Identification of low prostate-specific antigen, high Gleason prostate cancer as a unique hormone-resistant entity with poor survival: A contemporary analysis of 640,000 patients

5080 Background: The clinical implications of a low prostate-specific antigen (PSA) in high-grade prostate cancer are unclear. We examined the prognostic and predictive value of a low PSA in high-grade prostate cancer. Methods: We identified 642,975 patients in the National Cancer Database (n = 491,505) and Surveillance, Epidemiology, and End Results program (n = 151,470) with localized or locally advanced prostate cancer from 2004-2013. Patients were stratified by Gleason score (8-10 vs. ≤7) and PSA (≤2.5, 2.6-4.0, 4.1-10.0, 10.1-20.0, and > 20.0 ng/mL) for analyses. Multivariable Fine-Gray competing risks and Cox regressions were used to analyze prostate-cancer specific mortality (PCSM) and all-cause mortality (ACM), respectively. Results: 5.6% of Gleason 8-10 tumors were diagnosed with PSA ≤2.5 ng/mL. Among Gleason 8-10 disease using PSA 4.1-10.0 ng/mL as referent, PCSM was U-shaped with respect to PSA, with adjusted hazard ratio (AHR) of 1.75 (95% CI 1.05-2.92, P = 0.032) for PSA ≤2.5 ng/mL vs. 1.31, 0.88, and 1.60 for PSA 2.6-4.0, 10.1-20.0, and > 20.0 ng/mL. In contrast, PCSM was linear for Gleason ≤7 disease with AHR of 0.32 (95% CI 0.10-1.00, P = 0.050) for PSA ≤2.5 ng/mL vs. 1.13, 1.69, and 3.22 for PSA 2.6-4.0, 10.1-20.0, and > 20.0 ng/mL (PGleason*PSA interaction 2.5 ng/mL (AHR 0.87, 95% CI 0.81-0.94, P < 0.001) but trended toward increased ACM for PSA ≤2.5ng/mL (AHR 1.27, 95% CI 0.89-1.81, P = 0.194; PADT*PSA interaction= 0.026). Conclusions: Low PSA, high-grade prostate cancer appears to be a unique hormone-resistant entity with a high risk of PCSM that responds poorly to standard treatment. Further molecular classification and trials are urgently needed to develop biological insight into this entity and establish new treatment paradigms, potentially including chemotherapy or novel systemic agents

Laboratory eligibility criteria as potential barriers to participation by black men in prostate cancer clinical trials

73 Background: Eligibility criteria may disproportionately affect black patients and contribute to their underrepresentation in clinical trials. We studied this potential barrier by examining clinical trials in prostate cancer, a disease in which black men face higher incidence and mortality. Specifically, we investigated the use of serum creatinine (sCr) alone instead of race-adjusted measurements for renal function, and the use of an absolute neutrophil count (ANC) threshold that could exclude men with benign ethnic neutropenia, which afflicts 6.7-8% of black patients and could lead to the exclusion of patients despite having healthy immune systems. Methods: We identified 401 interventional prostate cancer clinical trials with an overall survival endpoint. The list of trials was collected on January 16, 2017 from clinicaltrials.gov using the following criteria – study type: interventional studies; conditions: prostate cancer; interventions: drug; outcome measures: overall survival. Characteristics gathered from each trial included sponsor type, phase, accrual goal, start year, and toxicity. Results: Overall, 47.9% (192) of these trials used either sCr alone and/or required participants to have ANC ≥1.5×109 cells/L. Specifically, 25.2% (101) of the trials used sCr alone to determine eligibility, and 41.4% (166) of the trials required patients to have an ANC ≥1.5×109 cells/L. Conclusions: Of clinical trials in prostate cancer, 47.9% used criteria that disproportionately excluded black patients. The reevaluation of these two eligibility criteria could improve minority trial enrollment. First, lowering the ANC cutoff for patients with benign ethnic neutropenia would increase the number of eligible black participants, as 89% of these patients have an ANC ≥1.0×109 cells/L. Second, using race-adjusted equations for renal function would take into account racial differences in creatinine. While adopting race-based differences in trial criteria may add slight logistical challenges when ensuring patients meet trial eligibility, these adjustments would prevent healthy patients from being excluded solely because of benign laboratory differences caused by their race

External beam radiation therapy and brachytherapy boost versus radical prostatectomy and adjuvant radiation therapy for high-risk prostate cancer

21 Background: Previous studies have suggested that combination external beam radiation therapy (EBRT) with brachytherapy boost (BT) for high-risk prostate cancer is associated with equivalent overall survival (OS) compared with radical prostatectomy (RP). However, it is not known whether RP with post-operative radiation therapy (PORT) can offer improved OS compared with combination RT (EBRT + BT + androgen deprivation therapy [ADT]) for patients with Gleason 9-10 high-risk disease. Methods: We identified all patients diagnosed with clinical T1-T3, Gleason 9-10, prostate-specific antigen (PSA) 0-40 ng/mL, and clinically node negative disease between 2004 and 2014 from the National Cancer Database. We divided patients into 4 treatment groups: EBRT + ADT, combination RT (EBRT + BT + ADT), RP, and RP + PORT. Only patients who received PORT within 360 days of surgery were included within the RP + PORT group. We compared OS utilizing inverse probability of treatment-weighted multivariable Cox proportional hazards regression modeling after accounting for clinical and demographic factors, including Gleason grade (9 versus 10), T-stage (T1, T2, T3), age, Charlson-Deyo comorbidity score (0, 1, versus 2), education quartile, income quartile, geographic location within the US, insurance status, facility volume, and race. Results: Median follow-up in the entire cohort was 4.5 years. The numbers of patients treated with EBRT + ADT, EBRT + BT + ADT, RP, RP + PORT were 6778, 924, 7111, and 1929, respectively. There were no significant differences in 5-year OS when comparing combination RT to RP (85.0% vs 85.7%, adjusted hazard ratio (AHR) 0.92, 95% confidence interval [CI] 0.77-1.10, p = 0.36) or RP + PORT (85.0% vs 85.6%, AHR 0.89, 95% CI 0.71-1.12, p = 0.34). Combination RT was associated with superior 5-year OS compared to EBRT + ADT alone (without BT boost) (85.0% vs 79.4%, AHR 1.26, 95% CI 1.07-1.48, p < 0.01). Conclusions: Our study suggests that for patients with Gleason 9-10 tumors, multi-modality surgical therapy is equivalent to combination RT

Prostate-directed radiation therapy and overall survival for men with M1a prostate cancer

101 Background: A recent randomized controlled trial demonstrated that radiation therapy to the prostate improves overall survival for men with newly diagnosed metastatic prostate cancer with a low metastatic burden. Most patients in this trial had bony metastases (stage M1b). The benefit of prostate-directed radiation therapy for men with metastases limited to non-regional lymph nodes (stage M1a) is unknown. We investigated the association between prostate-directed radiation therapy and overall survival for men with M1a prostate cancer. Methods: We identified 2,079 men from the National Cancer Database who were newly diagnosed with M1a prostate adenocarcinoma from 2004 through 2014 and had data on the use of androgen deprivation therapy, chemotherapy, and radiation therapy. Median follow-up was estimated using the reverse Kaplan-Meier method. The association between radiation therapy to the prostate and overall survival was examined using multivariable Cox proportional hazards regression analysis. Results: Overall, 12.7% (264) of patients received radiation therapy to the prostate. Median follow-up was 4.6 years (95% confidence interval 4.3-4.8 years). On multivariable analysis, when accounting for the use of androgen deprivation therapy and chemotherapy, Gleason grade group, clinical tumor and nodal stage, and prostate-specific antigen level at diagnosis, the use of radiation therapy to the prostate was associated with a significant improvement in overall survival (adjusted hazard ratio 0.60, 95% confidence interval 0.49-0.74, P<0.001). Adjusted median overall survival was 3.3 years for patients who did not receive radiation therapy to the prostate compared to 5.5 years for patients who did. Conclusions: Similar to newly diagnosed M1b prostate cancer with a low metastatic burden, patients with M1a prostate cancer may also derive a significant overall survival benefit from receiving radiation therapy to the primary prostate tumor. The use of prostate-directed radiation therapy for M1a patients should be further investigated

Practice patterns and outcomes among patients with N0M0 prostate cancer and a very high prostate-specific antigen

48 Background: There are limited data regarding practice patterns and outcomes among patients with a very high prostate-specific antigen (PSA) level ( > = 98.0 ng/mL) but clinically localized (N0M0) prostate cancer. Methods: We used the National Cancer Database (NCDB) to identify 748,825 patients with prostate cancer diagnosed 2004-2012. We subdivided these patients by PSA level (0-9.9, 10-19.9, 20-39.9, 40-59.9, 60-79.9, 80-97.9, and > = 98.0 ng/mL), nodal status (N0 vs N1) and the presence of distant metastases (M0 vs M1). We determined the rate of definitive LR therapy (pelvic and/or prostate radiation and/or radical prostatectomy) in each group. Overall survival was compared using Cox multivariable regression modeling after adjusting for patient race, income quartile, education quartile, age, and year of diagnosis. Results: Rates of definitive LR therapy for patients with PSA > = 98.0 ng/mL and N0M0 disease were significantly lower than they were for those with N1M0 disease (52.6% vs 60.4%, p = 98.0 ng/mL, 5-year OS was 91.6%, 84.3%, 80.2%, 84.1%, 81.8%, 80.2%, and 59.1%, respectively. Among those with N1M0 disease, 5-year OS was 63.2%, which in multivariable Cox regression modeling was not significantly different compared to those with PSA > = 98.0 ng/mL N0M0 disease (adjusted hazard ratio [AHR] 0.99, 95% confidence interval 0.91-1.09, p = 0.942). The survival benefit associated with LR treatment was larger among those with N0M0 high-PSA disease than among those with N1M0 disease (AHR of 0.26 vs 0.41, p-interaction = 98.0 ng/mL) have similar outcomes as patients with N1 disease but receive definitive LR therapy at a lower rate. It is possible that patients with N0M0 disease and PSA > = 98.0 ng/mL represent a population that should be treated as more similar to the N1M0 population, rather than the M1 population, including consideration of LR therapy in appropriate contexts

Surgical management versus combination radiotherapy in Gleason score 9-10 prostate cancer

135 Background: For men with Gleason score 9-10 prostate cancer, studies have demonstrated conflicting results on the outcomes from combination radiation therapy (ComboRT) with external beam radiation therapy plus brachytherapy boost versus radical prostatectomy (RP), with or without adjuvant radiation therapy (ART). Differences in patient selection and management may explain some of the disparate outcomes of prior reports. Methods: The Surveillance, Epidemiology, and End Results database identified 10,396 men managed with ComboRT versus RP (+/-ART). Competing-risks regression analysis with treatment propensity adjustment defined hazard ratios (aHR) for prostate cancer-specific mortality (PCSM), controlling for patient-specific demographic factors. To explore the possible effect of patient selection, analyses were conducted before and after excluding men from analysis if they had evidence-based indications for ART (adverse pathology, i.e. pT3-T4 or positive margins) but did not receive it. Results: Median age was 64 years; median follow-up was 69 months. Five-year PCSM was similar between patients treated with RP (with or without ART, regardless of pathologic features, N=8,934) and ComboRT (N=1,462) (6.9% vs 8.1%, aHR=0.94, 95% confidence interval [CI] 0.78–1.13, P=0.51). After excluding RP-treated men with adverse pathology who did not receive ART (N=4,527 excluded), patients treated with RP+/-ART (N=4,407) had improved 5-year PCSM compared with those treated with ComboRT (5.3% vs 8.1%, aHR=0.74, 95% CI 0.60–0.91, P=0.004). Conclusions: For Gleason 9-10 prostate cancer, ComboRT was associated with similar PCSM compared to RP, but risk-tailored surgical management may be associated with superior PCSM

Clinical and genomic characterization of low-prostate-specific antigen, high-grade prostate cancer

59 Background: The consequences of a low prostate-specific antigen (PSA) in high-grade (Gleason 8-10) prostate cancer are unknown. We sought to evaluate the clinical implications and genomic features of this entity. Methods: Clinical and transcriptomic data from 626,057 patients with N0M0 prostate cancer were collected from two national cohorts and a large transcriptome database. Multivariable Fine-Gray and Cox regressions analyzed prostate-cancer specific mortality (PCSM) and all-cause mortality, respectively. GRID data were used to analyze transcriptomic features. Results: For Gleason 8-10 disease, the distribution of PCSM was U-shaped by PSA (PSA 4.1-10.0 ng/mL = referent), with adjusted hazard ratio (AHR) 2.70 for PSA ≤2.5 ng/mL (P 20.0 ng/mL, respectively. In contrast, distribution of PCSM by PSA was linear for Gleason ≤7 with AHR 0.41 for PSA ≤2.5 ng/mL (P = 0.127) versus 1.38, 2.28, and 4.61 for PSA 2.6-4.0, 10.1-20.0, and > 20.0 ng/mL, respectively (PGleason*PSA interaction 2.5 ng/mL (AHR 2.15, P = 0.009; 47-month PCSM 13.8% versus 4.9%). Among Gleason 8-10 patients treated with definitive radiotherapy, androgen deprivation therapy (ADT) was associated with a survival benefit for PSA > 2.5 ng/mL (AHR 0.87, P 2.5 ng/mL (P = 0.046), with no such relationship for Gleason ≤7. Conclusions: Low-PSA, high-grade prostate cancer appears to be a unique entity that has a very high risk for PCSM, potentially responds poorly to ADT, and is associated with neuroendocrine genomic features

Impact of percent positive biopsy cores on cancer-specific mortality for patients with high-risk prostate cancer

78 Background: A high percent positive biopsy cores (PBC), typically dichotomized at ≥50%, is prognostic of worse cancer-specific outcomes for patients with low- and intermediate-risk prostate cancer. The prognostic value of ≥50% PBC for patients with high-risk disease is poorly understood. We examined the association between ≥50% PBC and prostate cancer-specific mortality (PCSM) for patients with high-risk prostate cancer. Methods: We identified 7,569 men from the Surveillance, Epidemiology, and End Results program who were diagnosed with high-risk prostate cancer (Gleason 8-10, prostate-specific antigen > 20 ng/mL, or cT3-T4 stage without evidence of nodal or metastatic disease) in 2010 or 2011 and had 6-24 cores sampled at biopsy. Multivariable Fine and Gray competing risks regression was utilized to examine the association between ≥50% PBC and PCSM, with adjustments for sociodemographic and clinicopathologic factors. Results: Median follow-up was 3.8 years (interquartile range 3.3-4.3 years). 56.2% of patients (4,253) had ≥50% PBC. The 4-year unadjusted cumulative incidences of PCSM were 2.0% (95% confidence interval [CI] 1.5-2.6%) and 5.6% (95% CI 4.9-6.4%) for patients with < 50% and ≥50% PBC, respectively. On multivariable analysis, the presence of ≥50% PBC was associated with a significantly higher risk of PCSM (adjusted hazard ratio [AHR] 1.95, 95% CI 1.43-2.66, P< 0.001). On subgroup analysis, ≥50% PBC was associated with a significantly higher risk of PCSM only for cT1-T2 disease (AHR 2.21, 95% CI 1.59-3.07, P< 0.001) but not cT3-T4 disease (AHR 0.77, 95% CI 0.33-1.81, P= 0.547), with a significant interaction ( Pinteraction= 0.012). Conclusions: In this large, contemporary cohort of patients with high-risk prostate cancer, ≥50% PBC was independently associated with a two-fold increased risk of PCSM for patients with cT1-T2, but not cT3-T4, tumors. Percent PBC should be used to routinely risk stratify men with high-risk disease and identify patients who may benefit from intensification of therapy, such as adding docetaxel or abiraterone to radiotherapy with androgen deprivation therapy, to optimize cancer-specific outcomes

Androgen deprivation therapy and overall survival for Gleason 8 versus Gleason 9-10 prostate cancer

23 Background: While the addition of androgen deprivation therapy (ADT) to external beam radiotherapy is known to improve overall survival in Gleason 8-10 prostate cancer, it has been hypothesized that Gleason 9-10 disease, which is less differentiated than Gleason 8 disease, may be less sensitive to ADT. To investigate this idea, we examined the association between ADT and overall survival for Gleason 8 versus Gleason 9-10 prostate cancer. Methods: We identified 20,139 men in the National Cancer Database diagnosed with localized or locally advanced, Gleason 8-10 prostate cancer from 2004 through 2011 who received external beam radiotherapy. Patients with clinical evidence of nodal or metastatic disease were excluded. Cox proportional hazards regression was used to examine the association between ADT and overall survival. Results: Median follow-up was 4.0 years. 78.2% (9,509) of the 12,160 men with Gleason 8 disease and 86.6% (6,908) of the 7,979 men with Gleason 9-10 disease received ADT. On multivariable analysis, ADT was associated with a significant improvement in overall survival for Gleason 8 patients (adjusted hazard ratio 0.79, 95% confidence interval 0.71-0.88, P< 0.001) but not Gleason 9-10 patients (adjusted hazard ratio 0.96, 95% confidence interval 0.83-1.10, P= 0.532), with a significant interaction ( Pinteraction= 0.020). When considering Gleason 9-10 patients separately as Gleason 9 and Gleason 10, a higher Gleason score correlated with an increased adjusted hazard ratio for the association between ADT and overall survival ( Pinteraction= 0.012). Conclusions: In contrast to the significant survival advantage of ADT for Gleason 8 disease, our results strongly suggest that Gleason 9-10 disease may be less sensitive to ADT and that a higher Gleason score predicts lesser sensitivity. Consideration should be given to treatment intensification for Gleason 9-10 patients through enrollment in clinical trials or potentially adding novel antiandrogens or docetaxel, which have shown efficacy in both castration-resistant and castration-sensitive settings