Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States

BackgroundClinical trials have demonstrated the efficacy of several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC); however, real-world data on their use, survival effect, and safety are limited. Using electronic health record data from the Flatiron Health database, we studied real-world treatment patterns and health outcomes in patients with mCRPC.Patients and MethodsWe conducted a retrospective, non-interventional cohort analysis of electronic health record data of patients with confirmed mCRPC between January 2013 and September 2017. The primary objective was to describe real-world treatment patterns, including treatment type, duration, and sequencing. Secondary objectives included describing patient characteristics and clinical outcomes.ResultsOf 2559 patients with mCRPC, 1980 (77%) received at least 1 line of life-prolonging therapy (abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223). Of patients receiving first-line therapy, 49% received second-line therapy, and of these, 43% received third-line therapy. Abiraterone/prednisone and enzalutamide accounted for 65% of first-line therapies and 54% of second-line therapies. Docetaxel was the most common third-line therapy (24%). Back-to-back use of abiraterone/prednisone and enzalutamide was common. Radium-223 monotherapy use was 2% in the first-line setting, 3% in the second-line setting, and 8% in the third-line setting. The median overall survival was longer in patients who received life-prolonging therapies (23.7 months; 95% confidence interval: 22.3-25.1 months) than in those who did not (10.1 months; 95% confidence interval: 9.1-11.5 months).ConclusionThese real-world insights on over 2500 patients with mCRPC supplement findings from randomized controlled trials and may help to inform clinical trial design, treatment guidelines, and clinical decision-making.     

Radium-223 in the Third-Line Setting in Metastatic Castration-Resistant Prostate Cancer: Impact of Concomitant Use of Enzalutamide on Overall Survival (OS) and Predictors of Improved OS

IntroductionRadium-223 (Ra-223) has been recommended for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). Second-generation hormone therapy in combination with Ra-223 in mCRPC has been utilized, yet its benefit has not been well elucidated. We investigated the potential survival benefit of concomitant enzalutamide with Ra-223 in the third-line setting and predictors of improved overall survival (OS).Patients and MethodsWe retrospectively identified 51 patients with bone-dominant mCRPC that were treated with Ra-223 in the postchemotherapy and post–hormone therapy setting, either alone (group A; n = 32) or with concomitant enzalutamide (group B; n = 19). The primary endpoint was to study the OS difference between groups A and B. The secondary endpoint was to identify predictors of improved OS with Ra-223 in the third-line setting.ResultsMean age was 70.9 years, median baseline prostatic-specific antigen (PSA) was 23.1 ng/mL, alkaline phosphatase was 91 IU/L, and hemoglobin was 12.5 g/dL. There was no difference in median OS between groups A and B, at 20.4 versus 17.5 months, respectively (P = .5186). In univariate and multivariate analyses, only pre–Ra-223 PSA < 30 ng/mL and Eastern Cooperative Oncology Group performance status < 2 were associated with improved OS.ConclusionIn our study cohort, concomitant use of enzalutamide with Ra-223 in the mCRPC setting was not associated with improved OS. Only pretreatment PSA < 30 ng/mL and pretreatment Eastern Cooperative Oncology Group performance status < 2 were associated with improved OS. Further prospective studies are warranted.     

Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TROPIC phase III trial

BackgroundCabazitaxel significantly improves overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel, but is associated with a higher rate of grade ≥3 neutropenia compared with docetaxel. We thus examined the relationship between cabazitaxel-induced grade ≥3 neutropenia, baseline neutrophil-lymphocyte ratio (NLR) and treatment outcomes.MethodsData from the experimental arm of the TROPIC phase 3 trial which randomly assigned men with mCRPC to cabazitaxel or mitoxantrone every 3 weeks, both combined with daily prednisone, were analysed. The influence on OS (primary end-point) and progression-free survival (PFS) of at least one episode of grade ≥3 neutropenia during cabazitaxel therapy was investigated using Cox regression models, adjusted for pain at baseline. The relationships with prostate-specific antigen (PSA) responses during cabazitaxel therapy and baseline NLR were also analysed.FindingsThe occurrence of grade ≥3 neutropenia during cabazitaxel therapy was associated with a prolonged OS (median 16.3 versus 14.0 months, hazard ratio (HR) [95% confidence interval] = 0.65 [0.43–0.97], p = 0.035), a twice longer PFS (median 5.3 versus 2.6 months, HR = 0.56 [0.40–0.79], p = 0.001) and a higher confirmed PSA response ≥50% (49.8% versus 24.4%, p = 0.005), as compared with patients who did not develop grade ≥3 neutropenia. Grade ≥3 neutropenia was more common in case of NLR <3 as compared with NLR ≥3 at baseline (88.8% versus 75.3%, p = 0.002). Combining low NLR at baseline and grade ≥3 neutropenia during therapy was associated with the longest OS (median 19.2 months) while high NLR at baseline and no grade ≥3 neutropenia was associated with a poor OS (median 12.9 months, HR 0.46 [0.28–0.76], p = 0.002). In the subgroup of neutropenic patients the median OS was 19.7 months in those treated with granulocyte colony-stimulating factor (G-CSF) and 16 months on those without G-CSF support.InterpretationThis post-hoc analysis of TROPIC suggests that the occurrence of grade ≥3 neutropenia with cabazitaxel is associated with improved OS and PFS. Patients with a low NLR at baseline were more likely to develop grade ≥3 neutropenia during cabazitaxel therapy and showed the longest OS. High NLR at baseline and no grade ≥3 neutropenia during therapy was associated with poor outcomes which may suggest insufficient drug exposure or a limited impact on the tumour-associated immune response. Primary or secondary prophylactic use of G-CSF had no adverse impact for outcome. If prospectively confirmed, these results would justify maintaining the intended cabazitaxel dose of 25 mg/m² whenever possible.     

Response to Subsequent Docetaxel in a Patient Cohort With Metastatic Castration-Resistant Prostate Cancer After Abiraterone Acetate Treatment

Introduction/BackgroundDocetaxel or AA are therapeutic options for mCRPC. We retrospectively analyzed clinical outcomes with subsequent docetaxel in patients with mCRPC after disease progression (DP) with AA to evaluate cross resistance between these therapies.Patients and MethodsPatients with chemotherapy-naive mCRPC who were treated with AA in previously reported phase I to III trials, who had DP, and were subsequently treated (not on study) with docetaxel, were included. Acquired AA resistance was defined as: PSA decline > 50% from baseline or radiographically stable disease for ≥ 8 months, with subsequent DP. All other patients were defined as having primary AA resistance. Efficacy outcomes after docetaxel therapy were analyzed.ResultsWe identified 23 patients who were treated with docetaxel after DP with AA, including 14 (61%) with acquired and 9 (39%) with primary AA resistance. Median duration between discontinuation of AA and docetaxel initiation was 2.7 months (range, 0.2-14.7 months). Subsequent docetaxel therapy led to ≥ 30% PSA decline in 15 patients (65%) and ≥ 50% PSA decline in 11 patients (48%). Median OS from date of first docetaxel dose was 12.4 months (95% confidence interval, 8.2-19.6). Patients with previous primary versus acquired AA resistance had similar outcomes with subsequent docetaxel therapy.ConclusionIn this retrospective analysis, the type of AA resistance did not appear to affect outcomes with subsequent docetaxel. The PSA response rates observed suggest a lack of cross-resistance between docetaxel and AA, but prospective studies are needed to evaluate for potential cross-resistance and optimize sequences of therapy in patients with mCRPC.     

Real-World Cabazitaxel Use and Outcomes in Metastatic Castrate-Resistant Prostate Cancer: The Impact of Response to First ARPI

BackgroundFor post-docetaxel treatment of metastatic castrate-resistant prostate cancer (mCRPC), cabazitaxel has demonstrated superior third line PFS and OS compared to androgen receptor pathway inhibitors (ARPIs) in patients who progress within 12 months on first ARPI. The impact of first ARPI response, in particular responses beyond 12 months, on cabazitaxel outcomes in real-world populations is uncertain, as are other factors impacting cabazitaxel use.Materials and MethodsmCRPC patients in Alberta, Canada who received docetaxel from October 1, 2012 to December 31, 2017 were included. We reviewed mCRPC therapies, correlating cabazitaxel use with patient characteristics and TROPIC trial inclusion/exclusion criteria. OS and PFS were evaluated in patients who received cabazitaxel, stratified by time to progression on first ARPI ≤ 12 months (poor ARPI responders, PAR) or >12 months (strong ARPI responders, SAR), using the Kaplan-Meier method.ResultsPAR patients had inferior OS compared to SAR patients (12.3 vs. 24.8 months, P < .001). OS was longer in PAR patients receiving cabazitaxel compared to those not treated with cabazitaxel (16.9 vs. 10.3 months, P = .015), but this benefit was not seen in the SAR group (17.1 vs. 32 months, P = .084). Cabazitaxel use was associated with reduced PFS first line post-docetaxel in SAR (3.5 vs. 14.7 months, P < .001) but not PAR patients.Of 592 patients, 170 (29%) received cabazitaxel post-docetaxel, compared to 280 (47%) and 250 (42%) for abiraterone and enzalutamide. 238 patients (40%) did not have a discussion of cabazitaxel documented. Cabazitaxel use was increased in patients who fit TROPIC trial criteria (P < .001).ConclusionsIn a real-world mCRPC cohort, cabazitaxel use was associated with longer OS among PAR patients, but crucially not among strong ARPI responders. Cabazitaxel was used less frequently and later than ARPIs post-docetaxel. These data help support first ARPI progression time as a consideration in treatment sequencing.     

Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer

BackgroundAT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC.Patients and methodsMen with progressive mCRPC despite androgen deprivation were eligible and randomized 1 : 1. Patients received docetaxel (75 mg/m² day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1–3. The primary end point was overall survival (OS).ResultsTwo hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel–prednisone (ADP) and placebo–DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72–1.55, P = 0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo–DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n = 34), outcomes appeared to favor ADP (median OS 19 versus 14 months).ConclusionsAT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.     

The Effect of Treatment Sequence on Overall Survival for Men With Metastatic Castration-resistant Prostate Cancer: A Multicenter Retrospective Study

IntroductionWe 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.Patients and MethodsWe retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive 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.ResultsThe 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, and 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 = .530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR, 0.82; P = .650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR, 1.58; P = .384).ConclusionThe 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.     

Clinical and Patient-Reported Outcomes of Advanced Urothelial Carcinoma Following Discontinuation of PD-1/L1 Inhibitor Therapy

IntroductionThe patterns of care and attrition of locally advanced or metastatic urothelial carcinoma (la/mUC) patients eligible for systemic therapy following PD-1/L1 inhibitors are unclear. The objective of this study was to evaluate the clinical characteristics and treatment patterns among patients with la/mUC following discontinuation of first-line (1L) or second-line (2L) PD-1/L1 inhibitor therapy.MethodsAn ambispective, multisite, chart review study was conducted in the United States, including patients with la/mUC. Eligible patients had initiated and subsequently discontinued PD-1/L1 therapy in the 1L or 2L setting for la/mUC between May 2016 and July 2018; with follow-up through October 2019. Patient characteristics, treatments, and overall survival (OS) were described. Patients had the option to complete a 1-time patient reported outcomes (PRO) survey.ResultsAmong 300 patients included in the chart review, 198 (66%) received 1L PD-1/L1 inhibitor and 102 (34%) received 2L PD-1/L1 inhibitor. Following discontinuation of PD-1/L1 inhibitor therapy, 34% (n = 68) received subsequent therapy in 2L and 29% (n = 30) in third-line (3L). The median OS post-1L PD-1/L1 inhibitor was 9.4 (95% CI 8.6-NA) and 2.5 months (95% CI 2.24-3.50) for those who received and did not receive subsequent therapy, respectively. Following 2L PD-1/L1 inhibitor discontinuation, the median OS was 5.7 (95% CI 5.1-7.8) and 3.98 (95% CI 3.29-4.87) months for those who received and did not receive subsequent therapy, respectively. Among those with PRO data, 64% reported experiencing cancer-related pain and 29.6% received an opioid. Only 12.7% reported having a caregiver, requiring approximately 13 h/d of service.ConclusionThe symptom and caregiver burden are high among real-world patients with la/mUC who discontinued 1L or 2L PD-1/L1 inhibitors and outcomes are dismal, with a minority receiving subsequent therapy. Patterns of care in the setting of 1L maintenance avelumab and novel agents require further investigation.     

The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival

Aims of the studyThere are no known predictive factors of response in men receiving chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). We investigated pre-treatment factors that predicted a ?30% PSA decline (30% PSAD) within 3 months of starting chemotherapy, and assessed performance of a risk group classification in predicting PSA declines and overall survival (OS) in men with mCRPC.MethodsIn TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline within 3 months. Predictive factors for a 30% PSAD were identified using multivariable regression in D-treated men (n = 656) and validated in M-treated men (n = 333).ResultsFour independent risk factors predicted 30% PSAD: pain, visceral metastases, anaemia and bone scan progression. Risk groups (good: 0–1 factors, intermediate: 2 factors and poor: 3–4 factors) were developed with median OS of 25.7, 18.7 and 12.8 months (p < 0.0001); 30% PSAD in 78%, 66% and 58% of men (p < 0.001); and measurable disease response in 19%, 9% and 5% of men (p = 0.018), respectively. In the validation cohort, similar predictive ability was noted for 30% PSAD, tumour response and OS. PCWG2 subtypes were also predictive but resulted in unequal grouping. C-indices were 0.59 and 0.62 for 30% PSAD and OS in the validation dataset, respectively.ConclusionsRisk groups have been identified and validated that predict PSAD and OS in men with mCRPC and may facilitate evaluation of new systemic regimens warranting definitive testing in comparison with docetaxel and prednisone. Prospective validation of this classification system is needed.     

Impact of Novel Hormonal Agents (Abiraterone,Enzalutamide) on the Development of Visceral and/or Brain Metastases in Patients With Bone-metastatic Castration-resistant Prostate Cancer

IntroductionThe overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients has improved since 2011 with the use of novel hormonal agents (NHAs). The incidence of brain metastases (mets) has been reported to increase since 2004 with the use of docetaxel, but not the incidence of visceral mets. Our objective was to study whether the use of NHAs increases the risk of developing visceral or brain mets (VBMs).Patients and MethodsmCRPC patients with mets limited to bone (bmCRPC), treated at Tours University Hospital between 2007 and 2015, were included retrospectively. The primary endpoint was to determine whether treatment with NHAs was associated with an increased incidence of VBMs. Secondary endpoints included the search for putative predictive factors to develop VBMs.ResultsOn 187 bmCRPC patients included, 65 developed VBMs. VBM incidence increased in bmCRPC patients alive after 2011, compared to patients who died before (39.7 vs. 24.6%, P = .04). Meanwhile, their median OS increased from 16.3 months to 28.5 months (P = .01). The longer was the treatment with NHAs, the lower was the risk of VBMs (HR = 0.96, 95% CI [0.94; 0.99]), whereas age < 70 years (HR = 3.33, 95% CI [1.50; 7.40]) and low PSA level at diagnosis (HR = 1.58, 95% CI [1.16; 2.15]) increased this risk.ConclusionThough retrospective, our results showed an increased incidence of VBMs in bmCRPC patients after 2011. However, this was not associated with NHA exposure duration. The role of NHA exposure remains unclear and needs further investigation.     

Glasgow Prognostic Score As a Prognostic Factor in Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel-Based Chemotherapy

BackgroundThe modified Glasgow Prognostic Score (mGPS), derived from C-reactive protein (CRP) and albumin levels, and the neutrophil-lymphocyte ratio (NLR) have demonstrated prognostic significance in a number of malignancies.Patients and MethodsBaseline mGPS and NLR were calculated in a prospective cohort of chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) (AT-101-CS-205 trial) who received docetaxel and prednisone ± AT101. Cox proportional hazards regression models estimated their effects on overall survival (OS).ResultsOf 220 eligible patients, mGPS and neutrophil and lymphocyte counts were available for 184, 193, and 112 patients, respectively. Albumin (hazard ratio [HR], 0.28; 95% confidence interval [CI]: 0.14-0.56; P < .001) and CRP (HR, 1.22; 95% CI, 1.00-1.48; P = .048) were independently prognostic for OS. An association between mGPS and OS was found (HR, 1.87; 95% CI, 1.35-2.59; P < .001; median survival, 23.5 months at mGPS 0 vs. 9.8 months at mGPS 2). mGPS was significant after controlling for 3 previously published nomograms or NLR (P ≤ .001). NLR was not prognostic for OS (HR, 0.98; P = .91), and no association between mGPS and toxicity was noted.ConclusionOur results demonstrate the prognostic role of the mGPS in mCRPC over variables previously identified. mGPS is inexpensive, easily measured, and could be incorporated into routine clinical testing if our results are confirmed in a subsequent validation study. The utility of the NLR in mCRPC remains uncertain despite evidence in other malignancies.     

Safety and Efficacy of Maintenance Therapy With a Nonspecific Cytochrome P17 Inhibitor (CYP17i) After Response/Stabilization to Docetaxel in Metastatic Castration-Resistant Prostate Cancer

BackgroundFrontline treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6 to 8 months. Ketoconazole, a nonspecific cytochrome P17 inhibitor (CYP17i), blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg three times daily [t.d.s]) has shown activity in mCRPC after progression to androgen deprivation. The role of a CYP17i after docetaxel treatment in the maintenance setting has been unexplored.MethodsWe identified 38 patients with mCRPC who showed progression to luteinizing hormone releasing–hormone agonists (LHRHa) and who were treated with a median of 7 cycles of frontline three-weekly docetaxel (75 mg/m²) plus prednisone (10 mg/d) and LHRHa. Medical charts of 20 patients who showed no progression to docetaxel were reviewed. After the last docetaxel cycle, 10 patients received LDK maintenance treatment plus prednisone (10 mg/d) and LHRHa, whereas 10 patients received LHRHa alone. TTP was the primary endpoint.ResultsAfter a follow-up of 27 months, disease in all patients receiving LHRHa alone progressed, whereas 8/10 patients progressed to maintenance therapy. Median TTP from docetaxel initiation was 11.5 months (95% confidence interval [CI], 6.3-16.6) for maintenance therapy and 9.2 months (95% CI, 8.5-9.9) for LHRHa alone (P = .047). The maintenance treatment was well tolerated. Only 1 patient experienced a grade 4 adverse event due to a nonsymptomatic pulmonary embolism.ConclusionThis is the first study evaluating a CYP17i for maintenance therapy after docetaxel therapy. We showed a 2-month significant benefit in TTP for patients with mCRPC treated with LDK maintenance therapy after docetaxel, with a favorable toxicity profile. A large prospective randomized study using a CYP17i is warranted.     

No significant impact of prior treatment profile with docetaxel on the efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer

The objective of this study was to retrospectively analyze the oncological outcomes of Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) who received cabazitaxel. This study included a total of 63 consecutive Japanese mCRPC patients treated with cabazitaxel following the failure of docetaxel, and assessed the prognostic significance of cabazitaxel therapy in these patients focusing on the association of efficacies between two taxane agents. After treatment with cabazitaxel (median 5 cycles), prostate-specific antigen (PSA) decline was observed in 39 patients (61.9%), including 13 (27.0%) achieving the response defined by PSA decline ≥50%. The median progression-free survival (PFS) and overall survival (OS) periods after the introduction of cabazitaxel were 4.1 and 14.8 months, respectively. The response rate to cabazitaxel was not significantly different between responders and non-responders to prior docetaxel, and there was no significant correlation between the PFSs with docetaxel and cabazitaxel. Furthermore, univariate analyses of several parameters identified the performance status (PS) and clinical symptoms, but not the cycles of docetaxel therapy, total amount of administered docetaxel or objective response to docetaxel therapy, as significant predictors of OS on cabazitaxel therapy, of which only PS was independently associated with OS on multivariate analysis. These findings suggest that oncological outcomes in Japanese mCRPC patients receiving cabazitaxel are generally satisfactory, irrespective of the profiles related to prior treatment with docetaxel, and that it might be preferable to introduce cabazitaxel to mCRPC patients with a good PS to maximize the prognostic benefit of this agent.     

Survival Outcomes From a Cumulative Analysis of Worldwide Observational Studies on Sequential Use of New Agents in Metastatic Castration-Resistant Prostate Cancer

IntroductionThe sequential use of a number of new agents (NAs) have improved the overall survival (OS) of patients with metastatic castration-resistant prostate cancer whose disease progresses after docetaxel (DOC) treatment. The aim of this study was to assess the cumulative survival outcomes of different sequencing strategies by evaluating the individual data from published studies of patients treated with a post-DOC treatment sequence of 2 NAs.Patients and MethodsThe patients’ individual data were analyzed to investigate whether different sequencing strategies lead to differences in OS.ResultsWe analyzed the data of 1099 evaluable patients. Among the patients treated with a second-line new hormone agent (NHA), median OS from the start of third-line treatment was significantly longer in the patients treated with cabazitaxel (CABA) than in those treated with abiraterone acetate or enzalutamide. Median cumulative OS (cumOS) from the start of second-line treatment was 21.1 months in the patients who received NHA then NHA, 22.1 months in those who received NHA then CABA, and 21.0 months in those who received CABA then NHA. Among the patients with a second-line progression-free survival of ≥6 months, median cumOS was significantly longer in patients who received CABA-including sequences than in those treated with NHA then NHA sequences (29.5 vs. 24.8 months; P = .03).ConclusionOur findings suggest that the sequential use of NAs with different mechanisms of action improves cumOS regardless of the order in which they are administered, thus supporting the hypothesis of cross-resistance between the 2 NHAs.     

Second-Line Cabazitaxel Treatment in Castration-Resistant Prostate Cancer Clinical Trials Compared to Standard of Care in CAPRI: Observational Study in the Netherlands

BackgroundCabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC).Patients and MethodsmCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response.ResultsFrom 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (≥ 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P = .067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS.ConclusionPatients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes.     

Radium-223 (Xofigo) with concurrent abiraterone or enzalutamide: predictive biomarkers of improved overall survival in a clinically advanced cohort

PurposeRadium-223 (Xofigo) is the first therapy with bone tropism for metastatic castrate-resistant prostate cancer (mCRPC) that has been shown to improve overall survival (OS). Although radium-223 has a positive effect on OS in men with mCRPC, there has been a paucity of reports from community practitioners, especially with regard to concurrent abiraterone and enzalutamide therapy. Significant differences in patient characteristics encountered may exist.Patients and methodsWe conducted a retrospective study of men with mCRPC who received at least 1 cycle of radium-223 (n = 35). Baseline pain and ECOG PS as well as concurrent usage of abiraterone or enzalutamide were recorded. Side effect profiles for each patient throughout treatment were noted.ResultsBaseline cohort characteristics include a median age of 75 years. 37% had an ECOG PS ≥ 2 and 23% reported severe pain at baseline. 31% received concomitant enzalutamide 31% concomitant abiraterone. Patients treated concurrently with either abiraterone or enzalutamide did not display additional toxicity. Median cohort OS was 10 months. Patients with no or mild pain had longer median OS than those with moderate or severe pain, 14 versus 7 months (P = 0.028). Patients with ECOG PS < 2 had longer median OS than those with ECOG PS ≥ 2, 13 versus 10 months (P = 0.0233).ConclusionThis study highlights key differences in patient characteristics encountered by community practitioners. In this population, which presented with clinically advanced disease, there was an improved survival benefit for those treated earlier in their disease. Radium-223 was well tolerated and concurrent treatment with abiraterone or enzalutamide did not add additional toxicity. These 2 points seem to advocate for aggressive and early treatment of patients with radium-223 in the community.     

Analysis of the Prognostic Significance of Circulating Tumor DNA in Metastatic Castrate Resistant Prostate Cancer

BackgroundThere has been considerable interest in ctDNA next generation sequencing platforms to assess genomic alterations in mCRPC given its accessibility and identification of temporal genomic data.Patientsand MethodsIn this retrospective analysis, we analyzed 63 patients who underwent ctDNA genomic profiling during their mCRPC disease course using a CLIA-certified commercial assay. The primary objective was to assess the feasibility of commercial ctDNA analysis in a real world mCRPC cohort. Key secondary objectives included assessment of the landscape of pathogenic ctDNA alterations and the prognostic significance of ctDNA detection on overall survival (OS).ResultsAmong the cohort, at the time of ctDNA collection, median age was 70 years, and 47.6% (N = 30/63) had bone-only metastases. ctDNA was detected in the majority of patients with at least 1 pathogenic alteration detected in 90.5% (N = 57/63) of individuals. The most common alterations detected were in AR, TP53, and PIK3CA. Actionable alterations with FDA-approved therapies were found in 15.8% (N = 10) of the cohort. The presence of ≤ 1 versus > 1 alteration on ctDNA analysis was strongly associated with inferior OS with a median OS of 26.1 versus 8.8 months, respectively (HR = 7.0, 95% CI, 2.2-23.1, P < .001). In multivariate analysis, the number of detected alterations remained a significant predictor for OS. Lastly, there was weak correlation between Prostate-Specific Antigen (PSA), and ctDNA characteristics.ConclusionctDNA is a viable next generation sequencing (NGS) platform in mCRPC and can be utilized to identify actionable alterations. The presence and extent of ctDNA alterations appear to be prognostic of OS in mCRPC.     

Safety and Feasibility of Radiation Therapy to the Primary Tumor in Patients With Metastatic Castration-resistant Prostate Cancer

IntroductionThe objective of this study was to evaluate the safety and feasibility of radiation therapy (RT) to the primary tumor in patients with metastatic castration-resistant prostate cancer (mCRPC).Patients and MethodsThis retrospective study included 105 patients with mCRPC who were treated between April 2004 and May 2019. We divided the patients into 2 groups: patients treated with RT to the primary tumor after they developed CRPC (RT group) and without (non-RT group). The primary purpose was safety assessed using the Common Terminology Criteria for Adverse Events. The secondary purpose included prostate-specific antigen (PSA) response, cancer-specific survival (CSS), and overall survival (OS). Background-adjusted multivariate analyses, with the inverse probability of treatment weighting (IPTW) method, were performed to evaluate impact of RT on CSS and OS.ResultsThe median age at CRPC diagnosis was 75 years, and the median follow-up period after CRPC diagnosis was 21 months. The adverse events rates related to RT in any grade and grade ≥ 3 were 55% and 23%, respectively. Nine (29%) patients achieved ≥ 30% PSA decline with RT. In multivariate analyses with the IPTW method, the CSS and OS in the RT group were significantly longer than those in the non-RT group. In subgroup analyses with the IPTW method, RT was significantly associated with improved OS in patients aged ≥ 75 years and patients with initial PSA ≥ 500 ng/mL, cT4, Gleason score ≥ 8, and high-volume metastatic burden.ConclusionsRT to the primary tumor is safe and feasible, and it has potential benefits on oncologic outcomes in patients with mCRPC.     

多西他赛再挑战治疗转移性去势抵抗性前列腺癌的疗效及预后因素

目的 评价多西他赛再挑战治疗一线多西他赛治疗有效的转移性去势抵抗性前列腺癌（mCRPC）患者的疗效，并分析预后因素。方法 回顾性分析120例mCRPC患者的临床资料，观察终点为第一序列多西他赛化疗后前列腺特异性抗原无疾病进展生存期（PSA PFS）和多西他赛再挑战后前列腺特异性抗原无疾病进展生存期（Rechallenge PSA PFS）以及mCRPC患者总生存期（OS）。采用Cox单因素和多因素回归模型对患者PSA PFS、Rechallenge PSA PFS和OS相关的预后因素进行分析。结果 中位随访时间32.73（13.27~98.56）月，30例（25%）患者仍存活。中位PSA PFS 13.89（7.67~39.00）月，中位Rechallenge PSA PFS 5.29（1.25~20.00）月，中位OS 27.13（12.40~60.50）月。多因素回归分析显示：第一序列多西他赛化疗与多西他赛再挑战之间的治疗间歇期（>6月vs.≤6月）与患者的PSA PFS显著相关，对多西他赛再挑战治疗反应性（获得部分反应vs.未获得部分反应）与Rechallenge PSA PFS显著相关，mCRPC患者就诊时基础血清PSA值及对多西他赛再挑战治疗反应性（获得部分反应vs.未获得部分反应）与OS显著相关。结论 多西他赛在一线使用多西他赛有效的mCRPC患者中再次使用疗效尚可，可作为此类患者后期治疗的一种选择。     

Patient characteristics and overall survival in patients with post-docetaxel metastatic castration-resistant prostate cancer in the community setting

It is unclear how treatment sequencing for metastatic castration-resistant prostate cancer (mCRPC) affects real-world patient outcomes. We assessed treatment sequences, patient characteristics and overall survival (OS) in post-docetaxel mCRPC patients. mCRPC patients receiving second-line cabazitaxel or androgen receptor-targeted therapy (ART; abiraterone/enzalutamide) post-docetaxel were identified using electronic medical records. OS was assessed from second-line therapy initiation using Cox regressions adjusting for: metastases; prostate-specific antigen (PSA); hemoglobin; alkaline phosphatase (ALP); albumin; second-line therapy initiation year. Following docetaxel (n = 629), 123 (19.6%) and 506 (80.4%) patients received cabazitaxel and ART, respectively. One hundred and ninety-five patients received additional treatments thereafter (54 following cabazitaxel; 141 following ART). Although patients receiving second-line cabazitaxel versus ART had similar disease characteristics at first-line therapy initiation, at second-line therapy initiation they had higher mean PSA (386.6 vs. 233.9 ng/mL) and ALP (182.0 vs. 167.3 u/L), lower mean hemoglobin (10.8 vs. 11.5 g/dL), and more frequently had intermediate/high-risk Halabi scores (61.8 vs. 48.4%); all p < 0.05. Overall, crude survival was not significantly different. Among Halabi high-risk patients, adjusted median OS was significantly longer in patients receiving cabazitaxel versus ART (HR 0.48; 95% CI 0.24–0.93; p = 0.030). Low albumin and hemoglobin led to similar findings (HR 0.43; 95% CI 0.23–0.80; p = 0.0077; HR 0.60; 95% CI 0.40–0.90; p = 0.014). Most post-docetaxel patients received second-line ART. Patients receiving second-line cabazitaxel had more high-risk features; however, second-line cabazitaxel administered after docetaxel may improve OS in patients with Halabi high-risk scores or low albumin/hemoglobin.