Treatment-Emergent Co-Morbidities and Survival in Patients With Metastatic Castration-Resistant Prostate Cancer Receiving Abiraterone or Enzalutamide

Secondary hormone therapy, abiraterone and enzalutamide, has improved outcomes for metastatic castration-resistant prostate cancer (mCRPC) and prolonged patients’ lives significantly. Various studies have compared the cancer-related outcomes, adverse effects, and drug-induced comorbidities in patients with mCRPC who are treated with abiraterone or enzalutamide. However, few studies have explored associations between survival and comorbidities or comprehensive analyzed newly developed comorbidities during and after secondary hormone therapy. We attempted to clarify whether the Charlson comorbidity index (CCI) overall or itemized is predictive for overall survival, and we compared newly developed comorbidities between abiraterone and enzalutamide groups. We extracted data about expenses and comorbidities for patients who have mCRPC, received abiraterone and enzalutamide and met pre-examination operation criteria between September 2016 and December 2017 from the Taiwan National Health Insurance database. A total of 1153 patients with mCRPC who received abiraterone (n = 782) or enzalutamide (n = 371) with or without previous chemotherapy were included. We used the propensity score to match confounding factors, including age, pre-existing comorbidities, and precipitating factors for comorbidity (e.g., hypertension, hyperlipidemia), to eliminate selection bias in the comparison of newly developed comorbidities. Cox regression analysis was used for overall survival. We found that enzalutamide is superior to abiraterone with regard to overall survival. Our study revealed that there is no statistically significant difference in development of new comorbidities between abiraterone and enzalutamide group. Moreover, the CCI score, rather than any single item of the CCI, was a statistically significant predictor for overall survival.

Download Full-text

The effect of treatment sequence on overall survival for men with metastatic castration-resistant prostate cancer: A multicenter retrospective study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.238 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 238-238

Author(s):

Shingo Hatakeyama ◽

Kazutaka Okita ◽

Hayato Yamamoto ◽

Takahiro Yoneyama ◽

Yasuhiro Hashimoto ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Real World ◽

Cox Regression ◽

Sequential Therapy ◽

Treatment Sequence ◽

Castration Resistant Prostate Cancer ◽

First Line ◽

Castration Resistant ◽

Significant Difference

238 Background: We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. Methods: We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naïve prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. Results: The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio: HR 0.84, P = 0.530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR 0.82, P = 0.650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR 1.58, P = 0.384). Conclusions: The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

Download Full-text

YB-1 variant and androgen receptor axis-targeted agents in metastatic castration-resistant prostate cancer patients

Pharmacogenomics ◽

10.2217/pgs-2020-0008 ◽

2020 ◽

Vol 21 (13) ◽

pp. 919-928

Author(s):

Ana Afonso ◽

Jani Silva ◽

Ana Rita Lopes ◽

Sara Coelho ◽

Ana Sofia Patrão ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Patients ◽

Cox Regression ◽

Progression Free Survival ◽

Castration Resistant Prostate Cancer ◽

Allelic Discrimination ◽

Cox Regression Analysis ◽

Castration Resistant ◽

Increased Risk

Aim: To evaluate the influence of YB-1 rs10493112 variant as a genetic marker for response to second-generation androgen receptor axis-target agents. Methods: A hospital-based cohort study of 78 patients with metastatic castration-resistant prostate cancer was conducted. Genotyping was performed by TaqMan® allelic discrimination technology. Main results: In abiraterone-treated and high-risk patients, YB-1 rs10493112 AA genotype carriers showed lower progression-free survival than C allele genotype patients (4 vs 17 months; p = 0.009). For carriers of AA genotype, multivariate Cox regression analysis revealed a fivefold increased risk of progression (p = 0.035). Conclusion: The study findings suggest that, for metastatic and castration-resistant prostate cancer patients, this polymorphism might be a putative marker for the clinical outcome.

Download Full-text

Evaluating the effect of therapy duration on survival in patients with metastatic castration-resistant prostate cancer receiving radium-223.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.e593 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. e593-e593

Author(s):

Noelle L. Williams ◽

Kamila Nowak-Choi ◽

Jenna Skowronski ◽

Tu Dan ◽

Harriet Belding Eldredge ◽

...

Keyword(s):

Prostate Cancer ◽

Second Generation ◽

Cox Regression ◽

Rank Test ◽

Maximal Effect ◽

Castration Resistant Prostate Cancer ◽

Cox Regression Analysis ◽

Castration Resistant ◽

Full Treatment ◽

Radium 223

e593 Background: The use of radium-223 in patients with metastatic castration-resistant prostate cancer (mCRPC) improves overall survival (OS) and quality of life. Combination of radium-223 with second-generation anti-androgens has further improved OS; however, the optimal length of radium-223 treatment for maximal effect remains unknown. Methods: We reviewed 35 consecutive patients with mCRPC who received radium-223 from December 2012 to August 2015 at Thomas Jefferson University. Patients were divided into two groups: those who received full treatment of 6 injections (n = 18) versus those who received less than 6 injections (n = 17). Kaplan-Meier analysis of OS were tested for difference by treatment group using Log Rank test. Univariable association with survival outcomes was calculated with univariable Cox regression and Log Rank tests. Results: Mean age was 73 ± 10 years and Karnofsky performance status (KPS) ranged from 50-90 (median, 80). Median follow-up was 13.9 months. Eighteen patients were receiving concurrent second generation anti-androgens at the start of treatment. Median OS was 12 months for patients who received 6 injections and 6.48 months for patients who received less than 6 injections (p = 0.0045). The results of univariate Cox regression analysis revealed full treatment was associated with increased OS (p = 0.0013). On multivariate analysis accounting for KPS, full treatment was significantly associated with improved OS (p = 0.0028). Conclusions: In this retrospective, single-institution analysis, we demonstrated that full course completion of radium-223 was associated with improved OS in patients with mCRPC. These patients should be optimally supported during treatment to allow for therapy completion.

Download Full-text

Abiraterone acetate plus prednisone/prednisolone compared with enzalutamide in metastatic castration resistant prostate cancer before or after chemotherapy: A retrospective study of real-world data (ACES).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.303 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 303-303

Author(s):

Prantik Das ◽

James Price ◽

Michael Jones ◽

Cristina Martin-Fernandez ◽

Akram Ali ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Radiographic Progression ◽

Progression Free Survival ◽

Abiraterone Acetate ◽

Castration Resistant Prostate Cancer ◽

Free Survival ◽

Castration Resistant ◽

Significant Difference ◽

Biochemical Progression

303 Background: Abiraterone acetate (a prodrug of abiraterone, which is a selective inhibitor of androgen biosynthesis) combined with prednisone/prednisolone (AA+P) and enzalutamide (ENZ) (an androgen-receptor–signalling inhibitor) have proven survival benefit in men with metastatic castration resistant prostate cancer (mCRPC) in chemo naïve and prior chemo patients. There have been no studies directly comparing the effectiveness of ENZ to AA+P in mCRPC patients. Methods: A retrospective, survival analysis study of 143 real world mCRPC patients (90 in AA+P and 53 in ENZ group) was conducted. Patients who started their treatment between 1st February 2012 and 31st May 2016 were included. The primary endpoint was biochemical progression free survival (PFS). Secondary end points were radiographic progression free survival (rPFS) and overall survival (OS). Data was analysed using Cox proportional hazards models, adjusting for covariates: prior radical or palliative treatment; Gleason score; baseline PSA; age; and chemo naïve or not. Results: After median follow up of 15 months (IQR 7 to 23) 112 events of biochemical progression were observed (71 in AA+P and 41 in ENZ). 41%in AA+P group and 30% patients in ENZ group received prior chemo. The chance of biochemical progression was significantly lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (Hazard Ratio 0.54, 95% CI 0.35 to 0.82, p=0.004. There was a trend implying the chance of rPFS could be higher among ENZ patients than AA+P patients (HR 1.24, 95% CI 0.76 to 2.02, p=0.4). OS is lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (HR 0.91, 95% CI 0.59 to 1.41, p=0.7). 38% of ENZ patients reported fatigue compared to 16% of AA+P patients while hypertension was reported slightly more in AA+P patients than in ENZ patients. Conclusions: This study showed a statistically significant difference in biochemical progression-free survival, favouring ENZ, but no significant difference in radiographic progression-free survival or overall survival.

Download Full-text

Treatment outcome and identification of factors influencing overall survival after Lu-177-PSMA-617 radioligand therapy in metastatic prostate cancer

Nuklearmedizin ◽

10.1055/a-1670-9500 ◽

2021 ◽

Author(s):

Charlotte A. Schneider ◽

Philipp Täger ◽

Jochen Hammes ◽

Thomas Fischer ◽

Alexander Drzezga ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Alkaline Phosphatase ◽

Regression Analysis ◽

Cox Regression ◽

Specific Antigen ◽

Castration Resistant Prostate Cancer ◽

Radioligand Therapy ◽

Cox Regression Analysis ◽

Cumulative Activity

Abstract Objective To examine the clinical benefit of Lu-177-PSMA-617 radioligand therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods Between November 2014 and December 2018, a total of 56 consecutive patients (median age 69.5 years; range 55–84 years) with mCRPC were included in this retrospective analysis. Patients received between 1 and 4 therapy cycles with a mean activity of 6.8 GBq per cycle. Biochemical response was evaluated using Prostate Cancer Working Group Criteria 3 (PCWG 3). Survival was assessed using Kaplan-Meier estimates and Cox proportional hazards regression analysis. This retrospective study was approved by the local ethics committee. Results A total of 139 treatment cycles with Lu-177-PSMA-617 were performed. A decline of 50% or more of prostate-specific antigen (PSA) level occurred in 54% and a PSA decline of any amount in 65% of patients. The estimated median overall survival (OS) was 16 months, in the chemotherapy subgroup 14 months. A longer OS was associated with a PSA-decline ≥50%, more than 2 cycles of therapy, cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l]. These identified predictors remained significant on uni- and multivariate Cox regression analysis. Moreover, 40% of the patients who were non-responders after the first therapy cycle turned into responders after the second one. Conclusion PSA-decline ≥50%, a cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l] were identified as key predictors of prolonged OS in patients with mCRPC. In contrast rapid clinical deterioration mostly due to skeletal carcinomatosis resulted in early treatment failure.

Download Full-text

Prognostic Value of Novel Liquid Biomarkers in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide: A Prospective Observational Study

Clinical Chemistry ◽

10.1093/clinchem/hvaa095 ◽

2020 ◽

Vol 66 (6) ◽

pp. 842-851

Author(s):

Guillemette E Benoist ◽

Inge M van Oort ◽

Emmy Boerrigter ◽

Gerald W Verhaegh ◽

Onno van Hooij ◽

...

Keyword(s):

Prostate Cancer ◽

Regression Analysis ◽

Observational Study ◽

Prognostic Value ◽

Cox Regression ◽

Response To Therapy ◽

Castration Resistant Prostate Cancer ◽

Time To Progression ◽

Cox Regression Analysis ◽

Castration Resistant

Abstract Background Several treatment options were recently added for metastatic castration-resistant prostate cancer (mCRPC). However, response to therapy is variable, and biomarkers that can guide treatment selection and response evaluation are lacking. Circulating RNAs are a promising source of biomarkers. We explored messenger RNAs (mRNAs), microRNAs (miRNAs), and long noncoding RNAs (lncRNAs) as potential biomarkers in liquid biopsies of patients with mCRPC treated with enzalutamide. Methods Forty patients were included in this prospective multicenter observational study. Whole blood was drawn at baseline and 1, 3, and 6 months after start of therapy. Four mRNAs, 6 miRNAs, and 5 lncRNAs were analyzed by quantitative PCR. RNA levels in 30 healthy individuals were used as controls. RNA expression data were analyzed by Kaplan–Meier and Cox regression analyses, and the primary end point was progression-free survival. Clinical factors were included in the multivariable Cox regression analysis. Results Levels of 2 miRNAs, miR-375 and miR-3687, and 1 lncRNA, N-acetylated alpha-linked acidic dipeptidase like 2 antisense RNA 2 (NAALADL2-AS2), were more than 2-fold higher in patients with mCRPC compared with healthy volunteers. Patients with higher levels of miR-375 or miR-3687 showed a shorter time to progression. Patients with higher levels of NAALADL2-AS2 showed a longer time to progression. In the multivariable Cox regression analysis, higher miR-375, miR-3687 and serum prostate-specific antigen concentrations were shown to be independent predictors for shorter time to progression. Conclusions We identified miR-3687 as a novel prognostic marker for response in patients with CRPC treated with enzalutamide, and we confirmed the prognostic value of miR-375.

Download Full-text

Prognostic Association between Common Laboratory Tests and Overall Survival in Elderly Men with De Novo Metastatic Castration Sensitive Prostate Cancer: A Population-Based Study in Canada

Cancers ◽

10.3390/cancers13112844 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2844

Author(s):

Christopher J. D. Wallis ◽

Bobby Shayegan ◽

Scott C. Morgan ◽

Robert J. Hamilton ◽

Ilias Cagiannos ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Clinical Decision Making ◽

Cox Regression ◽

De Novo ◽

Population Based ◽

Population Based Study ◽

Cox Regression Analysis ◽

Lymphocyte Ratio ◽

Laboratory Markers

De novo cases of metastatic prostate cancer (mCSPC) are associated with poorer prognosis. To assist in clinical decision-making, we aimed to determine the prognostic utility of commonly available laboratory-based markers with overall survival (OS). In a retrospective population-based study, a cohort of 3556 men aged ≥66 years diagnosed with de novo mCSPC between 2014 and 2019 was identified in Ontario (Canada) administrative database. OS was assessed by using the Kaplan–Meier method. Multivariate Cox regression analysis was performed to evaluate the association between laboratory markers and OS adjusting for patient and disease characteristics. Laboratory markers that were assessed include neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin, hemoglobin, serum testosterone and PSA kinetics. Among the 3556 older men with de novo mCSPC, their median age was 77 years (IQR: 71–83). The median survival was 18 months (IQR: 10–31). In multivariate analysis, a statistically significant association with OS was observed with all the markers (NLR, PLR, albumin, hemoglobin, PSA decrease, reaching PSA nadir and a 50% PSA decline), except for testosterone levels. Our findings support the use of markers of systemic inflammation (NLR, PLR and albumin), hemoglobin and PSA metrics as prognostic indicators for OS in de novo mCSPC.

Download Full-text

Next-generation androgen receptor inhibitors in non-metastatic castration-resistant prostate cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920978134 ◽

2020 ◽

Vol 12 ◽

pp. 175883592097813

Author(s):

Pernelle Lavaud ◽

Clément Dumont ◽

Constance Thibault ◽

Laurence Albiges ◽

Giulia Baciarello ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Androgen Receptor ◽

Androgen Deprivation Therapy ◽

Androgen Deprivation ◽

Next Generation ◽

Castration Resistant Prostate Cancer ◽

Free Survival ◽

Castration Resistant ◽

Recent Advances

Until recently, continuing androgen deprivation therapy (ADT) and closely monitoring patients until evolution towards metastatic castration-resistant prostate cancer (CRPC) were recommended in men with non-metastatic CRPC (nmCRPC). Because delaying the development of metastases and symptoms in these patients is a major issue, several trials have investigated next-generation androgen receptor (AR) axis inhibitors such as apalutamide, darolutamide, and enzalutamide in this setting. This review summarizes the recent advances in the management of nmCRPC, highlighting the favourable impact of next-generation AR inhibitors on metastases-free survival, overall survival and other clinically meaningful endpoints.

Download Full-text