Search

Objectives To estimate the lifetime health and economic outcomes of selecting active surveillance (AS), radical prostatectomy (RP), or radiation therapy (RT) as initial management for low- or favorable-risk localized prostate cancer. Methods A discrete-event simulation model was developed using evidence from published randomized trials. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Costs were included from a public payer perspective in Australian dollars. Outcomes were discounted at 5% over a lifetime horizon. Probabilistic and scenario analyses quantified parameter and structural uncertainty. Results A total of 60% of patients in the AS arm eventually received radical treatment (surgery or radiotherapy) compared with 90% for RP and 91% for RT. Although AS resulted in fewer treatment-related complications, it led to increased clinical progression (AS 40.7%, RP 17.6%, RT 19.9%) and metastatic disease (AS 13.4%, RP 6.1%, RT 7.0%). QALYs were 10.88 for AS, 11.10 for RP, and 11.13 for RT. Total costs were A$17 912 for AS, A$15 609 for RP, and A$15 118 for RT. At a willingness to pay of A$20 000/QALY, RT had a 61.4% chance of being cost-effective compared to 38.5% for RP and 0.1% for AS. Conclusions Although AS resulted in fewer and delayed treatment-related complications, it was not found to be a cost-effective strategy for favorable-risk localized prostate cancer over a lifetime horizon because of an increase in the number of patients developing metastatic disease. RT was the dominant strategy yielding higher QALYs at lower cost although differences compared with RP were small.

It remains unclear which patients with metastatic germ cell tumours (mGCTs) need prophylactic anticoagulation to prevent venous thromboembolic events (VTEs).To assess the risk and onset of VTEs stratified by risk factors.This multi-institutional retrospective dataset included mGCT patients treated with first-line platinum-based chemotherapy.Patients with prophylactic anticoagulation were excluded.A regression analysis was performed to select risk factors for VTEs. The simulated number needed to treat (NNT) and the number needed to harm (NNH) with prophylactic anticoagulation were calculated based on the cumulative incidences retrieved from this study and hazard rates of recently published trials describing the efficacy of prophylactic anticoagulation to prevent VTEs and the risk of bleeding events.From 1120 patients, 121 (11%) had a VTE, which occurred prior to chemotherapy in 49 (4%) and on or after chemotherapy in 72 (6%). Six patients (1%) had a bleeding event without anticoagulation. After backward regression, the one risk factor for a VTE during or after chemotherapy was the use of a venous access device. The simulated cumulative VTE incidence from prophylactic anticoagulation for patients on or after chemotherapy would translate into an NNT of 45 (95% confidence interval [CI] 36-56) and an NNH of 186 (95% CI 87-506). Limitations are mainly related to the retrospective nature of the study.The mGCTs associated VTEs are most common before and during, but not after, chemotherapy. Avoiding venous access device and/or prophylactic anticoagulation with an acceptable risk-benefit profile may decrease VTE occurring on chemotherapy.We found that venous thromboembolic events (VTEs) occur rarely after chemotherapy. Based on experience of prophylactic anticoagulation in other cancers, we conclude that the risk of VTE in men undergoing chemotherapy for metastatic germ cell tumours can be decreased by thromboprophylaxis with a reasonable risk-benefit profile and by avoidance of venous access devices.

The immunosuppressive cytokine interleukin- 8 (IL-8), produced by tumor cells and some myeloid cells, promotes inflammation, angiogenesis, and metastasis. In our discovery work, elevated serum IL-8 at androgen deprivation therapy (ADT) initiation portended worse overall survival (OS). Leveraging serum samples from the phase 3 CHAARTED trial of patients treated with ADT +/- docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), we validated these findings.Two hundred and thirty-three patients had serum samples drawn within 28 days of ADT initiation. The samples were assayed using the same Mesoscale Multiplex ELISA platform employed in the discovery cohort. After adjusting for performance status, disease volume, and de novo/metachronous metastases, multivariable Cox proportional hazards models assessed associations between IL-8 as continuous and binary variables on OS and time to castration-resistant prostate cancer (CRPC). The median IL-8 level (9.3 pg/ml) was the a priori binary cutpoint. Fixed-effects meta-analyses of the discovery and validation sets were performed.Higher IL-8 levels were prognostic for shorter OS (continuous: hazard ratio [HR] 2.2, 95% confidence interval [CI]: 1.4-3.6, p = .001; binary9.3: HR 1.7, 95% CI: 1.2-2.4, p = .007) and time to CRPC (continuous: HR 2.3, 95% CI: 1.6-3.3, p .001; binary: HR 1.8, 95% CI: 1.3-2.5, p .001) and independent of docetaxel use, disease burden, and time of metastases. Meta-analysis including the discovery cohort, also showed that binary IL-8 levels9.3 pg/ml from patients treated with ADT alone was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p = .007) and shorter time to CRPC (HR 1.4, 95% CI: 0.99-1.9, p = .057).In the phase 3 CHAARTED study of men with mHSPC at ADT initiation, elevated IL-8 portended worse survival and shorter time to castration-resistant prostate cancer independent of docetaxel administration, metastatic burden, and metachronous versus de novo metastatic presentation. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.

The successful development of effective cancer immunotherapy, in particular immune checkpoint inhibitors, has changed the treatment paradigm of many tumor types. In light of the limited efficacy of checkpoint inhibitors demonstrated in recent clinical trials in refractory prostate cancer, this review highlights important recent and ongoing studies that are shaping the pursuit of effective immunotherapy for prostate cancer.We review two overarching themes with respect to recent studies of prostate cancer immunotherapy: evolving therapeutic strategies and novel biological findings, including the landscape of predictive biomarkers of immunotherapy response.Novel and combinatorial immunotherapy strategies are being implemented across the clinical spectrum of prostate cancer. Greater understanding of complex tumor-immune interactions and the determinants of therapy response in prostate cancer is an area of intense investigation, and will inform both translational and clinical immuno-oncology research in the field.

Background Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life‐threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population. Methods Data were collected from mGCT patients receiving first‐line platinum‐based chemotherapy at 22 centers. Predefined variables included International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, long‐axis diameter of largest retroperitoneal lymph node (RPLN), Khorana score, and use of indwelling vascular access device (VAD). VTE occurring at baseline, during chemotherapy and within 90 days, was analyzed. Results Data from 1135 patients were collected. Median age was 31 years (range 10‐74). IGCCCG risk was 64% good, 20% intermediate, and 16% poor. VTE occurred in 150 (13%) patients. RPLN >3.5 cm demonstrated highest discriminatory accuracy for VTE (AUC 0.632, P, Venous thromboembolism can cause morbidity in germ cell tumor patients receiving chemotherapy; large retroperitoneal lymphadenopathy (RPLN) and indwelling vascular access devices (VAD) are significant VTE risk factors. VAD insertion should be avoided and thromboprophylaxis can be considered for large RPLN.

BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer).METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian.RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years.CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.

Background The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Patients and methods Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. Results The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). Conclusion This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Background TP53, PTEN, and RB1 tumor suppressor genes (TSGs) are recurrently altered in treatment-resistant prostate cancer. Cooperative loss of two or more TSGs may drive more aggressive disease. Objective To determine clinical outcomes of single and compound TSG alterations across the spectrum of prostate cancer. Design, setting, and participants Massively parallel targeted sequencing using castration-sensitive prostate cancer (CSPC; localized [L] and metastatic [M1]) and castration-resistant prostate cancer (CRPC) specimens (n = 285). TSG altered (TSG-alt) was any copy number loss or deleterious mutation of one or more TSGs (TP53, PTEN, and RB1). Outcome measurements and statistical analysis For L-CSPC, event-free survival (EFS) and time to CRPC were estimated. For M1-CSPC and M1-CRPC, overall survival (OS) was estimated. Cox regression models assessed the association between cumulative TSG hits (zero hits vs one hit vs two to three hits) and outcomes with multivariable analyses adjusted for clinicopathological factors. Results and limitations TSG variants increased with advanced disease (L-CSPC: 39%; M1-CSPC: 63%, M1-CRPC: 92%). TSG-alt L-CSPC had shorter EFS (median 2.6 yr, hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.22–3.13) and time to CRPC (median 9.5 mo, HR 3.36, 95% CI 1.01–11.16). Cumulative gene hits led to an incremental risk of relapse (EFS: one gene, HR 1.69, 95% CI 0.99–2.87; two to three genes, HR 2.70, 95% CI 1.43–5.08; both versus zero genes, p = 0.004). There was evidence of inferior OS with increasing TSG hits in the metastatic cohorts. Only four (8%) patients in the M1-CRPC cohort were TSG-neg, one of whom died after 5.2 yr. Multivariable analyses adjusting for mutational and copy number burden did not demonstrate a significant independent association of increasing gene hits and poorer outcomes. Conclusions Deleterious TSG variants are associated with an increased risk of relapse (L) and death (M1) in CSPC. Poorer outcomes are seen with compound gene hits in both early and advanced disease, and this may in part reflect increasing global genomic instability. Patient summary Men with prostate tumors with compound tumor suppressor gene mutations have poorer outcomes. These findings help identify patients with aggressive features who may benefit from intensified treatment.

BACKGROUND: In 2004, docetaxel was shown to prolong the overall survival (OS) of patients with metastatic castration-resistance prostate cancer (mCRPC). Since 2010, five new systemic therapies have been shown to prolong OS in men with mCRPC. We sought to evaluate the aggregate impact of these newer therapies on the OS of patients with mCRPC. METHODS: Two cohorts of patients diagnosed with mCRPC between 2004–2007, treated with drugs used in the limited treatment era only (A), and between 2010–2013, treated also with newer therapies (B), were identified from the Dana-Farber Cancer Institute database. The analysis endpoint was OS within 5 years after mCRPC diagnosis. Kaplan-Meier method assessed time-to-event distributions with median (95% confidence interval [CI]). A piece-wise regression model assessed the association between endpoint and treatment cohorts with estimate of hazard ratio (HR) with 95% CI within two time segments in univariate and multivariable analyses adjusting for relevant covariates. RESULTS: Compared to cohort A (n=318), cohort B (n=272) patients in newer therapy era demonstrated an OS advantage (2.8 v 2.2 years) with a 41% decreased risk of death (HR = 0.59; 95% CI, 0.47–0.74; P < .0001), and a 3-year OS rate of 46% v 33%. This benefit was accentuated (median OS 2.7 v 2.1 years; HR = 0.46; 95% CI, 0.32–0.67; P < .0001) in patients who initially presented with de-novo metastatic disease (de-novo). On multivariable analysis, longer OS was associated with cohort B v A and performance status 0 v 1. CONCLUSIONS: Using a single-institution registry, mCRPC patients treated since 2010 had a significant survival improvement versus those treated before 2010. Although the median survival was only modestly improved and less than predicted when simply adding each newer drug survival advantage, the cumulative benefit from the new therapies was more pronounced in longer term survivors and de-novo patients.

The appropriate management of localized or metastatic hormone-sensitive prostate cancer (HSPC) patients harboring tumor BRCA mutations (tBRCAm) is not well-characterized. We sought to evaluate the prevalence and clinical outcomes of patients with tBRCAm and localized or de novo metastatic HSPC. We performed a multicenter, international, retrospective cohort study of localized (cohort 1) and de novo metastatic (cohort 2) HSPC patients who underwent tumor BRCA1 and BRCA2 sequencing from 2013 to 2019. Primary endpoints included event-free survival (EFS) and metastases-free survival (MFS) for cohort 1, and time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) for cohort 2. Kaplan–Meier method and Cox regression models estimated the association of endpoints with tBRCA status. Of 399 identified patients with localized and de novo metastatic HSPC who underwent tumor BRCA1 and BRCA2 sequencing, 3.1% (8/258) patients of cohort 1 and 10.6% (15/141) patients of cohort 2 harbored tBRCAm. The median follow-up was 33 and 36 months, respectively. In cohort 1, median EFS was 18.1 vs. 57 months (p = 0.28) and MFS was 37 vs. 153.4 months (p = 0.08) for patients with tBRCAm compared to patients with no tBRCAm. In cohort 2, the TTCRPC was 24 vs. 19 months (p = 0.65) and OS was 64 vs. 60 months (p = 0.95) in patients with and without tBRCAm, respectively. While tBRCAm seems to be associated with greater relapse risk in localized disease, tBRCAm did not influence the clinical outcomes of patients presenting with de novo metastatic HSPC treated with conventional therapies. tBRCAm may exert different prognostic effects across the clinical spectrum of prostate cancer.

PURPOSE Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment. PATIENTS AND METHODS Data from 51 patients with CSI NS who experienced a relapse after adjuvant bleomycin, etoposide, and cisplatin (BEP) from 18 centers/11 countries were collected and retrospectively analyzed. Primary outcomes were overall and progression-free survivals calculated from day 1 of treatment at first relapse. Secondary outcomes were time to, stage at, and treatment of relapse and rate of subsequent relapses. RESULTS Median time to relapse was 13 months, with the earliest relapse 2 months after start of adjuvant treatment and the latest after 25 years. With a median follow-up of 96 months, the 5-year PFS was 67% (95% CI, 54% to 82%) and the 5-year OS was 81% (95% CI, 70% to 94%). Overall, 19 (37%) of 51 relapses occurred later than 2 years. Late relapses were associated with a significantly higher risk of death from NS (hazard ratio, 1.10 per year; P = .01). Treatment upon relapse was diverse: the majority of patients received a combination of chemotherapy and surgery. Twenty-nine percent of patients experienced a subsequent relapse. At last follow-up, 41 patients (80%) were alive and disease-free, eight (16%) had died of progressive disease, and one patient (2%) each had died from therapy-related or other causes. CONCLUSION Outcomes of patients with relapse after adjuvant BEP seem better compared with patients who experience relapse after treatment of metastatic disease but worse compared with those who have de-novo metastatic disease. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable NS relapse (< 2 years), and late viable NS relapse (> 2 years).

Background: There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations. Methods: This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months. Results: Of 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%). Conclusions: Patients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND Docetaxel is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC); however, many patients experience febrile neutropenia (FN) and cease treatment early due to toxicity. It is not known whether lower dose (LD) q3-weekly docetaxel impacts toxicity or efficacy. METHODS Multicenter retrospective study included 166 patients with mCRPC who received q3-weekly docetaxel between 2010 and 2015. Demographic, disease, chemotherapy (standard dose, SD > 60 mg/m2 vs LD ≤ 60 mg/m2 ) and toxicity data were collected. Univariable and multivariable logistic and competing risk regression models evaluated docetaxel-dose association with FN and early treatment cessation (ETC) due to toxicity. Associations between dose and efficacy end points were also evaluated. Analyses were repeated employing inverse propensity score weights. RESULTS Patients who received LD docetaxel (28.9%) were older with poorer Eastern Cooperative Oncology Group (ECOG) status. Fifteen percent of patients experienced FN, with a nonsignificant trend to lower incidence in the LD group (multiple adjusted odds ratio [OR] = 0.42; P = 0.21). Neither baseline patient nor prior treatment factors were predictive of FN. ETC due to toxicity occurred in 35%, with risk associated with increasing age, comorbidity count and poorer ECOG. There was no difference between LD and SD with respect to ETC due to toxicity, in unweighted and weighted analyses (LD vs SD, multivariable weighted hazard ratio [HR] = 1.47; P = 0.08). LD was associated with reduced prostate-specific antigen (PSA) response (50% vs 66.1%, multivariable weighted HR = 0.54; P = 0.03) and overall survival (median 7.9 vs 13.8 months, multivariable weighted HR = 2.19; P

162 Background: Through gene expression profiling (GEP), the PAM50 classifier demonstrates prognostic value in localized prostate cancer (PCa). Pre-clinical drug response models predict increased taxane sensitivity in luminal subtypes compared to basal subtype. Men with mHSPC and high-risk features have greatest benefit from androgen deprivation therapy (ADT) plus docetaxel (D) vs ADT alone. We therefore sought to test the prognostic and predictive value of PAM50 in pre-ADT specimens from E3805 CHAARTED. Methods: Whole transcriptomic profiling of formalin-fixed, paraffin-embedded primary PCa biopsies from pts enrolled in the E3805 CHAARTED trial of ADT vs ADT+D was performed using the Human Exon 1.0 ST microarray platform (Decipher Biosciences). Normalized gene expression was used to classify subjects as luminal A, luminal B or basal subtype. Multivariable analyses (MVA) adjusted for ECOG status, de novo metastasis vs prior local therapy and volume of disease. The primary endpoint was overall survival (OS). Secondary endpoint was time to castration resistant PCa (TTCRPC). Results: Successful GEP was completed in 160 of 198 pts with available specimens. Eighty (50%), 77 (48%) and 3 (2%) pts were classified as luminal B, basal and luminal A, respectively. High volume disease was similarly present in luminal B (79%) and basal (78%) subtypes. In the ADT arm, luminal B subtype was associated with shorter OS vs basal (HR 1.75, p=0.05); consistent in MVA. Pts with luminal B subtype treated with ADT+D showed significant improvement in TTCRPC and OS (Table). By contrast, basal subtype showed no OS benefit from ADT+D even in pts with high volume disease. Conclusions: We demonstrate that GEP identifies tumor subtypes associated with differential benefit from chemohormonal therapy for mHSPC. Luminal B subtype is associated with poorer OS with ADT alone and benefits from addition of D. Basal subtype shows a lack of OS benefit from upfront ADT+D. We plan to validate these findings in independent trial cohorts.[Table: see text]

402 Background: Recent trials randomising patients (pts) receiving systemic cancer therapy showed that prophylactic anticoagulation (PAK) halves the risk of venous thromboembolic events (VTE) and doubles the risk of bleeding (Khorana et al. & Carrier et al., both NEJM 2019). In pts with metastatic germ cell tumors (mGCT) VTE is a frequent complication but it remains unclear whether PAK should be recommended because the number of mGCT pts in those trials was small. We aimed to determine the risk of VTE before, during and after chemotherapy and in mGCT pts without and with risk factors for VTE (retroperitoneal lymph nodes, Khorana score, venous access device) and to calculate the number needed to treat (NNT) and number needed to harm (NNH) of PAK. Methods: This retrospective analysis included mGCT pts treated with first-line platinum-based chemotherapy. We excluded patients who received PAK, with a known history of coagulopathy or VTE and extracted data about VTE and bleeding events. Cumulative VTE incidence was calculate for patients without and with increasing number of known risk factors for VTEs. NNT and NNH were calculated by assuming similar hazard ratios (HR) to reduce VTEs and increase bleeding as previously published (HR 0.66 and 1.96, Khorana et al., NEJM 2019). Results: Out of 1039 pts, 132 (13%) presented with VTE, 6 (1%) with bleeding. One patients died of VTE and 1 because of bleeding. Patients without any VTE risk factors experience VTE in 20/347 (5%) which translated into a NNT of 55 compared to the NNH of 84 respectively. Before start of chemotherapy 52 (5%) pts (NNT=60) presented with VTE of which 22 were reported symptomatic 21 asymptomatic/incidentally detected VTE on staging scans (9 unknowns). During chemotherapy 79 (8%) pts (NNT=40) were diagnosed with VTE whereas 19 (2%) pts (NNT=162) were diagnosed with VTE after chemotherapy. Conclusions: Our analysis revealed that even mGCT patients without risk factors for VTE show a relevant cumulative VTE incidence of 7%. Especially before and during but not after chemotherapy the benefits of PAK to prevent VTE outweighs the small increased risk of bleeding.

547 Background: Cisplatin-based NAC followed by surgery is the gold standard treatment of non-metastatic MIBC. However, predictive biomarkers have not been established yet. Here, we addressed the relevance of TILs for NAC response and prognosis in MIBC patients (pts). Methods: We conducted a single center, retrospective cohort analysis of consecutive MIBC pts treated with cisplatin-based NAC followed by surgery. Pts with pathological complete response (pCR; ypT0/isN0) were grouped as responders, pts with pathological residual disease as non responders. TIL stromal count were assessed pre- and post-NAC. Next Generation Sequencing of selected genes was performed on pre-NAC samples. We catalogued the 3-years(y) relapse free rate and 3-y overall survival rate (OS, Kaplan Meier) for the overall cohort and by subgroups. Results: Of the 25 pts who received cisplatin-gemcitabine NAC, a total of 14 (56%) pts achieved a pCR and 11 (44%) had residual disease. NAC was discontinued in 17 (65%) after completing treatment; and in 8 (32%) pts after 2 cycles due to toxicity. Median follow-up was 54.2 months(mos). At baseline, median TIL count was 60% in the overall cohort. Numerically higher TIL count was observed among responders (80%) compared to non-responders (50%) ( p=0.22). Median TIL count post-NAC in residual samples was 40%, not significantly different to matched pre-NAC samples ( p=0.93). Overall, 3-y relapse free rate was 74.7% (95%CI 51.7-87.9); 3-y OS rate was 79.6% (95%CI 57.6-91) with 6 deaths of which 4 were related to metastatic disease. Table reports subset analyses. Most frequently altered genes were PIK3CA and TP53 in the overall cohort (each 20%) and in the responders subgroup (each 29%). Conclusions: In our study, pts who achieved pCR had numerically greater TIL infiltrate in baseline samples and pCR was associated with reduced risk of recurrence. TILs did not increase in residual tumors after NAC. The independent predictive value of TILs warrants assessment in large cohorts.[Table: see text]

Recent clinical trials have changed the treatment landscape for metastatic castration-sensitive prostate cancer. Ongoing and future studies using new therapeutic approaches hold the promise of further improving outcomes for patients with advanced prostate cancer.

PTEN deletion is associated with relapse after therapy for localized prostate cancer. There are limited data on PTEN loss as detected by immunohistochemistry (IHC) and the risk of lethal disease after surgery.To determine whether PTEN loss as detected by quantitative fluorescence IHC (FIHC) predicts lethal disease outcomes after surgery for prostate cancer.We used formalin-fixed, paraffin-embedded radical prostatectomy specimens to construct tissue microarrays and perform dual FIHC for PTEN and AMACR for masking tumor epithelium, plus semi-quantitative multispectral imaging analysis.The association of PTEN status analyzed continuously and dichotomously (low [expression in the lowest quartile] vs higher [expressionlowest quartile]) with disease outcomes (metastasis and death) was assessed with adjustment for age, Gleason score, and stage in multivariable analyses. The prognostic ability of PTEN was assessed using logistic regression models.Low PTEN expression was associated with a higher risk of metastatic disease as both a continuous (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.14-1.92; p0.003) and dichotomous (HR 1.92, 95% CI 1.02-3.63; p=0.04) variable. A significant association between low PTEN expression and poorer overall survival was observed (continuous: HR 1.89, 95% CI 1.37-2.63; p0.001; dichotomous: HR 2.66, 95% CI 1.34-5.28; p=0.005). Addition of PTEN status to clinicopathologic factors (age, Gleason score, and stage) incrementally improved a prognostic model assessing 10-yr outcomes for metastatic disease (area under the curve [AUC] 0.76 vs 0.80) and death (AUC 0.70 vs 0.75).Low PTEN expression detected by FIHC in primary prostate cancer is an independent prognostic biomarker for metastatic disease and death after definitive therapy. FIHC for PTEN is a viable clinical diagnostic assay in this context.We looked at loss of the PTEN protein in prostate tumors from men treated with surgery. Men with PTEN loss were at higher risk of metastasis and death. Assessing PTEN status may be useful in better determination of the risk of poorer outcomes.

Background High-dose chemotherapy (HDCT) with autologous stem-cell transplantation (aSCT) has been a standard therapy for relapsed metastatic germ-cell tumors (GCTs) over the last 2 decades, but there have been many changes in practice over time with respect to stem-cell source, mobilization, and conditioning regimens. Mobilization is impaired with greater cisplatin exposure. Patients and Methods Patients with relapsed GCT who received HDCT/aSCT at Dana-Farber Cancer Institute between 1997 and 2017 were identified. Diagnosis, first-line chemotherapy, stem-cell mobilization, HDCT, toxicity, and survival outcomes were annotated and descriptively summarized. Univariable associations of clinicopathologic features and relapse and survival were assessed. Time-to-event analyses were performed by HDCT type and duration. Results Thirty-five eligible patients were identified. The most common regimen before HDCT was paclitaxel, ifosfamide, and cisplatin, and it resulted in a high rate of successful initial mobilization (95%). Ten patients (29%) were mobilized with filgrastim and plerixafor (CXCR4 antagonist). All plerixafor-treated patients were mobilized with sufficient cells for 2 transplants. Oxazaphosphorine (cyclophosphamide or ifosfamide)-containing (O-C) HDCT was provided between 1997 and 2008, and subsequent patients were treated with high-dose carboplatin plus etoposide (CE). O-C HDCT was associated with excessive cardiac (33%), severe liver (93%), and renal dysfunction compared to CE. Two O-C–treated patients died of drug-related lung toxicity. Fifty-one percent of the cohort experienced relapse, and 46% died. Conclusion Plerixafor has a role in stem-cell mobilization and aSCT for relapsed GCT when cisplatin in bridging before HDCT may be problematic. O-C and CE HDCT regimens have different toxicity patterns that are clinically meaningful.

Background: Communication of prognosis and goals of care between oncologists, community health care providers (HCPs) and patients treated for advanced cancer facilitates optimal care planning. We aimed to review the frequency, content and timing of documented prognosis in written correspondence during the last year of life of advanced cancer patients. Methods: All patients who died during palliative care or medical oncology admission in 2015 at a large, Australian tertiary center were identified. Patients with incurable solid organ cancer and reviewed ≥1 times in oncology outpatient (OP) clinic were included. We reviewed all oncology OP consultation notes and letters, oncology discharge summaries and advanced care plans over a 12-month period before death. Both internal (OP notes) and external correspondence (OP letters; discharge summaries) were reviewed for documentation of qualitative and quantitative prognosis. Results: One hundred and forty-seven patients were included in the analysis [median age of 70 years, interquartile range (IQR), 58–77 years; males, 60%]. Most patients had a previous inpatient admission (73%). The median OP consultations per patient was 6 (IQR, 2–9) with a median rate of 63% (IQR, 41–87%) resulting in a correspondence letter. The majority of patients had a qualitative statement of prognosis documented in OP notes (63%) and external correspondence letters (61%). However only a minority had a documented quantitative prognosis in either OP notes (14%) or external correspondence letters (7%). The median time from documentation of qualitative and quantitative prognosis to death was 3.5 (IQR, 1.6–6.9) and 2.2 (IQR, 1.1–4.4) months, respectively. While almost all patients had a completed goals-of-care (GOC) form (99%), only 15% of patients had an advanced care plan. Conclusions: Documentation of qualitative and quantitative prognosis is infrequent despite multiple clinical encounters prior to patient death. This infers inadequate communication between oncologists and other HCPs which reduces insight into patient clinical trajectory and could result in differing care between providers.

5018 Background: Predictive genomic biomarkers in mCRPC remain elusive. Prior studies suggest that tumor suppressor (TS) loss is prognostic, and may result in less benefit from NHT, but no impact on D efficacy. We assessed genomic predictors of differential benefit of androgen receptor-targeted therapy and chemotherapy for mCRPC. Methods: Patients with mCRPC and targeted exome sequencing of biopsies obtained after metastatic diagnosis were identified (n=109). Patients with pure small cell histology (n=6) were excluded. Time from NHT or D start to clinical/radiographic progression (time to treatment failure, TTTF) was estimated by Kaplan-Meier method, with censoring at next therapy or last follow-up for non-progressors. Results: 80.1% of patients had bone and/or lymph node-only metastases at mCRPC diagnosis. In total, 87/103 (84.5%) and 61/103 (59.2%) received NHT and D for mCRPC, respectively. Median overall survival was 4.5 years from first mCRPC. The frequency and predictive association of selected recurrently-altered genes are detailed in the table. PTEN alterations (alts) were associated with worse TTTF on NHT, but not D, and a similar trend was observed with BRCA2. Biallelic RB1 loss was strongly predictive, conferring significantly shorter TTTF on both NHT and D. A score based on presence of tumor PTEN alt (1) and/or biallelic RB1 alt (1) was predictive of TTTF on NHT (median TTTF of score 0 vs 1 vs 2: 14.7 vs 12 vs 3.8 months; log rank p=0.003). Conclusions: The presence of single or compound PTEN and RB1 alts predict poorer outcomes with NHT for mCRPC. Chemotherapy may be a preferred therapeutic strategy for this patient population. [Table: see text]

IMPORTANCE Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. OBJECTIVE To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. DESIGN, SETTING, AND PARTICIPANTS A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry- matched controls. Statistical analysis took place from January to May 2018. MAIN OUTCOMES AND MEASURES Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. RESULTS Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8% ; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87 ; 95% CI, 1.65-8.86 ; nominal P = .006 ; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4 ; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30 ; 95% CI, 2.34- 17.31 ; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93 ; 95% CI, 1.53-9.95 ; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years ; 95% CI, 1.48-10.42 ; P = .009). CONCLUSIONS AND RELEVANCE This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

244 Background: Treatments and outcomes of men with nmCRPC in routine care are poorly described. We assessed the cumulative impact of new therapies in men who transition through nmCRPC using a single-institution database. Methods: We conducted a retrospective study of consecutive nmCRPC pts enrolled into a hospital-based registry at Dana-Farber Cancer Institute. Pts were analyzed by era of diagnosis of nmCRPC: 2000-2009 (when docetaxel was the only life prolonging metastatic CRPC therapy) (cohort A) and 2010-2018 (when new systemic therapies were approved for mCRPC or in trials for nmCRPC) (cohort B). We collected pt, treatment, metastasis-free survival (MFS) and overall survival (OS) data. Results: 230 men were included: 148 in cohort A and 62 in cohort B. Despite only 39% of cohort B pts receiving new hormonal therapies for nmCRPC, there was no difference in median MFS between both eras: 2.7 yrs (2.1-3.2) in cohort A and 2.2 yrs (1.4-3.3) in cohort B. 30% of pts in cohort A and 53% of pts in cohort B had two or more life prolonging mCRPC therapies at any time (Table). No difference in 3-year OS was seen but 4-year OS was numerically higher in cohort B, with a trend towards improved OS in the new era. Conclusions: In an era with access to more than one life prolonging therapy for mCRPC, greater use of these agents in pts who transition through nmCRPC to mCRPC did not improve 3-year OS but may impact longer term OS. [Table: see text]

86 Background: Given limited information about the prostate cancer (PC) immune infiltrate in men with localized disease, we profiled 6 markers and correlated them with risk of metastases after RP, using a single-institution cohort. Methods: Using a tissue microarray (TMA) with formalin-fixed, paraffin-embedded radical prostatectomy specimens, we performed a multiplex immunohistochemistry (IHC) analysis of immune checkpoint markers (PD1, PDL1), T-cell regulator / helper (FOXP3, CD4) and killer T cells (CD3, CD8). Quantitative multispectral imaging analysis was used to define the “density” of each marker: a ratio between number of positive cells divided by glandular and stromal area. Data collected included patient characteristics, time to biochemical relapse (BCR), time to metastasis (M1) and overall survival (OS). Results: TMA staining resulted data for at least one marker for 129 patients and all 6 markers for 109 patients. Median follow-up for this cohort was 14 years (0.25-27 years). As detailed in the table, either low CD8 or high PDL1 had a statistically significant association with biochemical and metastatic relapse and trend toward poorer OS on univariate analysis (UVA). A risk score of 0, 1 or 2 with CD8 low and PDL1 high each being one point revealed a strong association with higher score and incremental risk of BCR and metastasis. Conclusions: Multiplex IHC profiling of primary prostate cancer revealed high PDL1 and low CD8 density as poor prognostic markers alone and more impactful as part of a risk score for biochemical and metastatic relapse. [Table: see text]

653 Background: The pivotal clinical trials of CPI generally excluded pts with AD given concern for serious exacerbations. There is limited data on the safety and efficacy of CPI in this population. Methods: We conducted a retrospective single center analysis of RCC and UC pts treated with CPI. Pts were grouped by presence or absence of AD. We catalogued the incidence of new irAEs (CTCAEv4), AD exacerbations, objective response rate (ORR, RECIST 1.1), and overall survival (OS, Kaplan Meier). Competing risk models estimated cumulative incidences of irAEs and CPI discontinuation using 6 months (mos) as a benchmark. Results: 271 RCC and 220 UC pts were identified. Median followup was 21 mos for RCC and 13 mos for UC. 25 (9%) RCC and 27 (12%) UC had pre-existing AD; most commonly dermatologic and rheumatologic. A minority (3% RCC/4% UC) had clinically active AD requiring concurrent immunomodulators. AD exacerbations occurred in 8 (32%) RCC and 12 (44%) UC; median time to exacerbation was 86 (25-270) and 27 (8-300) days, respectively. Cumulative incidence of new irAEs at 6 mos was numerically higher in RCC AD pts (50% vs 37%). CPI discontinuation and clinical outcomes were similar among AD and non-AD pts (Table). Conclusions: CPI are active in advanced RCC and UC pts with pre-existing AD. Exacerbations and new irAEs should be expected, but AD pts can experience similar outcomes and rates of drug discontinuation. Larger scale investigations are warranted. [Table: see text]

First-line, potent androgen blockade for patients with newly diagnosed, advanced-stage, castration-sensitive prostate cancer is confirmed as an effective strategy by data from the STAMPEDE and LATITUDE trials. Herein, we highlight the benefits, discuss caveats and consider the clinical care implications of these findings.

e17041Background: Sipuleucel-T (Provenge) received FDA approval in April 2010 for pts with asymptomatic or minimally symptomatic mCRPC based on prolongation of overall survival. However, its adopti...

184 Background: Aberrations of tumor suppressors (TS) TP53, PTEN and RB1 are recurrent genomic events in PrCa and associated with adverse clinical outcomes. Preclinical data suggest that cooperative functional loss of these genes drives development of even more aggressive disease phenotypes. Methods: We identified a retrospective cohort of men with PrCa who underwent DFCI Oncopanel targeted sequencing (NGS) on prostate gland (n = 230) or metastatic tissue (n = 7) for TP53, PTEN and RB1. Biomarker(BM)-positive was defined as copy number loss or likely deleterious mutation of ≥1 TS. For pts presenting with localized disease, Kaplan-Meier method estimated time from biopsy preceding local therapy to PSA relapse/metastasis/death (EFS), castration resistance (CRPC) and death (OS). Cox model assessed association of BM status and outcomes, adjusted for age, clinical stage and Gleason score in multivariate analyses (MVA). For M1 disease, time from ADT start to CRPC and death was estimated. We explored the association of cumulative BM-positive gene hits (0 vs 1 vs 2/3) with EFS (local disease) and OS (M1 disease). Results: Of pts presenting with localized disease (n = 205), 39% were BM-positive and 73 (36%) relapsed after median follow-up of 3.1 years. BM positivity was associated with significantly shorter EFS (driven by PSA relapse) (median 2.6 years, HR 1.95, 95% CI 1.22-3.13) and time to CRPC (HR 3.36, 95% CI 1.01-11.16). MVA confirmed the association with EFS (HR 1.84, p = 0.029). More gene hits lead to incremental risk of relapse (1 gene: HR 1.8, 95% CI 1.09-2.99; 2/3 genes: HR 2.68, 95% CI 1.27-5.63; both vs 0 hits) and this remained significant in MVA (1 gene: HR 1.75, p = 0.05; 2/3 genes: HR 2.74, p = 0.04). 43 patients had relapsed or de novo M1 disease. BM positivity (enriched at 63% of M1) was associated with poorer OS (10 deaths [of 27 BM-pos] vs 0 deaths [of 16 BM-neg] at median follow-up 3.3 years, HR not eval). A trend to incremental worse survival with cumulative gene hits was again observed. Conclusions: Deleterious TP53, PTEN and RB1 variants are associated with a short time to PSA relapse in localized disease, occur at a higher frequency in M1 disease and confer poorer OS. Worse outcomes are seen with cumulative gene hits.

203 Background: From 2004 to 2009, mCRPC treatment options were limited to docetaxel (D), mitoxantrone, first generation anti-androgens (AA), estrogens, steroids, and ketoconazole, with only D showing OS benefit. Since 2010, five new therapies prolonged OS and were approved for mCRPC: sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, and radium 223. We sought to assess the aggregate impact of new therapies on OS. Methods: We used the DFCI CRIS database to identify cohorts of pts who developed mCRPC between 2004-2007 (cohort A) and 2010-2013 (cohort B). Therapies for mCRPC in each cohort were annotated. Given the median follow-up (FU) was 10.6 years (yrs) in cohort A and 4.6 yrs in cohort B, we evaluated OS, defined as time from mCRPC per PCWG3 criteria to death from all causes or last follow-up visit within 5 yrs (truncated OS). Kaplan-Meier method estimated the time to events distribution with median (95% CI). Cox proportional hazards model evaluated effects of treatment groups on disease outcomes with estimates of hazard ratio (95% CI). Results: Of the 583 pts identified, 317 (54%) were in cohort A and 266 (46%) in cohort B. Pts in cohort B had a significantly longer median OS (p

15 Background: Loss of PTEN expression correlates with poorer clinical outcomes after definitive therapy for non-metastatic (M0) PrCa. While most studies have used biochemical-based end points, there is limited data regarding PTEN loss by IHC and risk of lethal disease after surgery. Methods: A retrospective cohort of patients who underwent radical prostatectomy (RP) was identified from the Dana-Farber Prostate Clinical Research Information Systems (CRIS) database. Formalin-fixed, paraffin-embedded RP specimens were used to construct tissue microarrays and F-IHC for PTEN was performed. Using multispectral imaging analysis, tumor-only PTEN expression was quantified. PTEN expression was analyzed continuously and dichotomously (low [ < lower quartile] vs other [≥lower quartile]). Kaplan-Meier method estimated the distribution of time from RP to metastatic disease and overall survival (OS). Cox model assessed association of PTEN status and the disease outcomes, with adjustment of age, Gleason score and pathological stage in multivariate analyses (MVA). Prognostic ability of PTEN was also explored using a logistic regression model. Results: The analysis cohort comprised 91 patients with either non-lethal (no metastatic or biochemical relapse) or lethal disease (metastasis post-RP). The median follow-up was 12.4 years. PTEN low was significantly associated with lethal disease as both a continuous (HR 1.82, 95% CI 1.35-2.44) and dichotomous (HR 2.94, 95% CI 1.52-5.56) variable. Significant association of PTEN-low expression and poorer OS was observed (cont: HR 2.22, 95% CI 1.54-3.23; low vs other: HR 4.00, 95% CI 1.89-8.33). MVA models yielded consistent results. A prognostic model assessing 10-year disease outcomes showed incremental prognostic improvement with PTEN status added to age/Gleason/stage (lethal disease: area under curve (AUC) 0.79 vs 0.84 [+PTEN status]; death: AUC 0.71 vs 0.76 [+PTEN status]). Conclusions: Low PTEN expression by F-IHC in primary prostate cancer is an independent prognostic biomarker of lethal disease and death after surgery. Quantitative F-IHC for PTEN is a viable diagnostic assay in this context.

304 Background: Moderate frequencies of DDR gene variants exist in mPC. Their prognostic role in localized and mPC is unclear. This study aims to characterize DDR variants in a cohort of hormone sensitive localized and mPC and assess for association with outcome. Methods: A retrospective cohort of men with PC and ≥ 2 follow up visits at DFCI and targeted next generation sequencing of prostate or metastatic tissue was identified. Biomarker (BM) positive was defined as pathogenic changes in the following DDR genes: ATM BAP1 BRCA1 BRCA2 BRIP1 CHEK2 MSH2 MSH6 PALB2 PMS2. For localized PC, outcome endpoints included event-free survival (EFS) (time from prostate biopsy to PSA relapse/metastasis/death), metastasis-free survival (MFS) (time to metastasis/death), time to castration resistance (CRPC), and death (OS); for mPC, outcome events included time from androgen deprivation start to CRPC and OS. BM status was descriptively summarized. Kaplan-Meier method and Cox regression model assessed associations of BM status with clinical outcomes. Results: Of the 237 men included, 16 (7%) were BM positive; 12 (6%) in 205 localized PC, 6 (14%) in 43 mPC. BM positive genes included 9 (4%) ATM, 6 (3%) BRCA2, and 2 (0.8%) CHEK2. In men with localized PC, EFS events occurred in 58% (7/12) BM positive vs 34% (66/193) BM negative at median follow up of 3.1 years; BM positive trended toward a shorter EFS (median 1.9 vs 5 years) than BM negative (HR 2.17, 95%CI 0.99-4.76). MFS events were observed in 17% (2/12) BM positive vs 7% (15/193) BM negative. CRPC events occurred in 17% (2/12) BM positive vs 6% (11/193) BM negative. In men with mPC, there were CRPC events in 100% (6/6) BM positive vs 67% (25/37) BM negative at median follow up of 3.3 years; BM positive trended toward a shorter time to CRPC (median 4 vs 8.8 months) compared to BM negative (HR 1.87, 95%CI 0.76-4.64). There was no association between BM status and OS. Conclusions: DDR variants appear infrequently in localized PC but may portend a shorter time to PSA relapse and metastasis. Similarly, DDR variants in mPC may be associated with a shorter time to CRPC. Low frequency of variants and short follow up limit these analyses. The prognostic value of DDR variants remains unclear and requires further research.

3577 Background: Optimal treatment for locally advanced rectal cancer (LARC) includes neoadjuvant short-course radiotherapy (SCRT) or long-course chemoradiotherapy. One advantage of long-course tre...