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TPS285 Background: In pts with localized high-risk PC, disease recurrence rate following RP is ̃50% (Kane et al. J Urol. 2007). Treatment (tx) with androgen blockade before RP can reduce tumor burden post RP (Taplin et al. J Clin Oncol. 2014; McKay et al. Prostate Cancer Prostatic Dis. 2018; Efstathiou et al. Eur Urol. 2019). This study examines if 12 months of perioperative APA + ADT tx before and after RP with pelvic lymph node dissection (pLND) in localized/locally advanced high-risk PC improves pathologic complete response (pCR) rate and metastasis-free survival (MFS) vs PBO + ADT. Methods: PROTEUS, an international multicenter study, is enrolling ̃2000 pts with localized/locally advanced high-risk/very high-risk PC who are candidates for RP with pLND over 3 years at > 203 sites in 18 countries. Stratification variables: Gleason score (7 vs ≥ 8), pelvic node status (N0 vs N1), international region. Randomization: 1:1 to APA (240 mg/d) + ADT or PBO + ADT. Pts receive 6-month neoadjuvant tx followed by RP and then 6 months’ adjuvant tx. Primary end points: pCR rate and MFS. In addition to MFS based on conventional imaging, MFS based on PSMA PET or conventional imaging will be assessed as a separate end point. Both pCR and MFS are assessed by blinded independent central review. Conventional imaging by CT or MRI and bone scan are done at screening, within 4 weeks after RP, at biochemical failure (BCF), and then every 6 months after BCF until distant metastasis or death. During the direct perioperative period, APA/PBO is stopped 2 weeks prior to planned RP and then resumed 4 weeks after RP if post-RP imaging has been conducted to assess for lymphocele and disease progression and resolution to grade ≤ 1 of any clinically significant adverse events considered related to RP. To reflect evolving standard of care, the following protocol amendments were added: PSMA-PET imaging at 3 months post adjuvant tx, at BCF, and every 6 months until distant metastasis or death; cardiovascular and thrombotic risk assessment at screening, prior to, and after RP; and guidance for standard thrombotic prophylaxis in the perioperative setting. An independent data monitoring committee will review trial data. Clinical trial information: NCT03767244.

Background: The phase III SPARTAN study demonstrated that apalutamide significantly improves metastasis-free survival and overall survival vs. placebo in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). However, patients receiving apalutamide experienced falls more frequently vs. those receiving placebo (15.6% vs. 9.0%). Methods: 806 patients with nmCRPC randomized to apalutamide in SPARTAN and treated with apalutamide in addition to ongoing androgen deprivation therapy (ADT) were included in this post-hoc analysis investigating clinical variables associated with a subsequent fall. Time to a fall was assessed with Cox proportional-hazards models adjusted for baseline characteristics and time-varying factors. Statistical inference was based on final multivariable models. Results: Falls were reported for 125/803 (15.6%) patients treated with apalutamide and ADT. Most falls were grade 1 or 2 and did not require hospitalization. Median time from randomization to first fall was 9.2 months (range 0.1–25.3 months). In the final multivariable model of both baseline and after-baseline covariates, baseline patient characteristics (older age, poor Eastern Cooperative Oncology Group performance status, history of neuropathy, and α-blocker use before study treatment) remained significantly associated with fall; after-baseline clinical characteristics significantly associated with time to fall were development of neuropathy, arthralgia, and weight loss before fall. Conclusions: This analysis identified risk factors for fall among nmCRPC patients treated with apalutamide. Clinical management can minimize these identified risks while enhancing patient outcomes. Preventive interventions should be considered when the identified baseline conditions and post-treatment neuropathy, arthralgia, or weight decrease are present, to reduce risk of fall. CA extern

BackgroundPenile cancer represents a rare malignant disease, whereby a small caseload is associated with the risk of inadequate treatment expertise. Thus, we hypothesized that strict guideline adherence might be considered a potential surrogate for treatment quality. This study investigated the influence of the annual hospital caseload on guideline adherence regarding treatment recommendations for penile cancer.MethodsIn a 2018 survey study, 681 urologists from 45 hospitals in four European countries were queried about six hypothetical case scenarios (CS): local treatment of the primary tumor pTis (CS1) and pT1b (CS2); lymph node surgery inguinal (CS3) and pelvic (CS4); and chemotherapy neoadjuvant (CS5) and adjuvant (CS6). Only the responses from 206 head and senior physicians, as decision makers, were evaluated. The answers were assessed based on the applicable European Association of Urology (EAU) guidelines regarding their correctness. The real hospital caseload was analyzed based on multivariate logistic regression models regarding its effect on guideline adherence.ResultsThe median annual hospital caseload was 6 (interquartile range (IQR) 3–9). Recommendations for CS1–6 were correct in 79%, 66%, 39%, 27%, 28%, and 28%, respectively. The probability of a guideline-adherent recommendation increased with each patient treated per year in a clinic for CS1, CS2, CS3, and CS6 by 16%, 7.8%, 7.2%, and 9.5%, respectively (each p < 0.05); CS4 and CS5 were not influenced by caseload. A caseload threshold with a higher guideline adherence for all endpoints could not be perceived. The type of hospital care (academic vs. non-academic) did not affect guideline adherence in any scenario.ConclusionsGuideline adherence for most treatment recommendations increases with growing annual penile cancer caseload. Thus, the results of our study call for a stronger centralization of diagnosis and treatment strategies regarding penile cancer.

5066 Background: TITAN, a phase 3 PBO-controlled study in patients (pts) with mCSPC, showed APA + ADT improved radiographic progression-free survival and OS vs PBO + ADT. In this exploratory analysis, we report the relationships between biomarkers and OS in TITAN. Methods: Circulating tumor (ct)DNA and genomic aberrations in 17 PC-related genes, including androgen receptor (AR), were assessed at baseline (BL; 114 pts) and end of study treatment (EOST; 129 pts) using next-generation sequencing. ctDNA was assessed qualitatively; genomic aberrations were assessed within ctDNA-positive samples as inactivation (heterozygous/homozygous deletion or single nucleotide variant [SNV]) or activation (amplification or SNV). Associations of detected ctDNA/aberrations at BL or EOST with OS, and biomarkers at EOST with OS on subsequent therapies, were evaluated using univariate or multivariate analyses and Cox proportional hazards model; results were stratified by treatment arm. Results: Among pts from both treatment groups, 36% had detectable ctDNA, of which 27% had any genomic AR aberration and 24% had AR gene amplification at BL; prevalence of these biomarkers increased significantly from BL to EOST (Table). The most prevalent non-AR aberrations at BL ( TP53, homologous recombination repair [HRR] pathway, PTEN, RB1, and PIK3CA genes) increased at EOST but not significantly (Table). Among assessed aberrations, presence of ctDNA or any AR genomic aberrations at BL (HR, 1.9 or 6.7; all p < 0.05) and any AR genomic aberrations or PI3K pathway activation at EOST (1.7, p < 0.05 or 2.2, p < 0.001) was significantly associated with poor OS in multivariate analyses from both treatment groups. In univariate analyses of pts who received subsequent therapy (chemotherapy: 106; hormonal therapy: 161), worse OS was associated only with PIK3CA activation, PI3K pathway activation, or TP53 inactivation at EOST (3.7, p < 0.05; 2.4, p < 0.05; 3.0, p < 0.01, respectively) in chemo-treated pts. A small sample size in some biomarker subgroups limits interpretation. Conclusions: These hypothesis-generating data from TITAN show that presence of ctDNA or select AR and non-AR biomarkers at BL or EOST were associated with poor OS. The predictive value of these biomarkers for survival in mCSPC needs further confirmation. Clinical trial information: NCT02489318. [Table: see text]

6079 Background: Overexpression of AR is identified as a potential molecular target of SGC treatment. Combined androgen blockade (CAB) with bicalutamide has been evaluated previously, but the clinical usefulness of CAB with a next generation AR inhibitor has been unclear in SGC. We prospectively assessed the efficacy and safety of APA+GOS for pts with AR-expressing SGC. Methods: Eligible pts had fLA/RM SGC, and AR expression with at least 1% of cell nuclei immunohistochemistry staining positive. Pts were treated with APA 240 mg orally once daily and GOS 3.6 mg subcutaneously once 28 days. Primary endpoint was overall response rate (ORR) by central review according to RECIST v1.1, and a response (complete response [CR] or partial response [PR]) was confirmed by repeat assessments at least 4 weeks after the initial evaluation showing a response. Primary analysis was performed based on first 24 response evaluable (RE) pts who had been observed at least 24 weeks (Primary RE pts). The ORR was tested using exact test based on the binominal distribution, the null hypothesis for ORR of 14% was rejected when at least 8 of the 24 Primary RE pts were responders, and the efficacy was to be declared. Key secondary endpoints included clinical benefit rate (CBR), disease control rate (DCR), duration of response (DOR), and time to response (TTR) in the Primary RE pts, and overall survival (OS), progression free survival (PFS), and safety in the treated pts. Results: Twenty-six of the 31 pts treated with APA+GOS were regarded as RE by central review. For the 24 Primary RE pts, ORR was 25.0% (6/24), while 37.5% (9/24) including unconfirmed PR. Clinical benefit rate and DCR in the Primary RE pts were 50.0% and 70.8%, respectively. At the data cut-off (Apr 28, 2021), 5 of 6 pts with confirmed response were still on protocol treatment. Median PFS and OS in the treated pts were 7.43 months (mos) and not reached, respectively, with the median follow-up period of 8.57 mos. Grade 3 or higher treatment-related adverse events were reported in 4/31 (12.9%) pts, and the events were rash maculo-papular (n=2), anemia (n=1), and leukopenia (n=1). Conclusions: This is the first prospective trial evaluating CAB with APA for AR-expressing SGC. Although this study did not meet the predefined criteria of efficacy, clinically meaningful activity with well-tolerated safety profile of APA+GOS was shown. Clinical trial information: NCT04325828. [Table: see text]

5084 Background: Current management of HRLPC includes long-term ADT with primary RT. Despite definitive primary treatment, these pts have a high risk of metastasis and death. The phase 3 ATLAS study (NCT02531516) is investigating whether treatment intensification with the addition of APA to neoadjuvant and adjuvant treatment with gonadotropin-releasing hormone agonist (GnRHa) and external beam radiation therapy (EBRT) will improve metastasis-free survival (MFS) in high-risk pts. Here we describe (1) the distribution of baseline characteristics in this high-risk pt population and (2) the application of different RT regimens reflecting recent international guidelines and clinical practice changes for pts with HRLPC. Methods: Eligible HRLPC pts (Gleason score [GS] ≥ 8 or 7 and prostate-specific antigen [PSA] ≥ 20 ng/mL and stage ≥ cT2c), with ECOG PS 0/1 and Charlson Comorbidity Index (CCI) ≤ 3 are stratified by GS, pelvic nodal status, use of brachytherapy boost, and region; pts are randomized 1:1 to APA or PBO plus GnRHa for 30 (28-d) treatment cycles. Study treatment is applied neoadjuvant/concurrent to RT with APA 240 mg/d vs bicalutamide 50 mg/d for 4 cycles; another 26 cycles are completed adjuvantly after RT with APA 240 mg/d vs PBO. Primary end point is MFS (time from randomization to first distant metastasis on CT/MRI/bone scan by independent central review blinded to treatment or death from any cause). Imaging is conducted at baseline and q6m from biochemical failure until MFS. The protocol has been amended to include PET imaging (PSMA, fluciclovine, or choline). Results: Pts (N = 1503) were randomized at 266 sites in 24 countries in North America, Latin America, Europe, and Asia. The study is fully enrolled, but ongoing. Baseline characteristics for the total population: median age, 67 yrs; ECOG PS 0/1; 89%/11%; tumor classification at study entry: high-risk, 66%/very high–risk, 34%; median PSA, 6.3 ng/mL; cT2, 44%/cT3, 50%; cN1, 13%. In 90% of ATLAS pts, RT used was standard EBRT to prostate/pelvis over 6-8 weeks (cumulative 78-81 Gy); in 10%, recent hypofractionation schedules (per CHHiP or NRG/RTOG 0415) were applied (20x3 Gy/d or 28x2.5 Gy/d). 5.6% of pts had EBRT combined with brachytherapy (per ASCENDE-RT). Conclusions: Baseline characteristics of the ATLAS study population are reflective of pts with high- and very high–risk features and pelvic nodal involvement undergoing primary RT in clinical practice. The RT schedules applied reflect recent evidence and guideline changes for the use of hypofractionation in this pt population. ATLAS is an example of how RT can be included in phase 3 trials of HRLPC, in combination with next-generation androgen receptor inhibitors (eg, APA). Clinical trial information: NCT02531516.

89 Background: Addition of androgen receptor signaling inhibitors to ADT + DOC has been shown to improve clinical outcomes in pts with mCSPC. TITAN, a placebo-controlled phase 3 study, showed that APA + ADT improved overall survival (OS) and other clinical outcomes in mCSPC (Chi, J Clin Oncol 2021). This post hoc analysis of TITAN evaluated outcomes in pts who had received DOC prior to treatment with APA + ADT versus those who did not. Methods: In TITAN, 1052 pts were randomized 1:1 to APA (240 mg QD) or placebo added to ongoing ADT. We assessed radiographic progression-free survival (rPFS), OS, and time to prostate-specific antigen (PSA) progression in pts receiving DOC and ADT prior to adding APA vs those receiving only ADT plus APA. Outcomes by prior DOC were also assessed in pts with high- or low-volume disease at randomization (baseline [BL]) per adapted CHAARTED criteria, or those with matched BL characteristics. A Cox proportional hazards model was used to derive hazard ratios (HRs) and p values. rPFS was assessed using the first interim analysis cutoff (23 mo median follow-up); OS and time to PSA progression were assessed using the final analysis cutoff (44 mo median follow-up). Results: A total of 58/525 (11%) pts from the APA + ADT group had received DOC prior to randomization: 76% (n = 44) had high-volume disease, 62% (n = 36) had bone-only metastases, 16% (n = 9) had visceral metastases, and 59% (n = 34) had > 10 bone lesions. In the overall APA-treated population and in the subset of pts with high-volume disease, OS, rPFS, and time to PSA progression were similar in those who received prior DOC and those who did not (Table). Pts with low-volume disease also had similar results, although the number of pts was small. Clinical outcomes in pts with matched BL characteristics (including PSA and time from initial diagnosis to randomization, among others) were similar regardless of prior use of DOC (Table). The safety profile of APA was not substantially different between pts with or without prior DOC. Limitations of this analysis include lack of data on tumor volume and other disease characteristics at the initiation of prior DOC treatment; interpretation was based on small number of pts with prior DOC (only 11% of TITAN pts), most notably in the rPFS analysis. Conclusions: Prior use of DOC in pts with mCSPC did not further improve clinical benefits of APA + ADT in TITAN. Clinical trial information: NCT02489318. [Table: see text]

142 Background: In ACIS, APA + AAP improved radiographic progression-free survival in mCRPC vs AAP; difference in overall survival (OS) was not statistically significant. We report a prespecified analysis of androgen receptor (AR) or non-AR genomic/transcriptional aberrations, known to be associated with poor prognosis, and their associations with OS in patients (pts) with mCRPC. Methods: Circulating tumor (ct)DNA and aberrations in 17 PC-relevant genes were assessed using next-generation sequencing at baseline (BL; n = 197) and at end of study treatment (EOST; n = 140) (biomarker population). ctDNA was summarized qualitatively; genomic aberrations were normalized by ctDNA detection. AR splice variant version 7 (ARv7) was detected by quantitative RT-PCR. Cox proportional hazards model assessed association of OS with biomarkers in univariate/multivariate analyses overall and in pts receiving subsequent treatment (tx). Results: BL characteristics of biomarker and total study populations were similar. From BL to EOST: ctDNA detection did not differ (123/196 [63%] to 92/140 [66%], p=0.6); significant increases occurred in ARv7, AR mutations, and any AR aberration (Table). Prevalence of aberrations in PI3K and homologous recombination repair (HRR) pathways did not change from BL to EOST (40/123 [33%] to 34/92 [37%], p=0.5 and 18/123 [15%] to 14/92 [15%], p>0.9, respectively). Worse OS was associated with ctDNA detection or HRR pathway inactivation at BL (HR, 2.5 or 2.2; all p < 0.001) or presence of ctDNA, ARv7, AR amplification or inactivation of TP53, RB1, or RB1/TP35 pathway at EOST (2.2, p < 0.001; 2.1, p < 0.001; 2.6, p < 0.001; 1.5, p < 0.05; 1.7, p < 0.05; 2.1, p < 0.001, respectively) in univariate analyses. EOST ARv7, AR amplification, and inactivation of RB1, TP53, or RB1/TP53 pathway was associated with worse OS in pts receiving subsequent tx. Detection of ctDNA and RB1 inactivation at BL and RB1/TP53 pathway inactivation at EOST was strongly associated with worse OS (2.1, 3.3, 2.9, respectively, all p < 0.01) in multivariate analyses. Conclusions: In ACIS, AAP or APA + AAP tx was associated with increased AR mutations and ARv7 expression. Detection of ctDNA and select AR/non-AR aberrations may predict poor survival in mCRPC. These markers may be used to improve tx selection following confirmation of their predictive value. Clinical trial information: NCT02257736. [Table: see text]