Prognostic impact of dose reduction in androgen receptor pathway inhibitors for castration-resistant prostate cancer.

Background: Androgen receptor pathway inhibitors (ARPIs) such as abiraterone and enzalutamide have been shown to prolong survival in patients with advanced prostate cancer. However, there is limited evidence on the anticancer effect of a reduced dose of ARPIs. This study compared the prognosis in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC) between ARPI treatment with standard dose and treatment with reduced dose. Methods: Japanese patients who were treated with ARPI as first-line treatment for CRPC between 2014 and 2018 were included. The associations between dose reduction and clinicopathological factors, progression-free survival, and overall survival were investigated. Results: Of the 162 patients included, 33 (20.4%) patients had their dose reduced during ARPI treatment. In the multivariate analysis, higher PSA, abiraterone treatment, and dose reduction were significant prognostic factors for progression-free survival (PFS); however, dose reduction was not associated with overall survival. In the enzalutamide-treated group, the median PFS was 12.1 months (95% CI, 8.5-21.4 months) in the standard-dose group and 7.2 months (95% CI, 5.0-11.5 months) in the reduced-dose group (P = 0.038). Conclusion: This study suggests inferior oncological outcome when treated with reduced-dose ARPI for CRPC. Full-dose administration of ARPI for CRPC may be appropriate if feasible.

Prognostic significance of risk stratification in CHAARTED and LATITUDE studies among Japanese men with castration-resistant prostate cancer.

BACKGROUND: The CHAARTED and LATITUDE trials demonstrated a survival benefit of docetaxel and abiraterone for hormone-sensitive prostate cancer. In this study, we examined the impact of the risk stratification criteria used in the CHAARTED and LATITUDE trials on the prognosis of castration-resistant prostate cancer (CRPC). We also tested whether these risk stratification criteria could help in selecting effective initial treatment for CRPC. METHOD: Japanese patients with CRPC who were treated with docetaxel or androgen receptor pathway inhibitors such as abiraterone acetate or enzalutamide between 2014 and 2018 were included in this study. Clinicopathological factors, progression-free survival, and overall survival were investigated. RESULTS: Of 215 patients, 110 men (51.2%) and 93 men (43.3%) were grouped as high volume by CHAARTED criteria and high risk by LATITUDE criteria, respectively. Median progression-free survival was 10.3/4.5 months (P < 0.0001) for low/high volume (CHAARTED criteria) and 9.9/4.8 months (P = 0.0032) for low/high risk (LATITUDE criteria). The median overall survival was 44.8/17.4 months (P < 0.0001) for low/high volume (CHAARTED criteria) and 37.4/17.4 months (P = 0.0011) for low/high risk (LATITUDE criteria). The prognostic impact of CHAARTED and LATITUDE criteria was comparable between androgen receptor pathway inhibitors and docetaxel as first-line treatment for CRPC. CONCLUSION: The CHAARTED and LATITUDE criteria were prognostic, but not useful to discriminate the therapeutic outcome between androgen receptor pathway inhibitors and docetaxel for CRPC.

Anticancer Effect of Second-line Treatment for Castration-Resistant Prostate Cancer Following First-line Treatment with Androgen Receptor Pathway Inhibitors.

INTRODUCTION: Studies on the effect of androgen receptor pathway inhibitors (ARPI), docetaxel (DTX), and radium-223 (Ra-223) after first-line treatment with ARPI in patients with castration-resistant prostate cancer (CRPC) are scarce. This study compared the efficacy of treatment after ARPI for CRPC. METHODS: Patients with CRPC who received ARPI as first-line treatment and different second-line treatments were retrospectively reviewed. Clinicopathological backgrounds and treatment outcomes, including maximum prostate-specific antigen (PSA) decrease, progression-free survival (PFS), and overall survival (OS), were compared between second-line treatments. RESULTS: In total, 88 patients were enrolled. Forty-one (46.6%), 37 (42.0%), and 10 (11.4%) patients were treated with ARPI, DTX, and Ra-223, respectively. Patients whose PSA levels were not adequately reduced by first-line treatment with ARPI were eventually enrolled in the DTX treatment (P = 0.030). PSA decrease was not significantly different when comparing treatments. PFS in the DTX group was significantly better than in the other two groups (P = 0.023). In multivariate analysis, DTX was an independent prognostic factor for better PFS compared to ARPI (hazard ratio, 95% confidence interval; 0.44, 0.25-0.79, P = 0.006). Subgroup analysis showed a favorable impact of DTX on PFS in patients with Gleason score >8 (interaction P = 0.027) and a PSA decline >50% (interaction P = 0.019) during first-line treatment with ARPI. However, no significant difference in OS was observed between groups of different second-line treatments. CONCLUSIONS: This study suggests that in patients with CRPC, second-line treatment with DTX following progression in patients who received ARPI as first-line treatment is more beneficial compared with second-line treatment with ARPI or Ra-233.

Predictive factors of survival outcomes in first-line therapy for metastatic castration-resistant prostate cancer.

OBJECTIVES: To investigate predictive factors of survival of metastatic castration-resistant prostate cancer patients undergoing first-line treatment with androgen receptor pathway inhibitors or docetaxel. METHODS: Japanese patients with metastatic castration-resistant prostate cancer treated with androgen receptor pathway inhibitor or docetaxel between 2008 and 2018 were included. The differential impact of various clinicopathological factors on the outcome, including progression-free survival and overall survival, was compared between treatment with androgen receptor pathway inhibitor and docetaxel. RESULTS: Of 254 patients with metastatic castration-resistant prostate cancer, 119 (46.9%) and 135 (53.2%) were treated with androgen receptor pathway inhibitor and docetaxel, respectively. The multivariate analysis showed that androgen receptor pathway inhibitor was an independent prognostic factor for better progression-free survival (hazard ratio 0.62, 95% confidence interval 0.42-0.92, P = 0.016) and overall survival (hazard ratio 0.61, 95% confidence interval 0.41-0.93, P = 0.021), compared with docetaxel. Pretreatment prostate-specific antigen levels and time to castration-resistant prostate cancer were differentially associated with progression-free survival and overall survival between androgen receptor pathway inhibitor or docetaxel. In patients who presented <6 months to castration-resistant prostate cancer, progression-free survival was shorter in those treated with androgen receptor pathway inhibitor (median 1.1 months, 95% confidence interval 0.2-2.8 months) compared with those who received docetaxel (median 5.0 months, 95% confidence interval 1.8-6.7 months; P = 0.014). CONCLUSIONS: First-line therapy with androgen receptor pathway inhibitor is associated with a better prognosis when compared with docetaxel, even after adjustment for prognostic factors. However, a shorter time to castration-resistant prostate cancer is associated with better progression-free survival for patients receiving docetaxel, suggesting that docetaxel is the preferred option for patients with a shorter time to castration-resistant prostate cancer.

Differential prognostic impact of complete blood count-related parameters by prior use of novel androgen receptor pathway inhibitors in docetaxel-treated castration-resistant prostate cancer patients.

There are multiple reports on the value of complete blood count (CBC)-related parameters on prognosis in docetaxel-treated castration-resistant prostate cancer (CRPC) patients before the emergence of androgen receptor pathway inhibitors (ARPIs). We investigated the prognostic significance of CBC-related parameters in docetaxel-treated CRPC patients. Patients treated with docetaxel chemotherapy for CRPC between 2008 and 2018 were included. We analyzed the relevance of CBC-related parameters to oncological prognosis in docetaxel chemotherapy, associated with prior use of novel ARPIs. Among 144 Japanese men treated with docetaxel, 49 men (34.0%) had already received ARPI therapy. A high neutrophil-lymphocyte ratio (NLR) was a prognostic factor for poor progression-free survival and overall survival (OS) in both univariate and multivariate analyses. In addition, a low hemoglobin (Hb) level and a high systemic immune-inflammation index (SII) were prognostic factors of poor OS in univariate analysis. Hb level was a prognostic factor of OS in both ARPI-naive and ARPI-treated patients. However, a high NLR and SII were only associated with a poor prognosis in ARPI-naive but not in ARPI-treated patients. Hb, NLR, and SII have been suggested to be prognosticators in docetaxel-treated CRPC patients. The differential prognostic value of NLR and SII between ARPI-naive and ARPI-treated patients may require caution when using these markers in docetaxel-treated CRPC patients.

Prognostic Value of Lower Tract Urinary Symptoms in Clinically Regional Lymph Node-positive Prostate Cancer.

BACKGROUND/AIM: To explore the prognostic value of lower urinary tract symptoms (LUTS) in patients with newly diagnosed regional lymph node-positive prostate cancer. PATIENTS AND METHODS: The prognostic value of LUTS for progression-free (PFS) and overall (OS) survival, as well as the differential prognostic impact of radiotherapy by LUTS was investigated. RESULTS: Univariate Cox-model analysis showed a statistically significantly increased hazard risk for PFS and OS for men with International Prostate Symptom Score (IPSS)≥19 and Overactive Bladder Symptom Score (OABSS) ≥8 at diagnosis. Patients with lower IPSS had a better PFS at 5 years (70.0% vs. 51.9%, p=0.027) and OS at 5 year (89.3% vs. 73.6%, p=0.016). Similarly, a lower OABSS was associated with greater PFS at 5 years (67.4% vs. 23.4%, p<0.001) and OS at 5 years (85.3% vs. 57.1%, p=0.012). CONCLUSION: IPSS and OABSS were prognostic for PFS and OS in patients with regional lymph node-metastatic prostate cancer.

Lactate Dehydrogenase Is a Serum Prognostic Factor in Clinically Regional Lymph Node-positive Prostate Cancer.

BACKGROUND/AIM: Currently, there is no established prognostic serum parameter except PSA in clinically regional lymph node-positive prostate cancer. The aim of this study was to identify serum prognostic factors in clinically regional lymph node-positive prostate cancer. PATIENTS AND METHODS: Patients diagnosed with regional lymph node-positive prostate cancer between 2008 and 2017 were included. The prognostic value of serum parameters for progression-free survival (PFS) and overall survival (OS) was investigated. RESULTS: Univariate and multivariate analyses showed a statistically significant increased hazard risk for PFS and OS for men with lactate dehydrogenase (LDH) ≥230 IU/l at diagnosis. PFS at 5 years for patients with high and low LDH levels were 69.9% (95% CI=56.8-79.8%) and 18.9% (95% CI=1.23-53.2%), respectively (p=0.003). OS at 5 years for low and high LDH levels were 89.2% (95% CI=78.6-94.7%) and 46.3 (95% CI=11.2-76.2%), respectively (p=0.006). CONCLUSION: This study shows that LDH is an independent predictor of PFS and OS in patients with regional lymph node metastatic prostate cancer.

Prognostic impact of prior local therapy in castration-resistant prostate cancer.

OBJECTIVE: This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). METHODS: The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. RESULTS: In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40-0.79; P = 0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. CONCLUSIONS: This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.

Efficacy and Safety of 4-Weekly Docetaxel for Castration-Resistant Prostate Cancer.

We investigated the efficacy and safety profiles of 4-weekly docetaxel for castration-resistant prostate cancer. Patients treated with ≥2 courses of docetaxel chemotherapy (median, 70 mg/m2) between 2008 and 2018 were included. Among 125 Japanese men, 40 (32.0%) and 85 (68.0%) were treated with 3-weekly and 4-weekly regimens, respectively. In the 4-weekly regimen, the risks of progression, treatment failure, and any-cause mortality were comparable to those in the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. These data suggest that the 4-weekly regimen may be an acceptable option for selected patients.

Effect of Smoking on Oncological Outcome among Prostate Cancer Patients after Radical Prostatectomy with Neoadjuvant Hormonal Therapy.

We analyzed the association between smoking and oncological outcome after radical prostatectomy with neoadjuvant hormonal therapy. This study included men who had undergone radical prostatectomy with neoadjuvant hormonal therapy between 2003 and 2016. We evaluated the association between clinicopathological factors and smoking status as well as the prognostic significance of smoking status in biochemical recurrence. The patients' backgrounds were comparable between smokers and nonsmokers. Smoking status were identified as significant risk factors of biochemical recurrence. Smoking was a risk factor of biochemical recurrence, suggesting that smoking may promote cancer recurrence after surgical treatment combined with hormonal therapy.

The prognosis and the impact of radiotherapy in clinically regional lymph node-positive prostate cancer: Which patients are candidates for local therapy with radiation?

BACKGROUND: This study aimed to identify the prognostic and predictive factors of local radiotherapy in clinically regional lymph node-positive prostate cancer. PATIENTS AND METHODS: This study includes patients who were newly diagnosed with regional lymph node-positive prostate cancer between 2008 and 2017. We investigated the prognostic value of clinicopathological parameters for progression-free survival (PFS) and overall survival (OS) as well as the differential prognostic impact of radiotherapy by subgroup analysis. RESULTS: Among the 93 men enrolled as patients, 48 (51.6 %) were treated with radiotherapy. The biopsy positive core rate and biopsy Gleason score were associated with PFS, and the number of lymph node metastases was associated with both PFS and OS. Patients who underwent radiotherapy showed better PFS and OS. High-risk features (at least 2 criteria among ≥75% biopsy positive core rate, Gleason score ≥9, and ≥2 positive lymph nodes) were especially associated with improved outcomes after undergoing radiotherapy. CONCLUSION: We identified prognostic factors for clinically regional lymph node-positive prostate cancer and showed the benefits of local radiation therapy. Patients with high-risk features may be especially suitable candidates for radiotherapy.

Smoking effect on oncological outcome among men with prostate cancer after radical prostatectomy.

OBJECTIVE: To analyze the association between smoking and oncological outcome after radical prostatectomy in patients with prostate cancer. METHODS: This study included men who underwent radical prostatectomy between 2003 and 2013. The association of clinicopathological factors with smoking status and the prognostic significance of clinicopathological factors and smoking status on biochemical recurrence (BCR) were evaluated. RESULTS: Of the 1165 included patients, 226 (19.4%) were current smokers and 939 (80.6%) were nonsmokers. The median observation period was 39 months (interquartile range, 15-75 months). Current smokers were younger than nonsmokers and had higher PSA levels, higher biopsy and pathological Gleason scores, and more frequent lymph-node involvement than nonsmokers. Pathological Gleason score, extracapsular extension, seminal vesicle invasion, positive surgical margin, lymph-node involvement, and current smoking (hazard ratio [95% confidence interval]; 1.31 [1.00-1.72], P = 0.046) were identified as significant risk factors of BCR on univariate analysis. However, smoking status was not an independent predictive marker on multivariate analysis. CONCLUSIONS: Current smokers had adverse clinicopathological characteristics including high PSA level, high Gleason score, and lymph node involvement, suggesting that smoking promoted the progression of prostate cancer.

Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare.

OBJECTIVE: To investigate the potential relationship of steroid usage with prostate-specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10-20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. PATIENTS AND METHODS: This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease. RESULTS: PSA flare was recognized in 7.0-23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure. CONCLUSIONS: Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure.