overABSTRACT
BACKGROUND: Outcomes of castration-sensitive prostate cancer (CSPC) have improved owing to new therapies and early treatment, previously reserved for castration-resistant disease (CRPC). Prostatic-specific antigen (PSA) remains the most used marker to follow-up patients under treatment, but only limited data are available about the prognostic role of its changes over time and the impact of response to subsequent therapies. This analysis aims to assess the prognostic role of the magnitude and velocity of PSA response in CSPC and describe how this may affect the outcome to subsequent treatment outcomes in CRPC. PATIENTS AND METHODS: A retrospective analysis was performed on patients with de novo CSPC referring to six oncology centers in Italy. Clinical and pathological features were recorded. PSA response (PSA50), defined as a decrease > 50% compared to baseline, PSA velocity (PSAv), defined as any decrease in PSA levels over time and the deep and fast PSA response (4mPSA50), defined as the PSA response reached within the threshold of 4 months from the beginning of androgen deprivation therapy (ADT) have been evaluated for their impact on survival. Survivals were estimated using the Kaplan-Meier method and compared across groups using the log-rank test. Cox proportional-hazard models, stratified according to baseline characteristics, were used to estimate hazard ratios for overall survival (OS). RESULTS: A totals of 94.4% of patients had PSA50, which was correlated to longer OS compared to patients without PSA50 (56.0 vs. 14.8 months; p<0.001). The median PSAv was 6.9 (ng/dl)/month, which was predictive for longer OS: Each decrease of 1 (ng/dl)/month was able to improve OS by 0.2% (HR=0.998, 95%CI=0.997-1.000; p=0.008). A total of 47.9% of patients reached 4mPSA50, with a median OS and progression-free survival (PFS) to ADT-based therapy of 101.0 and 23.4 months compared to 41.9 and 11.0 months for those who did not (p<0.001), respectively. The independent prognostic role of 4mPSA50 was retained even when evaluated in multivariable analysis adjusted for other baseline characteristics and early docetaxel for CSPC. In CRPC, 4mPSA50 evaluated during CSPC retains its prognostic role even if it does not predict a different outcome between patients treated with abiraterone/enzalutamide or taxanes. CONCLUSION: Achieving a deep and fast PSA response correlates with a better outcome in patients with de novo mCSPC, also positively influencing the prognosis of the subsequent first-line therapy for CRPC disease.
Subject(s)
Prostate-Specific Antigen/metabolism , Prostatic Neoplasms, Castration-Resistant/diagnosis , Humans , Male , Progression-Free Survival , Retrospective Studies , Treatment OutcomeABSTRACT
Real-world data suggest a possible interplay between androgen deprivation therapy (ADT) and susceptibility to and the severity of SARS-CoV-2 infection. As ADT is the backbone of prostate cancer treatment, various authors have evaluated different patient cohorts but the evidence provided is conflicting. The aim of this review is to assess the available publications concerning the role of ADT in preventing or reducing the severity of SARS-CoV-2 infection. After a literature search we identified four full papers, five letters, and four meeting abstracts, but these used different search methods and the quality of the evidence varied. They frequently had different endpoints, did not report the status of the prostate cancer patients and evaluated heterogeneous populations. The available data do not support the view that ADT protects against SARS-CoV-2 infection. Larger and more precise studies are warranted, considering variables that affect infection outcomes as these significantly influence the reliability of the findings.
Subject(s)
COVID-19 , Prostatic Neoplasms , Androgen Antagonists , Humans , Male , Prostatic Neoplasms/complications , Prostatic Neoplasms/drug therapy , Reproducibility of Results , SARS-CoV-2ABSTRACT
BACKGROUND: Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m2, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration. RESULTS: The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1-20.6) in arm DE and 27.8% (95% CI 22.8-39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III-IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%). CONCLUSIONS: The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study's phase II design and the absence of an overall survival benefit. TRIAL REGISTRATION NUMBERS: EudraCT 2014-000175-43 - NCT02453009.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzamides/therapeutic use , Docetaxel/therapeutic use , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Prednisone/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Docetaxel/pharmacology , Female , Humans , Male , Middle Aged , Prednisone/pharmacologyABSTRACT
Introduction: Recently, there has been a paradigm shift in the treatment of advanced prostate cancer (PCa) because the approval of a number of new agents has significantly improved overall survival. However, as PCa is a heterogeneous disease that may be more or less aggressive and patients may be more or less responsive to treatment, it is often debated whether or not it is acceptable to avoid active therapies.Areas covered: This review discusses different settings of advanced PCa.Expert opinion: In metastatic castration-resistant PCa, it is unethical not to use active treatments but the use of both androgen receptor targeting agents (ARTA) in sequence should be avoided in most patients and the use of the available agents for fourth-line treatment or beyond should only be considered for highly selected patients. In metastatic hormone-sensitive PCa, patients with de novo disease should receive one additional agent in combination with androgen deprivation therapy (ADT), whereas patients in relapse should be managed with ADT alone. In non-metastatic castration-resistant prostate cancer (PCa), all patients with a PSA doubling time of ≤6 months should receive one ARTA, whereas the others might wait until there is an acceleration in the kinetics of their PSA levels.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Prostatic Neoplasms, Castration-Resistant/therapy , Prostatic Neoplasms/therapy , Androgen Antagonists/administration & dosage , Androgen Receptor Antagonists/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Humans , Male , Patient Selection , Prostate-Specific Antigen/blood , Prostatic Neoplasms/pathology , Prostatic Neoplasms, Castration-Resistant/pathology , Survival RateABSTRACT
BACKGROUND: Patients with cancer are at increased risk of complicated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, but it is still unclear if the risk of mortality is influenced by cancer type or ongoing anti-cancer treatments. An interesting debate concerning the potential relationship between androgen deprivation therapy (ADT) and SARS-CoV-2 infection has recently been opened in the case of prostate cancer (PC), and the aim of this multi-centre cohort study was to investigate the incidence and outcomes of SARS-CoV-2 infection in patients with metastatic castration-resistant prostrate cancer (mCRPC). PATIENTS AND METHODS: We retrospectively reviewed the clinical records of patients with mCRPC who developed SARS-CoV-2 infection, and recorded their baseline clinical characteristics, their history of PC and SARS-CoV-2 infection, and their oncological status and treatment at the time of infection. The primary study end point was the death rate and the possible impact of the patients' PC-related history and treatments on mortality. RESULTS: Thirty-four of the 1433 patients with mCRPC attending the participating centres (2.3%) developed SARS-CoV-2 infection, 22 (64.7%) of whom were hospitalised. Most of the patients were symptomatic, the most frequent symptoms being fever (70.6%), dyspnoea (61.8%), cough (52.9%) and fatigue (38.2%). After a median follow-up of 21 days (interquartile range: 13-41), 13 patients had died (38.2%), 17 recovered (50.0%) and four (11.7%) were still infected. The number of treatments previously administered for mCRPC had a significant impact on mortality (p = 0.004). CONCLUSIONS: Our findings contribute additional data to the current debate concerning the postulated protective role of ADT, which seems to be less in patients with metastatic PC.
Subject(s)
Betacoronavirus/isolation & purification , Bone Neoplasms/epidemiology , Bone Neoplasms/mortality , Coronavirus Infections/complications , Pneumonia, Viral/complications , Prostatic Neoplasms, Castration-Resistant/epidemiology , Prostatic Neoplasms, Castration-Resistant/mortality , Aged , Aged, 80 and over , Bone Neoplasms/secondary , Bone Neoplasms/virology , COVID-19 , Combined Modality Therapy , Coronavirus Infections/transmission , Coronavirus Infections/virology , Follow-Up Studies , Humans , Incidence , Italy/epidemiology , Male , Pandemics , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Prognosis , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/virology , Retrospective Studies , SARS-CoV-2 , Survival RateABSTRACT
BACKGROUND: Cancer-related pain, usually associated with bone metastases, is a frequent and debilitating morbidity in patients with prostate cancer. To date there are only limited data regarding the prognostic role of pain in men with metastatic castration-sensitive prostate cancer (mCSPC). The objective of our analysis was to assess if the presence of pain can be considered an independent prognostic factor in mCSPC patients. METHODS: A retrospective analysis was performed on patients with mCSPC referring to six oncology centers in Italy. Clinical and pathological features were recorded. Patients were considered to have pain if this was reported within the patient's file or in case of a chronic analgesic therapy was found among the concomitant medications. Survivals were estimated by the Kaplan-Meier method, and compared across groups using the log-rank test. Cox proportional hazard models, stratified according to the baseline characteristics, were used to estimate hazard ratios for overall survival (OS). All the variables were significant if p < 0.05. RESULTS: Data about pain were available for 365 cases and pain was present in 34.8% of patients. Pain was mainly associated with high value of prostate-specific antigen, metastatic bone extension regardless of the site, and lymph node involvement. mCSPC patients with pain had in most of the cases high-volume or Hr disease, and significant shorter OS (27.0 vs. 58.2 months, p < 0.001) and PFS (10.1 vs. 17.4 months, p < 0.001) compared to those without pain. The negative impact of pain on OS remained significant even if adjusted for CHAARTED or LATITUDE classification, and other significant baseline prognostic factors. CONCLUSIONS: This analysis supports the poor prognostic role of cancer-related pain in the setting of mCSPC patients. A prospective validation is required.
Subject(s)
Cancer Pain/epidemiology , Prostatic Neoplasms, Castration-Resistant/epidemiology , Aged , Androgen Antagonists/therapeutic use , Bone Neoplasms/blood , Bone Neoplasms/diagnosis , Bone Neoplasms/epidemiology , Bone Neoplasms/secondary , Cancer Pain/diagnosis , Cancer Pain/mortality , Cancer Pain/pathology , Clinical Trials as Topic , Humans , Italy/epidemiology , Male , Middle Aged , Prognosis , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/diagnosis , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective Studies , Survival RateABSTRACT
Androgen deprivation therapy (ADT) is a cornerstone of treatment for prostate cancer and, in recent years, androgen receptor (AR)-targeted therapies (abiraterone and enzalutamide) have both been used for the treatment of castration-resistant prostate cancer (CRPC). In our study, we sought to investigate the association between ADT and immune disorders, considering a potential role of androgens in the immune modulation. We retrospectively evaluated CRPC patients treated with abiraterone/enzalutamide between July 2011 and December 2018. We assessed the risk of developing immune alterations and their impact on outcome. We included 844 CRPC patients receiving AR-directed therapies, of whom 36 (4.3%) had autoimmune diseases and 47 (5.6%) second tumors as comorbidities. Median age was 70 years [interquartile range (IQR) = 63-75)]. We showed higher significant incidence of autoimmune diseases during their hormone sensitive status (p = 0.021) and the presence of autoimmune comorbidities before starting treatment with abiraterone/enzalutamide was significantly associated with worse overall survival (OS) (10.1 vs. 13.7 months, HR = 1.59, 95% CI 1.03-2.27, p = 0.038). In a multivariate analysis, the presence of autoimmune disorders was an independent predictor of OS (HR = 1.65, 95% CI 1.05-2.60, p = 0.031). In conclusion, CRPC patients with autoimmune alterations before starting AR-directed therapies may have worse prognosis. Further prospective studies are warranted to assess the role of immune modulation in the management of prostate cancer patients.
ABSTRACT
OBJECTIVES: stereotactic body radiation therapy (SBRT) use has increased overtime for the management of metastatic renal cell carcinoma (mRCC) patients, with a likely good control of irradiated lesions. We planned a retrospective multicenter Italian study, with the aim of investigating the outcome of treatment with SBRT for non-brain secondary lesions in mRCC patients. METHODS: all consecutive metastatic non-brain lesions from mRCC that underwent SBRT at nine Italian institutions from January 2015 to June 2017 were considered. The primary endpoint of the study was the lesion-PFS, calculated from SBRT initiation to the local progression of the irradiated lesion. RESULTS: 57 extracranial metastatic lesions from 48 patients with primary mRCC were treated with SBRT. At the median follow-up of 26.4 months, the median lesion-PFS was not reached (43 censored); 72.4% of lesions were progression-free at 40 months, with significantly better lesion-PFS for small metastatic lesions (<14â¯mm). SBRT was safe and the 1-year local disease control was 87.7%. After SBRT, 18 patients (37.5%) permanently interrupted systemic therapy. CONCLUSIONS: consistently with the previous literature, our findings support the use of SBRT in selected mRCC patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Renal Cell/therapy , Kidney Neoplasms/therapy , Radiosurgery , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Chemoradiotherapy/methods , Chemoradiotherapy/statistics & numerical data , Female , Follow-Up Studies , Humans , Italy/epidemiology , Kidney/diagnostic imaging , Kidney/pathology , Kidney Neoplasms/diagnosis , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Male , Middle Aged , Progression-Free Survival , Retrospective Studies , Tomography, X-Ray Computed , Tumor Burden/drug effects , Tumor Burden/radiation effectsABSTRACT
Over the last 10 years, a number of new agents approved for the treatment of metastatic castration-resistant prostate cancer have led to a significant improvement in overall survival. The addition of new agents to androgen deprivation therapy has also allowed a paradigmatic change in the treatment of metastatic hormone-sensitive prostate cancer by improving overall survival in comparison with androgen deprivation therapy alone. Furthermore, recent data concerning the efficacy of three different androgen receptor-targeting agents in patients with nonmetastatic castration-resistant prostate cancer have opened up new scenarios for future patients' management. Defining the best sequencing strategies for men with prostate cancer is a currently unmet medical need, and choosing treatment is often challenging for clinicians because of the lack of direct comparisons of the available agents. The aim of this paper is to provide a comprehensive review of the literature concerning current sequencing strategies for prostate cancer patients.
Subject(s)
Neoplasms, Hormone-Dependent/drug therapy , Prostatic Neoplasms, Castration-Resistant/drug therapy , Receptors, Androgen/genetics , Androgen Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Disease Progression , Disease-Free Survival , Humans , Male , Neoplasm Metastasis , Neoplasms, Hormone-Dependent/genetics , Neoplasms, Hormone-Dependent/pathology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathologyABSTRACT
AIM: To evaluate activity of metronomic cyclophosphamide (mCTX) in heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS & METHODS: We retrospectively evaluated a consecutive series of 74 mCRPC patients treated with at least one new agent after docetaxel failure, who received once-daily oral mCTX treatment at a fixed dose of 50 mg. RESULTS: The treatment was well tolerated. Sixteen percent of the patients experienced a major biochemical response. Median progression-free survival was 4.0 months, and median overall survival was 8.1 months. CONCLUSIONS: In the modern context of mCRPC, mCTX may represent a valuable and inexpensive alternative to new agents, which have shown similar activity in heavily pretreated patients.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Cyclophosphamide/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/secondary , Aged , Aged, 80 and over , Follow-Up Studies , Humans , Male , Middle Aged , Patient Safety , Retrospective Studies , Treatment OutcomeABSTRACT
In few years the scenario of metastatic prostate carcinoma treatment has radically changed due to improved knowledge of those mechanisms responsible of prostatic cancer cells survival and proliferation. Five new therapeutic agents (abiraterone acetate, enzalutamide, cabazitaxel, radium-223, sipuleucel-T), all able to improve overall survival, have been introduced in the management of metastatic castration-resistant prostate cancer. Moreover, recent evidences showed that adding docetaxel chemotherapy or abiraterone acetate to androgen deprivation therapy significantly increases overall survival of de novo castration-sensitive metastatic prostate cancer patients. Due to this rapid therapeutic evolution clinicians face one crucial challenge: the choice of the best treatment sequencing. In particular, there are no prospective data to guide clinical decision in patients with progressive disease after docetaxel or abiraterone acetate treatment for castration sensitive disease. In this review we provide an overview of the therapeutic agents available for both castration-sensitive and castration-resistant prostate cancer. We propose some biological and clinical insights helpful in selecting the most appropriate treatment for patients progressing after metastatic castration-sensitive prostate cancer treatment with docetaxel or abiraterone acetate.
Subject(s)
Prostatic Neoplasms, Castration-Resistant/therapy , Abiraterone Acetate/therapeutic use , Benzamides , Humans , Male , Neoplasm Metastasis , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Radium/therapeutic use , Taxoids/therapeutic use , Tissue Extracts/therapeutic useABSTRACT
BACKGROUND: Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting. PATIENTS AND METHODS: We conducted a multicenter retrospective analysis in the Triveneto region of Italy. RESULTS: One hundred fifty-eight patients received radium 223 in our region. After a median follow-up of 9.5 months, 75 patients died. The median overall survival (OS) was 14.2 months, and the median progression-free survival (PFS) was 6.2 months. Seventy-one (45%) patients achieved progression as best response. Thirty-seven (23%) patients stopped the treatment early because of progression. Eastern Cooperative Oncology Group performance status was prognostic for OS (18.4 vs. 12.3 vs. 7.5 months; 0 vs. 1, P = .0062; 0 vs. 2, P = .0002), whereas previous prostatectomy or docetaxel exposure were not. A neutrophil to lymphocytes ratio ≥ 3 significantly impacted OS (18.1 vs. 9.7 months; P < .001) and slightly impacted PFS (6.6 vs. 5.6 months; P = .05). Patients with a baseline alkaline phosphatase (ALP) value ≥ 220 U/L had worse OS and PFS (24.1 vs. 10.5 months; 7.2 vs. 5.5 months; P < .001). Patients with changes in ALP value achieved better OS (P = .029) and PFS (P = .002). There was no difference according to the line of therapy (0 vs. ≥ 1; P = .490). The main grade 3/4 toxicities were anemia, asthenia, and thrombocytopenia. CONCLUSION: This large real-world report confirms comparable OS and PFS data when compared with the pivotal study, as well as the predictive role of ALP and neutrophil to lymphocytes ratio. The definition of the optimal position of radium 223 in the treatment of metastatic castration-resistant prostate cancer has still to be defined.
Subject(s)
Prostatic Neoplasms, Castration-Resistant/radiotherapy , Radium/therapeutic use , Adult , Aged , Aged, 80 and over , Follow-Up Studies , Humans , Italy , Lymphocytes/pathology , Male , Middle Aged , Neutrophils/pathology , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective Studies , Survival Rate , Treatment OutcomeABSTRACT
AIM: To collect efficacy and safety data of enzalutamide after docetaxel, we retrospectively evaluated the Italian Named Patient Program results. PATIENTS & METHODS: Two hundred and nine metastatic castration-resistant prostate cancer patients were enrolled. Median age was 73 years. Total 42.1% patients had pain, 14.4% had a performance status of two and 59.8% had a Gleason score ≥8. Total 31.1% had previously received ≥2 chemotherapies, 15.3 and 12% had been previously treated with abiraterone and cabazitaxel, respectively and 14.8% had received both. RESULTS: Median progression-free survival and overall survival were 4.8 and 13.1 months, respectively. A prostate-specific antigen reduction ≥50% was observed in 49.1%. Total 32.7% abiraterone-pretreated patients achieved a biochemical response compared with 56% of abiraterone-naive patients. CONCLUSION: Enzalutamide was safe and well tolerated. Its antitumor activity in abiraterone-pretreated patients was limited.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/drug therapy , Adult , Aged , Aged, 80 and over , Androstenes/pharmacology , Androstenes/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzamides , Disease Progression , Docetaxel/pharmacology , Docetaxel/therapeutic use , Drug Resistance, Neoplasm , Humans , Italy/epidemiology , Kallikreins/blood , Kaplan-Meier Estimate , Male , Middle Aged , Nitriles , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/therapeutic use , Progression-Free Survival , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective StudiesABSTRACT
Patients who are carriers of inherited mutations in essential component of DNA repair pathways have a significantly higher lifetime risk for developing cancer compared to the population of reference. Recent advances in DNA next-generation sequencing technology have allowed screening for carriers of those mutations, allowing development of promising risk-reduction strategies and providing the rationale to personalize the therapeutic approach for these patients. New intriguing scenarios are opening nowadays for the management of prostate cancer in patients with germline or somatic mutations in components of DNA repair pathways (e.g., BRCA1 and BRCA2 genes), such as specific screening policies and new therapeutic strategies involving PARP inhibitors or platinum-based chemotherapy.
ABSTRACT
Androgen receptor is the major driver of and testosterone the natural growth factor of prostate cancer (PC). Studies exploring the relationship among circulating testosterone levels, PC aggressiveness, and patient prognosis showed contradictory results. We performed a comprehensive literature search for studies reporting the independent relationship between serum testosterone and prognosis of PC patients. Meta-analyses using random effects models were conducted to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). We identified 25 articles that evaluated the prognostic value of testosterone in early-stage PC (8 studies), in advanced PC either before (4 studies) or during androgen deprivation therapy (ADT) (5 studies), and in castration-resistant PC (8 studies). In early PC, serum testosterone level was not prognostic in terms of overall survival (HR = 1.03; 95% CI, 0.99-1.08; P = .19) and biochemical recurrence (HR = 0.99; 95% CI, 0.87-1.13; P = .93). In advanced PC, higher testosterone levels before ADT were associated with a reduced risk of death (HR = 0.58; 95% CI, 0.45-0.74; P < .0001). During ADT, lower levels were associated with a reduced risk of death (HR = 0.48; 95% CI, 0.28-0.81; P = .006) and progression (HR = 0.59; 95% CI, 0.46-0.77; P < .0001). In castration-resistant PC patients, higher testosterone levels predicted a reduced risk of progression (HR = 0.33; 95% CI, 0.11-0.97; P = .04) but not of death (HR = 0.86; 95% CI, 0.69-1.07; P = .18). The heterogeneity of the included studies is a major limitation of this meta-analysis. The relationship between circulating testosterone and PC prognosis varies in different clinical settings and according to ADT administration.
Subject(s)
Androgen Antagonists/therapeutic use , Prostatic Neoplasms/pathology , Testosterone/blood , Clinical Trials as Topic , Disease Progression , Humans , Male , Prognosis , Proportional Hazards Models , Prostatic Neoplasms/blood , Survival AnalysisABSTRACT
BACKGROUND: Metabolic syndrome (MS) and inflammation (INF) alterations are among the factors involved in cancer progression. The study aimed to assess the relationship between MS and INF and its effect on progression-free/overall survival (PFS/OS) in metastatic castration-resistant prostate cancer (mCRPC) treaed with abiraterone or enzalutamide. METHODS: We, retrospectively, evaluated patients with mCRPC in 7 Italian Institutes between March 2011 and October 2016. MS was defined by modified adult treatment panel-III criteria. INF was characterized by at least one of these criteria: neutrophil to lymphocyte ratio ≥ 3, elevated erythrocyte sedimentation rate or C-reactive protein. RESULTS: Eighty-three of 551 (15.1%) patients met MS criteria at baseline and 34 (6.2%) during treatment. MS patients (MS+) presented a greater INF profile compared to MS- (P<0.0001). Median PFS was 3.7 for MS+ vs. 8.7 months for MS- (hazard ratio [HR] = 2.77; 95% CI: 2.12-3.61; P<0.0001). Median OS was 6.9 and 19 months in MS+ and MS-, respectively (HR = 3.43; 95% CI: 2.56-4.58; P<0.0001). We also demonstrated INF led to shorter PFS and OS (4.5 vs. 8.5 months, HR = 1.48, 95% CI: 1.15-1.90, P = 0.002, and 11.2 vs. 18.8 months, HR =1.66, 95% CI: 1.26-2.18, P = 0.0003, respectively). The combination of MS with INF provided the identification of high-risk prognostic group (MS+/INF+ vs. MS-/INF-) with worse PFS (3.7 vs. 9 months, HR = 2.7, 95% CI: 1.88-3.89, P<0.0001) and OS (6.3 vs. 20.4 months, HR = 4.04, 95% CI: 2.75-5.93, P<0.0001). Multivariable analysis confirmed that MS was independently associated with PFS (HR = 2.07; 95% CI: 1.03-4.18; P = 0.041) and OS (HR = 4.87; 95% CI: 2.36-10.03; P<0.0001). The absence of INF as an independent predictor of survival underlined the correlation between MS/INF. CONCLUSIONS: Pretreatment identification of MS and INF alterations might represent an available and easy tool for better prognostication of patients with mCRPC. A prospective evaluation is warranted.
Subject(s)
Androstenes/adverse effects , Inflammation/mortality , Metabolic Syndrome/mortality , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/mortality , Adult , Aged , Aged, 80 and over , Benzamides , Follow-Up Studies , Humans , Inflammation/chemically induced , Male , Metabolic Syndrome/chemically induced , Middle Aged , Nitriles , Phenylthiohydantoin/adverse effects , Prognosis , Prostatic Neoplasms, Castration-Resistant/drug therapy , Retrospective Studies , Risk Factors , Survival RateABSTRACT
Abiraterone acetate, which targets enzymatic complexes playing a central role in steroidogenesis, demonstrated to increase survival significantly in both chemo-naive and docetaxel pretreated, becoming one of the drugs of choice for metastatic castration-resistant prostate cancer. More recently, this agent in combination to androgen deprivation therapy demonstrated to be efficacious also in metastatic castration-sensitive prostate cancer. The present review is aimed to outline the clinical development of abiraterone acetate, the pivotal trials which led to its approval for the clinical practice, new evidence about its efficacy in metastatic castration-sensitive prostate cancer, its place in the therapeutic landscape of prostate cancer and future directions of development.