Validation of the decipher genomic classifier (GC) in SAKK 09/10: A phase III randomized trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy (RP)

5010 Background: GC has been shown to independently prognosticate outcomes in prostate cancer. Herein, we validate the GC in a European randomized phase III trial of dose escalated SRT after RP. Methods: SAKK 09/10 (NCT01272050) randomized 350 patients with biochemical recurrence after RP to 64Gy vs 70Gy. No patients received androgen deprivation therapy (ADT) or pelvic nodal radiotherapy. A pre-specified statistical plan was developed to assess the impact of the GC on clinical outcomes. RP samples were centrally reviewed for the highest-grade tumor and those passing quality control (QC) were run on a clinical-grade whole-transcriptome assay to obtain the GC score (0 to 1; 0.6 for low-, intermediate-, and high, respectively). The primary aim of this study was to validate the GC for the prediction of freedom from biochemical progression (FFBP) using Cox multivariable analysis (MVA) adjusting for age, T-category, Gleason score, persistent PSA after RP, PSA at randomization, and randomization arm. The secondary aims were to evaluate the association of GC with clinical progression-free survival (CPFS) and use of salvage ADT. Results: Of 233 patients with tissue available, 226 passed QC and were included for analysis. The final GC cohort was a representative sample of the overall cohort, with a median follow-up of 6.3 years (IQR 6.0-7.2). GC score (continuous per 0.1 unit, score 0-1) was independently associated with FFBP (HR 1.14 [95% CI 1.03-1.25], p = 0.009). Higher GC scores were independently associated with CPFS, use of salvage ADT, and rapid biochemical failure ( < 18 months after SRT). High- vs. low/intermediate-GC showed a HR of 2.22 ([95% CI 1.37-3.58], p = 0.001) for FFBP, 2.29 ([95% CI 1.32-3.98], p = 0.003) for CPFS, and 2.99 ([95% CI 1.50-5.95], p = 0.002) for use of salvage ADT. Patients with high-GC had 5-year FFBP of 45% [95% CI 32-59] vs 71% [95% CI 64-78] in low-intermediate GC. Similar estimates for GC risk groups were observed in the 64Gy vs 70Gy in GC high (5-year FFBP of 51% [95% CI 32-70] vs 39% [95% CI 20-59]) and in low-intermediate GC (75% [95% CI 65-84] vs 69% [95% CI 59-78]). Conclusions: This study represents the first contemporary randomized controlled trial in patients with recurrent prostate cancer treated with early SRT without ADT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and radiotherapy dose, patients with a high-GC were more than twice as likely than a lower GC score to experience biochemical and clinical progression and receive salvage ADT. This data confirms the clinical value of Decipher GC for tailoring treatment in the postoperative salvage setting

Factors influencing noncompletion of radiotherapy among men with localized prostate cancer

199 Background: Treatment non-completion may occur with radiotherapy (RT), especially with protracted treatment courses such as RT for prostate cancer, and may affect the efficacy of RT. For men with localized prostate cancer managed with primary RT, we evaluated associations between rates of treatment non-completion and RT fractionation schedules. Methods: The National Cancer Database identified men diagnosed from 2004-2014 treated with primary RT. Patients receiving 180cGy/fraction (conventional), 200cGy/fraction (conventional), 250cGy/fraction (moderate hypofractionation), and 300cGy/fraction (moderate hypofractionation) were defined as having completed radiotherapy if they received ≥40 fractions, ≥37 fractions, ≥28 fractions, and ≥19 fractions, respectively. Stereotactic body radiotherapy (SBRT) was defined as 5-8 fractions of 600-800cGy/fraction. Odds ratios compared rates of treatment noncompletion, adjusting for various sociodemographic covariates. Propensity-adjusted multivariable Cox regression assessed the association between treatment completion and overall survival. Results: Of 93,079 patients, 90.5% (N = 84,260) received conventional fractionation, 2.3% (N = 2,181) received moderate hypofractionation, and 7.1% (N = 6,638) received SBRT. Rates of non-completion were 10.0% (N = 8,406) among patients who received conventional fractionation, 7.5% (N = 163) among patients who received moderate hypofractionation, and 1.7% (N = 115) among patients who received SBRT (OR versus conventional: 0.214, 95%CI 0.177-0.258, P < 0.001). The rate of non-completion among 15,417 African American patients was 11.8%, compared to 8.8% among 74,189 white patients (OR 1.39, 95%CI 1.31-1.47, P < 0.001). On subgroup analysis, the disparity in non-completion persisted for conventional fractionation (12.4% vs. 9.4%, OR 1.36, 95%CI 1.29-1.44, P < 0.001) and moderate hypofractionation (13.6% vs. 6.6%, OR 2.24, 95%CI 1.52-3.29, P < 0.001), but not for SBRT (2.0% vs. 1.6%, OR 1.25, 95%CI 0.76-2.06, P = 0.384). Non-completion was associated with worse survival on propensity-adjusted multivariate analysis (HR 1.37, 95%CI 1.31-1.43, P < 0.001). Conclusions: SBRT was associated with lower rates of RT non-completion among men with localized prostate cancer. African American race was associated with greater rates of treatment non-completion, although the disparity may be decreased among men receiving SBRT

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

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

Differential expression of PSMA and 18F-fluciclovine transporter genes in metastatic castrate-resistant and treatment-emergent small cell/neuroendocrine prostate cancer

24 Background: 18F-fluciclovine (Axumin) PET/CT imaging is recommended by the NCCN in the setting of biochemical recurrence, while prostate-specific membrane antigen (PSMA) PET/CT is preferred by the EAU. The utility of these methods in the post-androgen deprivation therapy (ADT) setting however, is less defined. Our objective was to compare relative gene expression of the molecular targets of these imaging modalities— fluciclovine transporter genes (LAT1-4, ASCT1-2) and PSMA—in metastatic castrate resistant prostate cancer (mCRPC) and treatment-emergent small cell/neuroendocrine prostate cancer (t-SCNC). Methods: Genome-wide expression profiles of five mCRPC cohorts (Aggarwal, Grasso, Kumar, Beltran, Robinson, et al) were used to characterize relative expression of fluciclovine transporter (LAT1-4, ASC1-2) and PSMA (FOLH1) genes. 3 cohorts (Kumar, Beltran, Aggarwal) were enriched with t-SCNC tumors. The GSE35988 cohort included primary tumors and mCRPC. RNA expression profiling methods were consistent within cohorts. Results: 518 mCRPC specimens were included. In the GSE35988 cohort, PSMA expression was downregulated in mCRPC when compared to primary localized tumors (p=0.01). PSMA expression was further depressed in t-SCNC when compared with mCRPC (p<0.001). Of the fluciclovine transporter genes, LAT1 and LAT4 were overexpressed in mCRPC when compared to primary tumors, while ASC2 was less expressed (p<0.001). LAT1 was further overexpressed in t-SCNC when compared to mCRPC, while LAT2 was less expressed (p<0.001). PSMA expression was negatively correlated with LAT1 (p<0.001) but positively correlated with LAT2 (p=0.006). Other fluciclovine transporters were not correlated. Conclusions: Expression of PSMA and a subset of fluciclovine transporter genes are inversely correlated in mCRPC and t-SCNC. These findings suggest that fluciclovine-based imaging may play a role in castrate resistant states. Clinical comparison between PSMA- and fluciclovine-based imaging modalities in mCRPC and t-SCNC is warranted

Characterization of PSMA and 18F-fluciclovine transporter gene expression in localized prostate cancer

295 Background: While 18F-fluciclovine PET/CT is approved in the US and recommended by the NCCN, prostate-specific membrane antigen (PSMA) PET/CT is more common in Europe/Australia and recommended by the EAU. Less is known about the biology of lesions detected by either modality. 18F-fluciclovine PET relies on radiotracer uptake by amino acid transporters LAT1-4 and ASCT1-2. PSMA PET is dependent on surface expression of PSMA. We compared relative expression of PSMA and fluciclovine transporter genes in radical prostatectomy (RP) samples to determine their distribution across subtypes and correlation with outcomes. Methods: Gene expression data of 19,102 RP samples were analyzed using the Affymetrix Human Exon 1.0 ST microarray. 1,135 patients had long term follow up. Associations between expression of PSMA and fluciclovine transporter genes (LAT1-4 and ASCT1-2) and pathologic variables, molecular subtypes, and clinical outcomes were conducted. Results: All fluciclovine transporter genes (LAT 1-4, ASCT1-2) were expressed at lower levels than PSMA (p <0.0001). PSMA expression was positively correlated with genomic risk score and pathologic Gleason score (p<0.0001), but LAT2-3 and ASCT2 were inversely correlated with genomic risk in primary tumors (p<0.0001) and less expressed in GS 9-10 tumors (p<0.0001). PSMA expression was associated with worse metastasis-free survival (MFS) (HR 1.45, p=0.001) and lymph node involvement (HR 2.14, p<0.0001). Expression of LAT2, LAT3, ASCT2 expression was associated with better MFS (HR 0.85, 0.63, 0.74, p<0.0001-0.04). After multivariable adjustment, PSMA expression remained independently prognostic of poorer MFS (HR 1.3, p=0.028). Luminal B subtype was notable for PSMA overexpression; Luminal A was enriched in ASCT2 and LAT2 (p<0.0001). PSMA expression did not correlate with ERG fusion prostate cancers, but LAT2, ASCT1, and ASCT2 were overexpressed in ERG fusion negative tumors (p<0.0001). Conclusions: PSMA expression is associated with more aggressive disease and poorer clinical outcomes than fluciclovine transporter genes in localized prostate cancer. Molecular subtypes of prostate cancer vary in PSMA and fluciclovine transporter gene expression

Development and validation of a novel clinical-genomic risk group classification for prostate cancer incorporating genomic and clinicopathologic risk

5000 Background: It is clinically challenging to integrate genomic classifier results that report a continuous numerical risk of recurrence into treatment decisions for prostate cancer (PCa). We aimed to develop a novel clinical-genomic risk system that can readily be incorporated into treatment guidelines for localized PCa. Methods: Four multi-center cohorts (n = 6928 men; 5937 prospective samples and 991 retrospective samples with long-term follow-up) were utilized to identify and validate our clinical-genomic risk system in radical prostatectomy (RP) samples and subsequently in pre-treatment biopsy samples. All patients’ FFPE tissue underwent microarray analysis, and the expression values for 22 prespecified biomarkers that constitute Decipher were extracted. Cumulative incidence curves were constructed to estimate metastasis risk. C-indices were calculated to compare NCCN and CAPRA score to our clinical-genomic system. Results: With a median follow-up of 8 years for men in our RP cohort, the 10-year distant metastasis rates for NCCN low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.8%, 9.4%, 40.1%, and 41.4%, respectively. Our 3-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.7%, 30.7%, and 57.7%, for low, intermediate, and high-risk, which were validated in our pre-treatment biopsy cohort with 10-year rate of distant metastasis of 0%, 30.3%, and 63.2%, respectively. C-indices for the clinical-genomic system (0.84, 95%CI 0.62-0.92) were significantly improved over NCCN (0.71, 95%CI 0.59-0.84) and CAPRA (0.71, 95%CI 0.60-0.81) score. A total of 33.4% of men would be reclassified by the clinical-genomic system, and specifically 17.1%, 41.3%, and 19.4% of men in NCCN low, intermediate and high risk groups would be reclassified by our new system. Conclusions: The use of a readily available genomic classifier in combination with clinicopathologic variables can generate a simple to use 3-tier clinical-genomic risk system that is highly prognostic for distant metastasis, is more accurate than clinical risk, and can be easily incorporated into NCCN guidelines to inform treatment decisions

Transcriptome profiling of NRG Oncology/RTOG 9601: Validation of a prognostic genomic classifier in salvage radiotherapy prostate cancer patients from a prospective randomized trial

276 Background: Decipher is a genomic classifier (GC) that estimates risk of prostate cancer (PCa) distant metastases (DM) post-radical prostatectomy (RP). Herein, we validate the GC within the context of a randomized phase 3 trial. Methods: RP specimens from patients on the NRG/RTOG 9601 phase 3 placebo-controlled randomized trial of salvage radiotherapy (sRT) +/- 2 years of bicalutamide (NCT00002874) were centrally reviewed and the highest-grade tumor underwent RNA extraction. Samples passing quality control (QC) were run on a clinical-grade whole-transcriptome assay to assign the GC score (scale 0-1). Our NCTN-CCSC approved pre-specified statistical plan (NRG-GU-TS002 CSC0075) included the primary objective of validating the ability of the GC to independently prognosticate the cumulative incidence of DM, with secondary endpoints of prostate cancer-specific mortality (PCSM) and overall survival (OS). Results: Of patients with tissue available, 352 passed QC and were included for analysis. The final GC cohort was a representative sample of the overall cohort, with a median follow-up of 13 years. On multivariable analysis, the GC (continuous variable) was independently associated with DM (HR 1.19 [95%CI 1.06-1.35], p=0.003), PCSM (HR 1.37 [95%CI 1.18-1.61], p<0.001), and OS (HR 1.16 [95%CI 1.06-1.28], p=0.002) after adjusting for age, race, Gleason score, T-stage, margin status, entry PSA, and treatment arm. The estimated absolute impact of bicalutamide on 12-year OS was less in patients with lower vs higher GC scores (2.4% vs 8.9%), further demonstrated in men receiving early sRT at PSA <0.7 ng/mL (-2.0% vs 5.0%). Conclusions: This is the first validation of this GC in a prospective randomized trial cohort and demonstrates association of the GC with DM and PCSM independent of standard clinicopathologic variables. The GC may help personalize shared decision-making to weigh the absolute benefit from the addition of bicalutamide to sRT

Prostate cancer specific mortality and overall survival outcomes for salvage radiation therapy after radical prostatectomy

9 Background: Early salvage radiation therapy (SRT) following radical prostatectomy (RP) has been shown to reduce biochemical recurrence and distant metastases. We aim to identify factors predictive of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) from a consortium database from 10 academic institutions. Methods: 2,454 node-negative patients (pts) with detectable post-prostatectomy PSA ( ≥ 0.01 ng/mL) treated with SRT ± neoadjuvant/concurrent androgen deprivation therapy (N/C ADT) were included. Cumulative incidence and Kaplan-Meier methods were used to estimate rates of PCSM and ACM, respectively. Univariate and multivariable analyses (MVA) were performed by competing risks regression and Cox proportional hazards methods for PCSM and ACM. Results: Median follow-up was 5 years from SRT completion and 8 years from date of RP; 24% had pathologic Gleason score (GS) of ≤ 6, 56% GS 7, and 19% GS ≥ 8; 56% extraprostatic extension (EPE), 18% seminal vesicle invasion (SVI), 58% positive surgical margins, and 16% received N/C ADT. Median age at RP and SRT were 62 years (IQR 56-66) and 64 years (59-69), respectively. Median SRT dose was 66 Gy (IQR 65-68) and median pre-SRT PSA was 0.5 ng/mL (IQR 0.3-1.1). MVA performed from SRT completion date demonstrated higher pre-SRT PSA (HR = 2.1), higher GS (GS 7 vs. ≤ 6: HR 2.0; GS ≥ 8 vs. 6: HR 3.3) , SVI (HR 2.5), year of SRT (2000-2004, 1995-1999, 1985-1994 vs. 2005-2012; HR 2.9, HR 2.5, HR 3.6, respectively) were significantly associated with higher PCSM. These same variables were all significantly associated with higher PCSM and ACM rates calculated from both SRT completion date and date of RP. Conclusions: Initiation of early SRT at lower post-operative PSA levels following RP is associated with reduced risk of PCSM and ACM, even when calculated from RP date to account for lead time bias. Other factors significantly associated with PCSM include higher GS, SVI, and earlier year of SRT. [Table: see text

Optimal timing of post-prostatectomy radiotherapy for prostate cancer with high-risk pathologic features: A multi-institutional analysis

24 Background: The use of radical prostatectomy (RP) as initial treatment of high-risk/locally-advanced prostate cancer is increasing but patients (pts) with adverse pathologic features such as positive surgical margins or T3 disease have up to 70% recurrence risk. These high-risk pts may be managed with adjuvant radiotherapy (ART) or early salvage radiotherapy (ESRT). The optimal timing of post-operative radiotherapy is unclear. Methods: Individual data from 1566 consecutive pts with pT2N0M0/R1 or pT3N0M0/R0-1 disease who underwent post-prostatectomy ART or ESRT (1987-2013) at 10 academic centers were pooled. Post-irradiation freedom from biochemical failure (FFBF), freedom from distant metastases (FFDM), prostate-cancer specific survival (PCSS), and overall survival (OS) were compared using Kaplan-Meier and multivariate competing-risks regression (MVA) analyses. Propensity score (PS) matching was used to account for covariates potentially associated with treatment allocation. All outcomes were measured from the date of surgery to address lead time bias. Results: After PS-matching, median follow-up after surgery was 66 vs. 73 months for the ART and ESRT groups, respectively, and baseline characteristics were well-matched. ART was associated with higher FFBF (12-yr: 69% vs. 43%; log-rank P < 0.0001), FFDM (12-yr: 95% vs. 85%; log-rank P = 0.03), PCSS (12-yr: 99% vs. 94%; log-rank P = 0.048), and OS (12-yr: 91% vs. 79%; log-rank P = 0.01). ART, lower Gleason score, lower T-stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on MVA for BF. Sensitivity analysis demonstrated that the decreased risk of BF associated with ART remained significant unless more than 56% of ART pts were cured by surgery alone. This threshold is greater than the estimated 12-yr FFBF of 46% after RP alone as determined by a contemporary nomogram. Conclusions: To the best of our knowledge, this represents the largest multi-institutional study to date comparing ART to ESRT. ART was associated with reduced biochemical recurrence, distant metastases, and death compared to ESRT for high-risk pts, pending prospective validation