Long-Term Second Malignancies in Prostate Cancer Patients Treated With Low-Dose-Rate Brachytherapy and Radical Prostatectomy.

PURPOSE: Second malignancy is a rare but potentially lethal event after prostate brachytherapy, but data remain scarce on its long-term risk. The objective of this study is to estimate the number of pelvic second malignancies following brachytherapy compared to radical prostatectomy (RP). MATERIALS AND METHODS: We retrospectively reviewed patients treated with low-dose 125I brachytherapy and RP in British Columbia from 1999 to 2010. Kaplan-Meier estimates for pelvic (bladder and rectum), invasive pelvic, any second malignancy, and death from any second malignancy were assessed. Cox multivariable analyses were performed adjusting for initial treatment type, age, post-RP adjuvant/salvage external beam radiation therapy status, and smoking history. RESULTS: Two thousand three hundred seventy-eight brachytherapy and 9089 RP patients were included. Median age was 66 years (interquartile range [IQR] 61-71) and 63 years (IQR 58-67), respectively. Median follow-up time to event or censured was 14 years (IQR 11.5-17.3). The Kaplan-Meier estimates for pelvic second malignancy at 15 and 20 years were 6.4% and 9.8%, respectively, after brachytherapy, and 3.2% and 4.2% after RP. Time to any second malignancy and time to death from any second malignancy were not significantly different (P > .05). On Cox multivariable analysis, brachytherapy, compared to surgery, was an independent factor for pelvic (hazard ratio [HR] 1.81 [95% CI 1.45-2.26], P < .001) and invasive pelvic second malignancy (HR 2.13 [95% CI 1.61-2.83], P < .001). Increased age and smoking were also associated with higher estimates of events (P < .001). CONCLUSIONS: After adjustment for age, post-RP adjuvant/salvage external beam radiation therapy status, and smoking status, numerically higher long-term HRs of pelvic and invasive pelvic second malignancy in patients treated with brachytherapy compared to RP were noted.

Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial.

BACKGROUND: Abiraterone acetate plus prednisone and enzalutamide are both used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the best sequence in which to use both drugs, as well as their second-line efficacy. METHODS: In this multicentre, randomised, open-label, phase 2, crossover trial done in six cancer centres in British Columbia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group B). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from baseline) on second-line therapy, analysed by intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357. FINDINGS: Between Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group B (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group B had crossed over. Time to second PSA progression was longer in group A than in group B (median 19·3 months [95% CI 16·0-30·5] vs 15·2 months [95% CI 11·9-19·8] months; hazard ratio 0·66, 95% CI 0·45-0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3-33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for abiraterone (χ2 p<0·0001). The most common grade 3-4 adverse events throughout the trial were hypertension (27 [27%] of 101 patients in group A vs 18 [18%] of 101 patients in group B) and fatigue (six [10%] vs four [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in group A and 20 (20%) of 101 patients in group B. There were no treatment-related deaths. INTERPRETATION: Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit. FUNDING: Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Terry Fox New Frontiers Program, BC Cancer Foundation, Jane and Aatos Erkko Foundation, Janssen, and Astellas.

Real-world evaluation of access-driven Canadian treatment sequences in progressive prostate cancer (REACTIVATE).

INTRODUCTION: The results of the phase 3 ALSYMPCA trial showed that Radium-223 (Ra-223) improves overall survival (OS) and delays onset of first symptomatic skeletal event vs. placebo in patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of the REACTIVATE study was to inform the optimal placement of Ra-233 in the treatment sequence by evaluating clinical outcomes and healthcare resource utilization using real-world data from multiple Canadian provinces. METHODS: This retrospective cohort study analyzed patient outcomes according to Ra-223 placement using administrative databases of four Canadian provinces, encompassing 4301 patients with mCRPC who received at least two lines of life-prolonging therapy (LPT) for mCRPC. Outcomes included OS, event-free survival (EFS), and healthcare resource utilization. Each province was analyzed separately. RESULTS: OS, measured from the start of second-line LPT, differed between provinces: those in Ontario receiving second-line Ra-223 had a longer OS vs. those receiving it in third-line or later (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66-0.95). There was no difference between lines of therapy in patients in British Columbia (HR 1.165, 95% CI, 0.894-1.518, p=0.2576), and OS was numerically worse but not statistically significant in patients receiving Ra-223 in second-line in Quebec (HR 1.44, 95% CI, 0.93-2.24). Other outcomes also varied across provinces, with second-line use of Ra-223 being associated with longer EFS and reduced healthcare utilization vs. third-line use in Ontario but not in Quebec. CONCLUSIONS: Significant heterogeneity exists in the management and outcomes of mCRPC between provinces, particularly regarding the placement of Ra-223 in the treatment sequence.

Real-world experience managing unresectable or metastatic small cell carcinoma of the prostate.

INTRODUCTION: Unresectable and metastatic small cell carcinoma of the prostate (SCPC) is a rare and aggressive disease that is under-represented in clinical trials. We carried out a retrospective chart review of metastatic or unresectable SCPC patients at British Columbia (BC) Cancer centers, studying diagnosis and treatment patterns. METHODS: Drug-dispensing records from the six BC Cancer centers were obtained from 2002-2017. For each patient, information was collected on baseline information prior to therapy and for each line of treatment. Treatments at each line were compared regarding time to progression and overall survival by Kaplan-Meier curves. RESULTS: Forty-one patients received treatment; 65.6% had metastatic disease and 61% had pure small cell carcinoma. Median time from treatment to death was 10 months (95% confidence interval [CI] 6-16). Patients with initially prostate-confined disease had a better median overall survival (mOS) of 21 months (95% CI 13-34) compared to those with initially locally advanced (mOS 19 months, 95% CI 5-37) and metastatic disease (mOS 8 months, 95% CI 6-10) (log-rank p=0.0364). All patients received either cisplatin- or carboplatin-based combination chemotherapy as the first-line treatment and 36.7% received second-line therapy. Time to second-line therapy was eight months for those who presented with metastatic SCPC, compared to 13 months for those with initial non-metastatic SCPC. CONCLUSIONS: This single-province, multi-institution cohort reports data on unresectable and metastatic SCPC and highlights the poor prognosis of this rare disease entity.

Small cell carcinoma of the bladder: A population-based analysis of long-term outcomes after radical cystectomy and bladder conservation with chemoradiotherapy.

INTRODUCTION: We aimed to describe the oncological outcomes after radical cystectomy and chemo-radiation for localized small cell bladder cancer (SCBC). METHODS: This population-based analysis of localized SCBC from 1985-2018 in British Columbia included an analysis (analysis 1) of cancer-specific survival (CSS) and overall survival (OS) of patients treated with curative-intent radical cystectomy (RC) and radiation (RT), and an analysis (analysis 2) of CSS and OS in patients treated with RC and chemoRT consistent with the SCBC Canadian consensus guideline. RESULTS: Seventy-seven patients who were treated with curative intent were identified: 33 patients had RC and 44 had RT. For analysis 1, five-year OS was 29% and 39% for RC and RT, respectively (p=0.51), and five-year CSS was 35% and 52% for RC and RT, respectively (p=0.29). On multivariable analysis, higher Charlson comorbidity index (CCI) and the lack of neoadjuvant chemotherapy (NAC) were associated with worse OS, while higher CCI and Eastern Cooperative Oncology Group (ECOG) were associated with worse CSS. For analysis 2, five-year OS was 56% and 58% for the RC and chemoRT groups, respectively (p=0.90), and five-year CSS was 56% for RC and 71% for chemoRT (p=0.71). Four of 42 (9.5%) chemoRT patients had RC at relapse. CONCLUSIONS: SCBC is a rare entity with a poor prognosis. RC and chemoRT offer similar CSS and OS for localized SCBC, even when focusing the analysis on patients treated according to the modern consensus guidelines. NAC should be considered for eligible patients. Both chemoRT and RC treatment options should be discussed with patients with SCBC.

Effectiveness of first-line abiraterone versus enzalutamide among patients ≥80 years of age with metastatic castration-resistant prostate cancer: A retrospective propensity score-weighted comparative cohort study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects the elderly. There is limited data assessing the efficacy and tolerability of abiraterone acetate (AA) versus enzalutamide in this population. OBJECTIVE: To compare the clinical efficacy and tolerability of AA versus enzalutamide in patients ≥ 80 years with mCRPC. DESIGN, SETTING AND PARTICIPANTS: A retrospective propensity-weighted comparative cohort study of first-line AA versus enzalutamide among patients with mCRPC aged ≥80 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Inverse probability treatment weights based on propensity scores were generated to assess the treatment effect of AA versus enzalutamide on time to PSA progression (TTPP), time to progression (TTP) (first of PSA/radiographic/clinical progression) and overall survival using a weighted Cox proportional hazards model. PSA response rate (PSA RR) was compared between groups using Χ2. RESULTS AND LIMITATIONS: One hundred fifty-three patients received AA, and 125 received enzalutamide. Enzalutamide was associated with higher PSA RR (61.6% vs 43.8%, P < 0.004), and TTP (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50-0.88, P = 0.01) but not TTPP (HR 0.73, 95% CI 0.53-1.01, P = 0.06). There were significantly more dose reductions with enzalutamide (22.9% vs 44.8%, P > 0.001) but there was no interaction between median proportion of full dose received and TTPP or TTP for either drug. Rates of treatment discontinuation (for reasons other than progression) were also significantly different between AA and enzalutamide (28.8% vs 40.8%, respectively, P = 0.04). The most common reason for dose reductions and discontinuation of enzalutamide was fatigue (30.4% and 5.6%, respectively). CONCLUSIONS: Despite more dose reductions and a higher treatment discontinuation rate, enzalutamide was associated with a higher PSA RR and longer time to progression, than AA. Given that clinical outcomes were not adversely impacted by decreased treatment exposure, dose modification may be a useful treatment strategy to balance toxicity and tolerance.

A Population-Based Study of Palliative Radiation Therapy for Bone Metastases in Patients Dying of Prostate Cancer.

PURPOSE: Increasing the survival of patients with metastatic prostate cancer (PCa) may affect the demand for palliative radiation to bone (PRTB). Our aim was to characterize the use of PRTB in patients who died of PCa in British Columbia between 2003 and 2015. METHODS AND MATERIALS: All patients with a diagnosis of PCa who died during the study period (n = 23,260) were identified from a population-based provincial registry. Patient and treatment characteristics were analyzed. PRTB utilization rate was calculated by year and location. Survival was calculated from the first and the last course of PRTB. RESULTS: A total of 5701 patients died of PCa, with a median survival from diagnosis of 5.2 years. The overall PRTB utilization rate was 38.6%, with an increasing trend over time. Multiple courses of PRTB were frequent, with 51% of patients receiving ≥2 courses of PRTB. Of the patients who died of PCa (15.2% of the PRTB cohort), 5.4% received PRTB within the last 4 weeks of life, 60% of whom received multiple fractions. Rural areas had a lower referral rate and lower use of PRTB. Patients with longer survival tended to receive multiple courses of treatment. The median survival after the first course of PRTB increased from 8.2 months in 2003 to 2004 to 9.4 months in 2013 to 2014 (P = .04). CONCLUSIONS: PRTB is only used in a minority of patients dying of PCa. The majority who die of PCa after PRTB do so within a year of their first course. The use of multifractionation was common in the last 4 weeks of life. Survival after first PRTB increased minimally over time, and additional research is required to identify its association with recent changes in practice. The referral rate and PRTB utilization rate differ between rural and nonrural locations, underlying the importance of accessibility and referral for utilization of PRTB. Investigating other barriers and ensuring equitable access to radiation are needed.

Health-related Quality of Life for Abiraterone Plus Prednisone Versus Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer: Results from a Phase II Randomized Trial.

BACKGROUND: Abiraterone and enzalutamide are associated with side effects that may impair health-related quality of life (HRQoL). OBJECTIVE: To assess patient-reported HRQoL, depression symptoms, and cognitive function for abiraterone versus enzalutamide. DESIGN, SETTING, AND PARTICIPANTS: We randomized 202 patients in a phase II study of abiraterone versus enzalutamide for first-line treatment of metastatic castration-resistant prostate cancer (ClinicalTrials.gov: NCT02125357). INTERVENTION: Patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Patient Health Questionnaire-9 (PHQ-9) questionnaires, and Montreal Cognitive Assessment (MoCA) cognitive assessments at baseline and on treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To compare the change in FACT-P scores over time between treatment arms, we used a mixed model for repeated measures (MMRM). For FACT-P domains where there was an interaction between the treatment arm and age, we constructed separate models for patients aged <75 and ≥75yr. We compared the proportion of patients with clinically meaningful change from baseline for FACT-P, and the proportion of patients with an abnormal score and median change from baseline for PHQ-9 and MoCA using Fisher's exact test and Mann-Whitney U test. RESULTS AND LIMITATIONS: In the MMRM analysis, there was a positive test for interaction in the treatment arm by age for total FACT-P (p=0.048). FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the ≥75-yr model (p=0.003), with no difference in the <75-yr model (p>0.9). A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p=0.013; 39% vs 23%, p=0.015). The distribution of change in PHQ-9 scores from baseline favored abiraterone at weeks 4, 8, and 12. These analyses were not prespecified, and results should be considered to be hypothesis generating. CONCLUSIONS: Patient-reported outcomes favored abiraterone compared with enzalutamide with differences in FACT-P HRQoL and PHQ-9 depression scores. Differences in the total FACT-P scores were seen only in the elderly patient subgroup. PATIENT SUMMARY: In this report, we examined the change in patient-reported quality-of-life scores from the start of treatment over time for patients treated with abiraterone versus enzalutamide for metastatic castration-resistant prostate cancer. We found that elderly patients treated with abiraterone had better quality of life over time, with no difference between treatments for the younger subgroup of patients.

Pain response in a population-based study of radium-223 (Ra223) for metastatic castration-resistant prostate cancer.

INTRODUCTION: Clinical trials have shown that radium-223 (Ra223) can prolong survival and improve quality of life in patients with metastatic castration-resistant prostate cancer (mCRPC). The objectives of this study were to evaluate pain responses with Ra223 at a population-based level and to determine if there is an association between pain response and alkaline phosphatase (ALP) response. METHODS: All patients from the Vancouver and Kelowna Cancer Centers (CC) in British Columbia who were treated with Ra223 between June 2015 and December 2016 were identified. Patients completed the Brief Pain Inventory (BPI) just prior to each Ra223 injection. Pain response was defined as a two or more point improvement in worst pain relative to baseline, without an increase in pain medication level. ALP was determined at each visit, with a response threshold defined as a 30% decrease from baseline, consistent with the definition of response used in the ALSYMPCA trial. RESULTS: A total of 65 patients in Vancouver and Kelowna CC received Ra223 during the study period and 56 patients had at least one BPI record, of which 44 (79%) patients were assessable for change in worst pain. Of the assessable patients, 23 (52%, 95% confidence interval [CI] 38-67) had a pain response, although the use of concurrent external beam radiotherapy was a confounder in four cases. Of the 44 patients assessable for change in worst pain, 59% had ALP responses greater than 30%. An ALP response was seen in 56% of pain-responders vs. 43% of non-pain-responders. There was no association between pain response and ALP response (Phi =-0.05; p=0.77). CONCLUSIONS: Ra223 administration was associated with a meaningful pain response rate in this cohort. There was no correlation between pain response and ALP response.

A prognostic model for stratifying clinical outcomes in chemotherapy-naive metastatic castration-resistant prostate cancer patients treated with abiraterone acetate.

INTRODUCTION: Recently, a prognostic index including six risk factors (RFs) (unfavourable Eastern Cooperative Oncology Group performance status [ECOG PS], presence of liver metastases, short response to luteinizing hormone-releasing hormone [LHRH] agonists/antagonists, low albumin, increased alkaline phosphatase [ALP] and lactate dehydrogenase [LDH]) was developed from the COU-AA-301 trial in post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate. Our primary objective was to evaluate this model in a cohort of chemotherapy-naive mCRPC patients receiving abiraterone. METHODS: We identified 197 chemotherapy-naive patients who received abiraterone at six BC Cancer Agency centres and who had complete information on all six RFs. Study endpoints were prostate-specific antigen (PSA) response rate (RR), time to PSA progression, time on treatment, and overall survival (OS). PSA RR and survival outcomes were compared using Χ2 test and log-rank test. Multivariable Cox proportional hazard analysis was performed to identify RFs independently associated with OS. RESULTS: Patients were classified into good (0-1 RFs), intermediate (2-3 RFs), and poor (4-6 RFs) prognostic groups (33%, 52%, and 15%, respectively). For good-, intermediate-, and poor-risk patients, PSA RR (≥50% decline) was 60% vs. 42% vs. 40% (p=0.05); median time to PSA progression was 7.3 vs. 5.3 vs. 5.0 months (p=0.02); and median OS was 29.4 vs. 13.8 vs. 8.7 months (p<0.0001). CONCLUSIONS: The six-factor prognostic index model stratifies clinical outcomes in chemotherapy-naive mCRPC patients treated with abiraterone. Identifying patients at risk of poor outcome is important for informing clinical practice and clinical trial design.

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer.

Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444-57. ©2018 AACR.See related commentary by Jayaram et al., p. 392This article is highlighted in the In This Issue feature, p. 371.

A population-based study of the use of radium 223 in metastatic castration-resistant prostate cancer: Factors associated with treatment completion.

INTRODUCTION: Radium 223 (Ra223) given for six cycles has proven efficacy in clinical trials, but its population-level generalizability has not been well-described. The objectives of this study were to describe population-based Ra223 use in the abiraterone and enzalutamide era and identify factors associated with completion. METHODS: All Ra223 patients at the British Columbia Cancer Agency between September 2013 and February 2016 were identified. Patients who completed <5 vs. ≥5 cycles were compared on patient characteristics, lines of prior therapy, prostate-specific antigen (PSA) and alkaline phosphatase (ALP) decline >30% from baseline (R30%), and survival, to identify factors associated with therapy completion. RESULTS: Ninety-one patients were identified; 48 (52.7%) completed >5 cycles. Median overall survival (mOS) was 10.7 months, PSA and ALP R30% were 21% and 52%, respectively. Completion of <5 cycles was associated with higher baseline ALP (p=0.05) and lower baseline hemoglobin (Hb) levels (p=0.03). Patients in the ≥5 cycles group had longer mOS than those in the <5 cycles group (16.2 vs. 5.9 months; p<0.0001), as well as higher PSA R30% (33.3% vs. 7.0%; p=0.002) and ALP R30% (66.7% vs. 34.9%; p=0.03). Patients with ALP ≥220 and Hb ≤118 had 3.85 times the odds of not completing ≥5 cycles vs. ALP <220 and Hb >118. CONCLUSIONS: Compared to clinical trials, patients in a population-based setting had more lines of therapy and shorter survival. Lower ALP and higher hemoglobin were associated with completion of >5 cycles, longer mOS, and greater incidence of PSA and ALP response.