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20 Background: Metastatic castration-sensitive prostate cancer (mCSPC) primarily affects older men (OM). In this post-hoc analysis we investigated the safety and efficacy of abiraterone acetate + prednisone (AAP) in older (≥ 70 years) and younger (< 70 years) patients in PEACE-1. Methods: Men with de novo mCSPC were allocated to standard of care (SOC), SOC + AAP, SOC + radiotherapy (RXT), or SOC + AAP + RXT in this 2x2 design phase 3 trial. SOC was initially androgen deprivation therapy (ADT) alone, then from Oct 2015 onwards, the use of docetaxel (D) was authorized as part of SOC (at the investigator’s discretion until 2017, then, following the publication of LATITUDE and STAMPEDE trials, accrual was restricted to men receiving ADT+ D). Efficacy and safety in OM included in PEACE-1 were analyzed with the same methods used in the overall trial (Lancet 2022; 399: 1695-1707). Results: A total of 741 younger men (YM) (63%) and 431 OM (37%) were randomized. OM presented with more altered PS (ECOG 1-2) (36% vs 26% p=0.0003) and less frequent use of docetaxel (D) as part of SOC (66% vs 51% p

170 Background: In the primary analysis of the phase 3 MAGNITUDE study, NIRA/AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations. Here, we report results from IA2 of secondary endpoints in MAGNITUDE. Methods: 423 eligible pts with mCRPC and HRR alterations (HRR+ cohort) were randomized 1:1 to receive NIRA/AAP (n = 212) or placebo (PBO)/AAP (n = 211). At the prespecified IA2, secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]) were formally assessed and the primary rPFS endpoint was updated in the HRR+ cohort, with sensitivity analysis performed for the subgroup of pts with BRCA alterations. Results: Updated descriptive rPFS results at IA2 (cutoff: June 17, 2022) were consistent with the primary analysis in the HRR+ cohort. In the BRCA subgroup, NIRA/AAP extended median rPFS to 19.5 mos vs 10.9 mos with PBO/AAP. NIRA/AAP led to statistically significant benefit in TSP in the HRR+ cohort with consistent benefit in the BRCA subgroup. Continued consistent improvement of TCC was seen with NIRA/AAP in the HRR+ cohort and in the BRCA subgroup. There was a trend towards improved OS with NIRA/AAP in the BRCA subgroup in the primary stratified analysis and the multivariate analysis (MVA), accounting for imbalances in key baseline characteristics. BRCA pts treated with NIRA/AAP experienced delayed time to worst pain intensity (HR, 0.70; 95% CI, 0.44, 1.12; nominal P = 0.1338) and pain interference (HR, 0.67; 95% CI, 0.40, 1.12; nominal P = 0.1275) compared to PBO/AAP. The safety profile at IA2 was consistent with that of the primary analysis, with no new safety signals observed. Conclusions: With 26.8 months of median follow-up, there was a statistically significant and meaningful clinical benefit in TSP and meaningful clinical benefit in TCC. Additionally, updated rPFS results from MAGNITUDE IA2 were consistent with the primary analysis; OS benefit was not conclusive due to immaturity and will be followed through to final analysis. Taken together, these data continue to support the use of NIRA/AAP in pts with mCRPC and BRCA alterations or select other HRR gene alterations. Clinical trial information: NCT03748641 . [Table: see text]

5060 Background: Results from the international, randomized, double-blind, phase 3 MAGNITUDE study demonstrated that NIRA + AAP improved radiographic progression-free survival, time to cytotoxic chemotherapy, and time to symptomatic progression, with manageable toxicity in pts with mCRPC and HRR alterations (9-gene panel). Here, we report HRQoL and pain in MAGNITUDE. Methods: Eligible pts with mCRPC and HRR alterations were randomized 1:1 to NIRA + AAP or placebo (PBO) + AAP orally daily in 28-day cycles. Pts had ECOG status ≤1 and a Brief Pain Inventory–Short Form (BPI-SF) worst pain score ≤3 in prescreening. HRQoL assessments on day 1 of specified cycles included Functional Assessment of Cancer Therapy–Prostate (FACT-P) and BPI-SF. Changes from baseline were compared between treatment arms using repeated measures analysis. Proportional hazards regression models were used to compare time to deterioration (TTD) in worst pain intensity between arms. Results: Compliance for FACT-P and BPI-SF was > 80%. Most pts maintained low pain levels over time. Repeated measures analyses showed no clinically meaningful differences in pain over time or between arms. Median TTD in pain intensity was not reached in either arm. At the 25th percentile, there was a trend toward longer TTD in pain intensity with NIRA + AAP vs PBO + AAP (11.1 vs 10.1 mo; HR, 0.87; 95% CI, 0.61-1.24). HRQoL was maintained with NIRA + AAP, with no clinically meaningful differences in FACT-P total score over time or between arms. There was a trend toward greater worsening in early cycles on FACT-P physical wellbeing with NIRA + AAP vs PBO + AAP, driven by events within the known safety profile of NIRA + AAP (worsening of side effect bother, lack of energy, and nausea); however, overall, most pts reported minimal side effect burden (Table). Conclusions: In MAGNITUDE, most pts maintained low pain levels and positive HRQoL over time, with no clinically meaningful differences between treatment arms, further supporting the use of NIRA + AAP in pts with mCRPC and HRR alterations. Side effect burden was perceived as low in both arms. Although more pts on NIRA+AAP reported worsening side effects, the symptoms were generally perceived as mild. Clinical trial information: NCT03748641. [Table: see text]

2596 Background: Given that most of cancer patients treated with anti-PD1/PD-L1 immune checkpoint blockers (ICB) do not derive benefit, there is a crucial need to identify reliable predictive biomarker of response. Besides PD-1, several key immune checkpoints, such as CTLA4, LAG3, TIM3 and TIGIT, are associated with a T cell exhausted phenotype and play a crucial role in leading to cancer immune evasion. The impact of simultaneous expression by T cells of distinct inhibitory receptors on outcome of patients treated with ICB is still unknown. Methods: We analyzed the tissue samples, collected before ICB initiation, from patients with solid tumors and included in an institutional molecular profiling program (NCT02534649). We used multiplexed-immunohistofluorescence with the following panel CD3/PD1/TIM3/LAG3/TIGIT/CTLA4, and performed immune cell characterization using multispectral images analysis. We then investigated the correlation between coexpression of T cell-associated exhaustion markers, clinical response rate, progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards models. Results: Four hundred thirty five patients were included in the analysis (NSCLC: n=207, 47.6%; sarcoma: n=42, 9.7%; urothelial: n=30, 6.9%; others: n=156, 35.9%). Digital pathology analysis allowed us to identify a population of “super-exhausted” T cells characterized by the co-expression of PD1, LAG3, TIGIT and TIM3 which was enriched in 125 cases (28.7%), and was significantly associated with better PFS (HR 1.60, CI95 1.26-2.04, p1 %) was significantly associated with better PFS (HR 0.61, CI95 0.46-0.81, p

5020 Background: NIRA + AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations in the Phase 3 MAGNTUDE study. There is a paucity of data supporting use of PARP inhibitors in pts with HRR gene alterations other than BRCA1/2. We report on the efficacy of NIRA + AAP in pts with mCRPC and a qualifying single gene HRR alteration other than BRCA1/2. Methods: A pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate (ORR) across 186 pts (91 randomized to NIRA + AAP, 95 to PBO + AAP) with an alteration in the ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene (excluding cooccurring alterations) . This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity are also presented. Results: (Table). Pts with PALB2 or CHEK2 alterations had consistent improvement across all endpoints. In pts with ATM alterations benefit was observed in TCC, TSP, TPSA and ORR. There was benefit only in TPSA and ORR for pts with CDK12 alterations. When combined into functional groups, pts with an alteration in the HRR-Fanconi pathway ( BRIP1, FANCA, and PALB2) as well as pts with a HRR associated alteration ( CHEK2 or HDAC2) showed improvement in all endpoints. Conclusions: These data support the overall conclusions of the MAGNITUDE primary analysis and support benefit of NIRA + AAP in pts with HRR mutations beyond BRCA1/2. Clinical trial information: NCT03748641. [Table: see text]

12000 Background: Pain is the most common symptom experienced by patients with advanced cancer. Acetaminophen (APAP, commonly known as paracetamol) alone or in combination with a weak opioid, such as codeine or tramadol, is usually considered as the first-line strategy to manage mild-to-moderate pain in this setting. Although generally considered to be safe, several evidences suggest that APAP may have negative immunomodulatory effects. Randomized studies have shown that APAP use is associated with blunted vaccine immune responses. Given its potential to impair vaccine effectiveness, the World Health Organization stated in 2015 that administration of APAP before or at the time of vaccination is not recommended. This study aimed to assess APAP impact on efficacy of immunotherapy in patients with cancer. Methods: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICB): the CheckMate 025 trial, n = 297 (NCT01668784, sponsor: Bristol Myers Squibb), the institutional biomarker program BIP n = 34 (NCT02534649, sponsor: Institut Bergonié, Bordeaux, France) and the institutional biomarker program PREMIS n = 297 (NCT03984318, sponsor: Gustave Roussy, Villejuif, France). APAP immunomodulatory effects were evaluated on a pre-clinical tumor model (MC38) and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. Results: Detectable plasma APAP levels at treatment onset was associated with a significantly worse clinical outcome in ICB-treated cancer patients (HR for progression-free survival : 1.43, 95% CI 1.07–1.91, p = 0.015; HR for overall survival: 1.78 95% CI 1.18–2.68, p = 0.006), independently of other prognostic factors (age, performance status, number of previous lines of treatment, tumor type, number of metastatic sites, presence of liver metastases, LDH levels). APAP significantly reduced ICB efficacy in the pre-clinical MC38 model, as well as the production of PD1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly upregulated upon treatment with ICB in cancer patients taking APAP. Conclusions: This study provides strong pre-clinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.

12 Background: Approximately 20% of mCRPC has alterations in genes associated with HRR and is responsive to PARP inhibitors (PARPi) such as NIRA. Combined PARPi with androgen receptor pathway targeting may also benefit unselected mCRPC. MAGNITUDE assessed whether adding NIRA to AAP improves outcomes in pts with mCRPC with or without alterations in HRR associated genes. Methods: MAGNITUDE (NCT03748641) is a randomized, double-blind phase 3 study. In eligible mCRPC pts, ≤4 mos of prior AAP for mCRPC was allowed. Pts with (HRR biomarker [BM]+; ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and without specified gene alterations (HRR BM-) were randomized 1:1 to receive NIRA 200 mg once daily + AAP or placebo (PBO) + AAP. Primary endpoint was radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in the BRCA1/2 group followed by all HRR BM+ pts. Secondary endpoints were time to initiation of cytotoxic chemotherapy (TTCC), time to symptomatic progression (TTSP) and overall survival (OS). Other endpoints included time to PSA progression (TTPP) and objective response rate (ORR). Results: 423 HRR BM+ pts were randomized to NIRA + AAP (n = 212) or PBO + AAP (n = 211). Median age was 69, 23% had prior AAP, 21% had visceral metastases, and 53% had BRCA1/2 mutations. Median follow-up was 18.6 mos. NIRA + AAP significantly improved rPFS by BICR in the BRCA1/2 subgroup and in all HRR BM+ pts, reducing the risk of progression or death by 47% (16.6 vs 10.9 mo) and 27% (16.5 vs 13.7 mo) respectively (Table), vs PBO + AAP. Investigator assessed rPFS was consistent with BICR. NIRA + AAP delayed TTCC, TTSP, and TTPP and improved ORR in HRR BM+ pts (Table). First interim analysis of OS is immature. The preplanned futility analysis in 233 HRR BM- pts showed no benefit of adding NIRA to AAP in the prespecified composite endpoint (first of PSA progression or rPFS; HR, 1.09; 95% CI, 0.75-1.57). No new safety signals were seen. In HRR BM+ pts, 67% and 46.4% had grade 3/4 AEs and 9% and 3.8% discontinued treatment in the NIRA + AAP and PBO + AAP arms, respectively. There were no clinically significant differences in overall quality of life (FACT-P). Conclusions: NIRA + AAP improves rPFS and other clinically relevant outcomes in pts with mCRPC and alterations in HRR associated genes. There was no evidence of benefit with the addition of NIRA to AAP in HRR BM- pts with mCRPC. Clinical trial information: NCT03748641. [Table: see text]

492 Background: Immune checkpoints inhibitors (ICIs) have recently changed therapeutic landscape of la/mUC. Recent studies suggested an improvement of response to salvage chemotherapy (CT) after ICIs in several cancer types including urothelial carcinoma. We assumed that efficacy of CT rechallenge after ICIs may be improved compared to second-line CT without previous ICIs in patients (pts) with la/mUC. Methods: CIMUC is a French multicentric retrospective study including all pts with la/mUC initiating second or third-line CT from January 1st 2015 to June 30th 2020. Two groups of pts were defined: pts in group 1 (G1) were treated with a second-line CT without previous ICIs; pts in group 2 (G2) were treated with third line CT after ICIs. Primary endpoint was objective response rate (ORR: proportion of patients with complete or partial response, according to RECIST 1.1 criteria) in G2 versus G1. Secondary endpoints were progression-free survival (PFS), defined as time from initiation of second or third-line CT to disease progression or death from any cause, and toxicities. This study is supported by the French Genito Urinary Group (GETUG). Results: 553 pts were included. Baseline characteristics of the 2 groups are summarized in the Table. ORRs were 31% (95%CI [26.5-35.5]) and 29.2% (95%CI [21.9-36.6]) respectively in G1 and G2, without statistically significant difference (p=0.617), even after adjustment for Bellmunt risk factors (p=0.3214). In subgroups analysis, no difference in ORR was observed by type of CT (platinum or taxanes), duration of response (DOR) to first-platinum-based CT (< 12 months or ≥ 12 months) and FGFR-status. We did not identify any predictive factor of OR in G2 in multivariate analysis. Median PFS were 4.6 months (95%CI [3.88; 5.06]) and 4.86 months (95%CI [4.11; 5.45]), respectively in G1 and G2. Grade 3/4 hematologic toxicity occurred in 35% and 22.4%, respectively in G1 and G2. Conclusions: While ORR was not superior in G2 versus G1, pts derive comparable benefit in a further line of treatment (G2) in terms of ORR and PFS. Despite limits inherent to any retrospective study, CIMUC represents one of the largest retrospective studies in this setting.[Table: see text]

5000 Background: Historically, androgen deprivation therapy (ADT) was the standard of care (SOC) for men with mCSPC. Since 2015, combining ADT with either docetaxel, novel hormonal therapies, or radiotherapy to the primary tumor (RXT) (for those with low burden metastases) was shown to improve overall survival (OS) and thus has become the new SOC. It is unknown whether combining these new treatments on top of ADT further increments outcomes. Methods: Men with de novo mCSPC were randomized to SOC, SOC + abiraterone acetate-prednisone (abiraterone), SOC + RXT, or SOC + abiraterone + RXT. SOC was initially ADT alone, then from Oct 2015 onwards the use of docetaxel was authorized as part of SOC (at the investigator’s discretion until 2017, then, following the publication of the LATITUDE and STAMPEDE trials, accrual was restricted to men receiving ADT+docetaxel). The trial has two co-primary endpoints of radiographic progression-free survival (rPFS) and OS with type I error of 0.1% and 4.9%, respectively. The required number of rPFS events to achieve 80% power has been reached for the abiraterone question (not yet for the RXT question). The interaction between abiraterone and RXT was first tested using a Cox model adjusted for stratification factors (performance status, type of castration, metastatic burden, and when applicable, docetaxel). A hierarchical testing was used to test the effect of abiraterone: overall population, then ADT+docetaxel population. Results: From Nov 2013 to Dec 2018, 1173 men were enrolled (SOC was ADT+docetaxel in 710 pts and ADT alone in 463 pts), median age 67y (IQR: 60-72), high volume 57%, low volume 43%. The median follow-up is 3.5y. No interaction was detected between the effect of abiraterone and that of RXT (p = 0.64), allowing to pool abiraterone arms for comparisons. rPFS was significantly improved in the abiraterone arm in the overall population (HR: 0.54 (0.46-0.64), p < 0.0001; medians: 2.2 vs 4.5 years) and in the ADT+docetaxel population: (HR: 0.50 (0.40-0.62), p < 0.0001; medians: 2.0 vs 4.5 years). bPFS (PFS including PSA progression as an event) also significantly favored abiraterone in the overall population (HR: 0.40 (0.35-0.47), p < 0.0001; medians: 1.5 vs 3.8 years) and in the ADT+docetaxel population (HR: 0.38 (0.31-0.47), p < 0.0001; medians: 1.5 vs 3.2 years). OS is maturing. Grade 3-4 adverse events reported in > 5% of pts within the first 6 months in the ADT+docetaxel population included neutropenic fever (4.5% vs 5.4%), liver toxicity (19.7% vs 13%), and hypertension (12.2% vs 8.6%) in the abiraterone and control arms, respectively. Conclusion: Adding abiraterone to ADT + docetaxel significantly improves rPFS in men with de novo metastatic prostate cancer, with about 2.5 years of absolute benefit in medians, and no meaningful additional short-term toxicity. Clinical trial information: NCT01957436.

5046 Background: Darolutamide (Daro) and enzamutamide (Enza) are both next generation androgen receptor inhibitors with demonstrated activity in men with CRPC. Although both agents are associated with survival improvement, their toxicity profiles are different. To help decipher whether this may impact on patient preference, we designed the ODENZA trial. Methods: ODENZA is a prospective, randomized, open-label, multicenter, cross-over, phase II trial of preference between Daro and Enza in men with asymptomatic or mildly symptomatic metastatic CRPC. Patients were randomized 1/1 to receive Daro 1200 mg/d for 12 weeks followed by Enza 160 mg/d for 12 weeks (Daro-Enza arm) or the reverse sequence (Enza-Daro arm). In both arms, the second treatment was given in absence of evidence of cancer progression at week 12. The primary endpoint was patient preference between the two drugs, as assessed by a questionnaire at week 24. The Prescott's test was used to determine treatment preference in patients fullfilling pre planned criteria (exposure to both treatments, no progression at week 12, and completion of the preference questionnaire). A p-value greater than 0.05 indicates that there is no difference in preference between treatments. Stratification factors were performance status and prior taxane for mCSPC. After week 24, patients went on to an extension period during which they received the chosen treatment until progression or toxicity. The main secondary objectives included reasons for preference, response at week 12, cognitive assessment, and toxicity. Results: Overall 249 pts were randomized, median age 72y (68; 79), ECOG PS 0 (56%), prior taxanes (22%). Two hundred pts fulfilled the pre-planned criteria for evaluation of the preference primary endpoint : 97 (48.5% [41.3;55.7]), 80 (40.0% [33.0;47.0]), and 23 (11.5% [6.8;16.2]) chose Daro, Enza, and had no preference, respectively (unilateral p-value of 0.92). After preference assessment, 186 patients entered the extension period: 103 (55.4%) and 83 (44.6%) received Daro and Enza respectively. The most common factors influencing patient preference all numerically favored Daro over Enza, without significant differences were: less fatigue (44% vs 29%), ease of taking the medication (37% vs 31%), better quality of life (36% vs 28%), ability to be more active (26% vs 15%), ability to concentrate (22% vs 15%) and less falls (6% vs 3%). A PSA50 response was achieved in 76.2% and 83.9% at week 12 with Daro and Enza respectively (p = 0.13). Fatigue was the most frequently reported all grade adverse event at week 12, in 21% and 36% with Daro and Enza, respectively. Conclusions: More patients with early mCRPC preferred Daro over Enza, although the difference did not reach significance, with fatigue as the key influencing factor. Clinical trial information: NCT03314324.

e16557 Background: In the current era of Immune checkpoint inhibitors (ICI), the role and timing of nephrectomy is still unknown. We aimed to evaluate the oncological outcomes of patients with metastatic renal cell carcinoma (mRCC) managed with nephrectomy for residual disease after complete response (CR) or major partial response (mPR defined as > 80%) on metastatic sites following ICI. Methods: Patients who underwent nephrectomy after prior ICI between 2015 and 2020 were retrospectively included and clinicopathological data were reviewed. Perioperative data, postoperative complications, toxicities related to ICI, continuation or discontinuation of systemic treatment following surgery, and 1-year oncological outcomes were recorded. Results: Twenty-five patients without initial cytoreductive nephrectomy at diagnosis underwent delayed nephrectomy after long ICI administration because of CR (or mPR) on metastatic sites. Median age was 62 years [38-79]. 88% of patients had clear cell RCC on the initial biopsy. IMDC prognostic group was intermediate (80%) or poor (20%). ICI was administered as first-line therapy in 56.0% of cases and as second-line option after TKI in 44.0% of cases. Treatments regimens were: nivolumab + ipilimumab (n = 12), nivolumab + tivozanib (n = 2) or nivolumab alone (n = 11). The mean duration of ICI treatment was 11.8 months (range: 3-38 months) and the mean number of cycles was 19 (range: 6-75). Twelve patients had a CR on metastatic sites while 13 patients had a mPR ( > 80%). Overall, 64% of patients experienced toxicities related to ICI treatment. Median operative time was 210 minutes [90-345] and mean blood loss was 558 cc [40-4000]. In 80.0% of cases, surgeons experienced difficulties in finding dissection plans due to adhesions and/or inflammatory infiltration. The 30-day Clavien-Dindo postoperative complication rate was 36.0%, including 1 surgery-related death. Pathological report showed lymphocyte and/or macrophage infiltration in 60% of cases and complete pathological response (pT0) in 3 cases (12%). After a mean follow-up of 19.4 months, 79.2% of the patients were free from progression and 70.8% free from systemic treatment. The recurrence-free survival (RFS) and overall survival (OS) at 1 year were 79.5% and 89.8% respectively. CR on metastatic sites was significantly associated with good RFS compared to mPR (1-year RFS = 100% vs. 56.8%, median RFS = 21.6 vs. 4.25 months, p = 0.006) while the duration of IO treatment exposure was not. Conclusions: Nephrectomy following ICI for mRCC can be a difficult procedure. However, it may provide good long-term RFS, with systemic treatment discontinuation following surgery in most cases. This strategy may be offered in well-selected patients, especially in case of CR on metastatic sites before surgery.

429 Background: Patients (pts) with advanced UTC who fail first-line therapy have poor prognoses. Durvalumab (D; anti-PD-L1) 10 mg/kg every 2 weeks is approved for treatment of metastatic urothelial carcinoma (mUC) after progression on platinum-based chemotherapy (CT). Further understanding of long-term safety and efficacy of D in platinum and non-platinum pretreated pts, using a fixed dose every 4 weeks (Q4W), is of value. Methods: Module A of the phase IIIb STRONG study (NCT03084471) investigated the safety of fixed-dose D (1500 mg, Q4W) in pts with urothelial and nonurothelial UTC who progressed on or after platinum/non-platinum CT. The primary endpoint was the number of pts with adverse events of special interest (AESIs) – events with an inflammatory or immune-mediated mechanism that may require interventions (eg, steroids/immunosuppressants), including immune-mediated adverse events (imAE). AEs with onset date on or after the date of first dose and up to 90 days after study discontinuation were included. Secondary endpoints included serious AEs and overall survival (OS). Exploratory endpoints included objective response rate (ORR) and disease control rate (DCR) (investigator assessed per RECIST 1.1). Results: A total of 867 pts received D monotherapy. Median age was 68.1 yr and 80.0% were male; 87.1% had an ECOG PS 0-1 and 12.7% had ECOG PS 2. Most (96.3%) had urothelial UTC, including urothelial variants. Tumor PD-L1 expression was high (≥25%) in 239/577 (41.4%) pts with available data. Median treatment and follow-up duration were 12.1 wk (range 1-128) and 13.8 mo (range 0.0-28.8), respectively. Safety data are reported in the table. Deaths related to study treatment occurred in 9 pts (1.0%). At data cutoff (March 31, 2020), 30.8% of pts were in survival follow-up. Median OS was 7.0 mo (95% CI: 6.4-8.2); OS rate at 1 and 2 yr was 35.8% (95% CI: 32.5-39.2) and 20.2% (95% CI: 16.5-24.1), respectively. ORR was 17.7% with complete responses in 5.1% of pts. DCR at 6 mo was 33.0%. Median OS of subgroups: PD-L1 high or low: 9.3 mo (95% CI: 6.7-12.7) and 6.5 mo (95% CI: 5.8-8.1); ECOG PS 0-1 or 2: 8.4 mo (95% CI: 7.2–9.8) and 3 mo (95% CI: 2.0-4.1); urothelial and nonurothelial UTC: 7.0 mo (95% CI: 6.4-8.2) and 7.0 mo (95% CI: 2.7-10.2), respectively. Conclusions: Fixed-dose D monotherapy Q4W is convenient with an acceptable safety profile in previously treated pts for UTC. Long-term safety and efficacy data reported are consistent with published studies of D and other IO agents in this setting. Clinical trial information: NCT03084471 . [Table: see text]

385 Background: Personalized chemotherapy based on tumor marker decline is the new standard in poor prognosis germ-cell tumor in Europe since 2014 (GETUG 13, Lancet, Fizazi et al). The purpose of this study was to analyze the reproducibility of the princeps study in patients not selected in clinical routine between 2014 and 2018. Methods: Patients (pts) were eligible if they had at least one criteria of IGCCCG classification for poor prognosis group. They had to be treated according the study terms of GETUG 13 study and did not received prior treatment. They had to received 1 BEP (Bleomycin, Etoposide, Cisplatin). Tumor markers (HCG and AFP) were dosed between day 18 and 21. Then, they received 3 additional BEP if they had favorable tumor marker decline or intensive chemotherapy if they had unfavorable decline. Results: This retrospective study included 104 patients in 14 french centers treated between 2013 and 2018: 22,1 % (n = 23) in the favorable group (Fav), 77,9 % (n = 81) in the unfavorable group (Unfav). Thirty-two pts had PS ≥ 2. In Unfav, there were more pts with HCG > 50 000 UI/L (44,2 % vs 13 %, p = 0,0067), neutrophil-to-lymphocyt ratio was also higher (median 6,4 vs 4,5, p = 0,0199). At cycle 1, all pts received BEP in Fav and 87,5 % (n = 70) in Unfav. After chemotherapy and surgery, 65,2 % in Fav and 41,3 % in Unfav obtained complete response. At 30 months (median follow-up), Fav-OS was 80,5 % (IC95% 55,8 – 92,2) and Unfav-OS was 64,4 % (IC95% 52 – 74,4). At 30 months, rates were 69,6 % (IC95% 46,6 -84,2) and 63.5 % (IC95% 51,9 – 73) respectively. In GETUG 13 study, 3-years OS was 84 % in Fav and 73 % on Unfav; 3-years PFS was 70 % and 59 % respectively. Seven pts died because of toxicity in Unfav (No one in Fav). Neuropathy, anemia and thrombopenia were more frequent in Unfav. Salvage high-dose chemotherapy with stem-cell transplant was required in 4 (66,7 %) pts in Fav and 8 (36,4 %) pts in Unfav. Conclusions: This study showed a reproducibility of the princeps study in terms of PFS and OS. Toxicity seemed more important in real world. For the congress, results will be reported with 50 additional pts.

5539 Background: In the randomized Phase III PROfound trial (NCT02987543), olaparib significantly prolonged radiographic progression-free survival compared with physician’s choice of new hormonal agent (pcNHA, enzalutamide or abiraterone) in men with mCRPC and HRR gene alterations, whose disease had progressed on prior NHA. Olaparib significantly improved time to pain progression in Cohort A. We report additional patient reported outcome measures of HRQoL in the overall study population (Cohorts A+B). Methods: HRQoL was assessed in the overall study population using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing, social wellbeing, and prostate cancer subscale (PCS). The Trial Outcome Index (TOI; PWB+FWB+PCS) and FACT Advanced Prostate Symptom Index (FAPSI-6: derived from 6 FACT-P items) were also calculated. Adjusted mean change and time to deterioration in scores were statistically analyzed. Results: Baseline FACT-P total score was similar for both treatment arms. FACT-P total and subscale scores during treatment were all higher for olaparib vs pcNHA, with clinically meaningful differences between treatment arms in the adjusted least square (LS) mean changes from baseline in all but FWB and FAPSI-6 (Table). The time to deterioration in FACT-P total and TOI, FAPSI-6, PWB and PCS scores favored olaparib but were not statistically significant, with hazard ratios ranging from 0.68 to 0.94. Further HRQoL results for cohort A will also be presented. Conclusions: Olaparib delayed deterioration in HRQoL scores vs pcNHA and was associated with better HRQoL functioning over time compared with pcNHA in men with mCRPC and HRR gene alterations. Clinical trial information: NCT02987543 . [Table: see text]

798 Background: In the context of a new cancer or relapse, the high sensitivity (Se) (95-100%) of PET-CT with 18F-FDG can lead to the demonstration of hypermetabolic mediastinal adenopathies. Its lower specificity (Sp) (89%) can require histological examination. We report the results of a prospective, single-center study evaluating the diagnostic performance of EUS-FNA in this indication. Methods: Prospective single-center study featuring patients in whom PET had revealed hypermetabolic mediastinal lymphadenopathy requiring diagnostic certainty. All EUS-FNA were performed with a 19-gauge needle (EchoTip, Cook Endoscopy). Main objective: To evaluate the diagnostic performance in terms of Se and Sp of EUS-FNA in the characterization of hypermetabolic mediastinal adenopathies in PET in the context of a new cancer or relapse. Secondary objectives: To evaluate the negative predictive value (NPV) of the EUS-FNA and to evaluate the percentage of surgical diagnostic procedures avoided. The standard technique was a thoraco-abdominopelvic CT scan at 6 months and at 12 months. Results: 52 patients were eligible and evaluable for the primary endpoint. The most common primary cancers were mammary (17.3%) and bronchial (13.5%). The lymph nodes were analyzed as malignant in 44.2% of cases, benign in 50% of cases and atypical or suspicious in 3.8% of cases. The malignant lymph nodes were metastatic for breast cancer in 21.7% of cases, bronchial cancer in 17.4% of cases, colorectal cancer in 17.4% of cases and prostate cancer in 13% of cases. The Se of the EUS-FNA was 92% (95% CI 0.74-0.99) and the Sp 100%. NPV was 87% (95% CI: 0.59-0.98). A diagnostic surgical procedure was necessary in 2% of the cases. PET and EUS-FNA often allowed the modification of the therapeutic strategy. Conclusions: When a confirmed diagnosis is required, the diagnostic accuracy of the minimally invasive procedure of EUS-FNA, is sufficiently robust to avoid a surgical diagnosis technique. The combination of PET and EUS-FNA may alter the therapeutic strategy that would have been considered after PET alone. Clinical trial information: NCT01892501.

358 Background: Abiraterone acetate (AA), a CYP17A1 inhibitor, has been approved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Germline polymorphisms in genes involved in androgen biosynthesis or transport may influence response and survival in this setting. Methods: ABIGENE is a multicentric prospective non-randomized pharmacogenetic study (NCT01858441). The primary objective was to investigate the association between 13 SNPs in genes related to AA pharmacology (CYP17A1, SLCO2B1 and SLCO2B3) and radiographic progression-free survival (rPFS), according to PCWG2 criteria, in pts with mCRPC treated with first-line AA + prednisone. The main secondary objectives were to evaluate the impact of these SNPs on radiographic and PSA response, overall survival (OS) and toxicity. SNPs were detected in blood samples before starting AA and analyzed by pyrosequencing or PCR-RFLP methods. Kaplan-Meyer’s curves with log-rank tests and cox regression models were used to identify relationships between SNPs and survival. Chi2 tests and student t-tests were used to identify association with response rate and toxicity. Results: 147 pts in 17 french centers were included between 2013 and 2017. Here are presented the results for the first 109 pts. The median follow-up was 28.7 months. Overall response rate (ORR) was 17%, and 74% pts had stable disease as the best response. Median rPFS was 10.9 months (95% CI 9.2-15.3). One SNP (rs10883782) in CYP17A1 was associated with rPFS on AA therapy (Table). Two other SNPs in CYP17A1 (rs4919683) and SLCO2B1 (rs1077858) were significantly associated with radiographic response. Data on PSA response, OS and toxicity will be presented at the meeting. Conclusions: This is the first prospective dedicated study to show an association between SNPs related to androgen metabolism and clinical outcome in mCRPC treated with AA. Clinical trial information: NCT01858441. [Table: see text]

307 Background: Frequent overexpression and correlation with stage and survival has been reported with the EGF-R pathway in ATCC. Methods: 93 patients (pts) with locally advanced or metastatic bladder or upper urinary tract (UUT) transitional cell carcinoma were planned with a 1:2 randomisation ratio. Patients with K-Ras or H-Ras mutations were excluded. dd-MVAC included M 30 mg/m2d1, V 3 mg/m2d2, D 30 mg/m2d2 and cisplatin 70 mg/m2d2 (d1 = d14) with G-CSF support. PANI 6 mg/kg was given on d2. The number of pts was determined from the 9-month median progression-free survival (PFS) rate reported with dd-MVAC. Using a one stage Fleming design, the dd-MVAC+PANI combination will be considered to be active if at least 37 patients among 70 do not show tumor progression at 9 months (p0 = 0.50, p1 = 0.70, alpha = 0.08 and beta = 0.03). As basal-like subtype might be related to Anti-EGFR treatment response, the phenotype was determined using a Keratin 5/6 and GATA3 double immunostaining (8 basal like among 58 cases tested). Results: From September 2010 to November 2015, 96 patients (bladder 68, UUT 21, both 8) received dd-MVAC (33) or dd-MVAC+PANI (63). No significant difference was observed among baseline characteristics and prognostic factors. The median number of cycles was 6 (1-6) in both arms. At least one grade > 2 toxicity was observed in 79% and 76% of patients in the dd-MVAC and PANI arms, respectively. More dermatological adverse events were observed in the PANI arm. Objective responses were reported in 23 (70%) pts in the dd-MVAC arm and 30 pts (48%) in the PANI arm. With a median follow-up of 27 months, PFS was 6.8 months and 5.7 months in the dd-MVAC and PANI arms respectively; OS was 20.2 months and 12.5 months in the dd-MVAC and PANI arms, respectively. No association was observed between PFS and basal-like feature for patients treated by MVAC+PANI. Molecular subtyping is in progress to confirm this observation at mRNA level. Conclusions: When combined with dd-MVAC, PANI does not seem to improve efficacy in pts with ATCC. Clinical trial information: NCT02818725.