Molecular profiling of solid tumors is increasingly essential in oncology practice, guiding diagnosis-prognosis and providing patients with access to molecularly matched therapies that can improve outcomes. In this study, 554 patients with advanced solid tumors were evaluated through the POWER (Precision Oncology at Western University) study, a first of its kind Canadian study, designed to prospectively assess the clinical impact of expanded pan-cancer next-generation sequencing (NGS) panel testing on patient management, in real-world oncology practice and evaluate the overall health system impact. The findings reveal that 79% of patients had clinically relevant variants, and nearly 28% experienced changes in treatment eligibility because of the identification of novel druggable mutations. Additionally, the analysis shows that a pan-cancer NGS panel significantly impacted patient management, with 18% of patients receiving access to clinical trials and off-label therapy with expected better outcomes and 19% (31/162) patients, previously tested by tumor-specific panels, experiencing management changes when tested through POWER. This study also highlights the broader health system impact: access to safer treatment options (14.5%), change in management (17.6%), treatment sequence changed (17.3%), and Ministry of Health formulary treatment saved (12.5%). These results underline the benefits of expanded NGS testing over tumor-specific panels in guiding personalized treatment decisions, optimizing patient care, and enhancing health care delivery in oncology.

Fibroblast growth factor receptor (FGFR) alterations are targetable in metastatic urothelial carcinoma (mUC). Identifying FGFR alterations currently requires tissue testing, which is limited by sample availability and cancer heterogeneity. Plasma circulating tumor DNA (ctDNA) offers a complementary testing strategy, but the added value of ctDNA relative to conventional FGFR alteration assessment remains unclear. Here, in a prospective, multicentre study, we show that ctDNA testing has high concordance with tissue FGFR testing and identifies additional actionable FGFR alterations. We profile plasma from 208 patients with mUC undergoing clinical FGFR tissue testing for erdafitinib eligibility. In evaluable baseline samples, FGFR alteration frequency is 26% in either tissue or ctDNA. Among 125 patients with baseline detected ctDNA and paired tissue results, FGFR status is concordant in 90%, and ctDNA has an 84% sensitivity for tissue-detected alterations while also identifying 7 additional cases. Serial plasma collections post-baseline further clarify FGFR status. In 21 patients who received erdafitinib after testing, the median progression-free survival is 7.5 months, and one patient with a ctDNA-exclusive FGFR alteration remained on erdafitinib for 33 months. Our results support clinical uptake of ctDNA FGFR testing in combination with tissue-based approaches in mUC.

460 Background: Immune checkpoint inhibitor-tyrosine kinase inhibitor (IO-TKI) combinations have transformed first-line treatment for metastatic renal cell carcinoma (mRCC). Pembrolizumab-axitinib (PA) and pembrolizumab-lenvatinib (PL) have each demonstrated efficacy in randomized trials, but real-world comparative data remain limited. Methods: We conducted a retrospective cohort study using the CKCis registry. Patients with confirmed mRCC who received first-line PA or PL were included. Primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety. Results: A total of 632 patients were identified (median age 66; 73.5% male), including 516 (81.6%) with clear cell and 116 (18.4%) with non-clear cell histology. Of these, 549 (86.9%) received PA and 83 (13.1%) received PL. Median follow-up was 28.9 months. Baseline characteristics were generally comparable between groups, although differences were observed in histology, performance status and the distribution of brain and lung metastases. At 12 months, the PFS rate was higher with PL compared with PA (75.9% vs. 57.1%); 5-year PFS was 36.2% vs. 25.9%, respectively (P < 0.01). 12-month OS was 93.9% for PL and 85.2% for PA; 5-year OS was 65.9% vs. 51.4% (P = 0.0172). For non-clear cell histology, 12-month OS was 91.6% for PL and 78% for PA (P = 0.0335). Among clear cell histology, 12-month OS was 94.9% for PL and 86.6% for PA (P = 0.0884). In the IMDC favourable-risk group, 12-month OS rate was 100% with PL and 95.2% with PA (P = 0.5994). For intermediate/poor IMDC risk, 12-month OS rate was 92% with PL and 82.3% with PA (P = 0.0145). Multivariable Cox analysis adjusting for age and IMDC risk showed that PA was associated with an increased risk of death compared with PL (HR = 2.15; 95% CI, 1.14-4.06; P = 0.019). IMDC risk was an independent predictor of OS, with patients in the intermediate/poor-risk group demonstrating a 94% higher hazard of death relative to those in the favourable-risk group (HR = 1.94; 95% CI, 1.32–2.87; P = 0.001). Dose reductions of the TKI occurred more frequent with PL (50%) than with PA (35.3%). Both regimens were associated with manageable but frequent toxicities. Fatigue, diarrhea, and anorexia were commonly observed with PA. PL showed a similar overall profile but a higher rate of Grade 3 proteinuria. No Grade 5 events occurred. Conclusions: In this real-world mRCC cohort, treatment with PL was associated with better PFS and OS compared to PA, but higher dose modification rates. These findings align with outcomes observed in pivotal trials and suggest that PL may offer a clinically meaningful benefit in routine practice. Prospective studies are needed to validate these results and to further explore the balance between efficacy and tolerability among first-line IO-TKI combinations.

Anaplastic thyroid cancer (ATC) is highly lethal. Although patients with the BRAFV600E alteration respond to the type I RAF inhibitor (RAFi) dabrafenib with trametinib, most rapidly develop adaptive or acquired resistance. Here, multi-region whole-genome, high-coverage whole-exome, and single-nuclei RNA sequencing of tumors from ATC patients undergoing type I RAFi and MEKi therapy reveals that reactivation of the mitogen-activated protein kinase (MAPK) pathway, along with immunosuppressive macrophage proliferation, may underlie the development of acquired resistance. Screening of several RAFi reveals that ATC cell lines are exquisitely sensitive to the type II RAFi naporafenib, which inhibits EphA2-mediated MAPK signaling. Further, naporafenib and trametinib overcome both innate and acquired treatment resistance to dabrafenib and trametinib in ATC cell lines and patient-derived xenograft models. Finally, we describe a mechanism of acquired resistance to naporafenib through compensatory mutations in MAST1. Taken together, our work rationalizes the clinical investigation of type II RAFi in the setting of thyroid cancer.

490 Background: Bone Metastases (BM) occur in approximately 30% of mRCC patients (pts) with evidence suggesting that they portend a worse prognosis. Systemic therapies such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICI) are felt to be active in these pts, with radiation therapy (RT) often employed for BM-directed treatment. The evidence for and use of BPAs, such as bisphosphonates and denosumab, is limited in the current ICI era. We investigated the outcomes of mRCC pts with BM and use of BPA in a contemporary real-world cohort. Methods: We analyzed data collected from the prospectively maintained, multi-institutional Canadian Kidney Cancer Information System (CKCis). Patients with clear cell mRCC treated between January 2011-June 2023 were included. Outcomes were compared between BM+ and BM- pts using Cox proportional hazards models. Kaplan-Meier estimates were used to assess time to treatment failure (TTF) and overall survival (OS) adjusted by IMDC criteria. Results: Of 2,307 patients with clear cell mRCC, 893 (39%) had BM+, of whom 691 (77%) underwent RT, and 139 (16%) received a BPA. Median follow-up was longer for BM- patients (34.6 vs 29.1 mos). Significant differences were noted in Karnofsky performance status (> 80%: 84% vs 78%), IMDC risk group (intermediate/poor: 76% versus 82%) use of RT (35% vs 78%), and use of BPAs (2% vs 16%) between BM- vs BM+ pts (all p < 0.05). In our cohort, first-line treatment in BM+ pts was monotherapy TKI (67%), doublet ICI (20%), and combination TKI+ICI (13%). Median TTF was similar in BM- vs BM+ pts: 9.6 vs 8.6 mos (HR 0.92; 95% CI 0.91-1.02). However, median OS was higher in BM- vs BM+ pts: 57.6 vs 35.8 mos (HR 0.67; 0.58-0.76; p<0.0001); this was consistent irrespective of type of systemic therapy. In BM+ pts, those who did not receive BPAs had a lower TTF (7.9 vs 13.4 mos) and OS (34.0 vs 46.0 mos); however, these were not statistically different when adjusted by IMDC criteria (TTF HR 1.2; 0.95-1.51 and OS HR 1.12; 0.85-1.46). There was no significant difference in TTF (HR 0.89; 0.72-1.10) or OS (HR 0.94; 0.73-1.22) in BM+ pts selected to receive RT. Conclusions: BM remain a poor prognostic factor in mRCC in this contemporary cohort of patients. While BPA use was limited, we observed no improvement in TTF or OS in BM+ pts with their use. These data warrant further investigation of BPA in mRCC including assessment of SREs and potential complications.

PURPOSE:This multi-institutional phase I/II study evaluated the safety and efficacy of tremelimumab (T) and durvalumab (D) in combination with stereotactic body radiotherapy (SBRT) in oligometastatic head and neck squamous cell carcinoma (HNSCC) (ClinicalTrials.gov identifier: xxxxxx). METHODS:Patients with oligometastatic HNSCC (2-10 lesions) received D (1500 mg) and T (75 mg) for four monthly cycles, followed by D monotherapy for an additional eight monthly cycles. SBRT was administered to 2-5 lesions during cycle 2. In phase I, the primary endpoint was safety, while in phase II, the primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included local control, out of SBRT field objective response rate, and overall survival (OS). RESULTS:Thirty-three evaluable patients were recruited (accrual interrupted by COVID-19). Patients had received 1, 2, and 3 prior lines of systemic therapy in 48%, 21%, and 9% of cases, respectively. The median SBRT dose was 45 Gy (range: 18-50) in 3-5 fractions. There were 9 Grade 3-4 AEs related to D and T, occurring in 7 (21%) patients. One patient experienced a Grade 5 AE due to SBRT (radionecrosis following mucosal re-irradiation); no other Grade 3-5 AEs were attributed to SBRT or the SBRT-immunotherapy combination. Median PFS was 12.8 months (95% CI: 7.17-27.2) with a 6-month PFS of 72.7% (95% CI: 59.0-89.6), while median OS was 28.4 months (95% CI: 22.9-38.9). CONCLUSION:Dual-checkpoint inhibition combined with SBRT was well tolerated and led to promising 6-month PFS, meeting both safety and primary endpoints.

PURPOSE:This study evaluates the impact of treatment de-escalation from 70 Gy to 60 Gy on patient-reported outcomes (PROs) and toxicity for patients with T1-2 p16-positive oropharyngeal squamous cell carcinoma (OPSCC) treated with primary radiotherapy as part of the BLINDED-FOR-REVIEW trials. METHODS:Patients with p16-positive OPSCC treated with primary radiotherapy in the BLINDED-FOR-REVIEW randomized trials were included in this post-hoc analysis. Patient demographics, tumor and treatment characteristics were compared between patients who received radiation with 70 Gy (BLINDED-FOR-REVIEW, usually with cisplatin every 3 weeks) vs. 60 Gy (BLINDED-FOR-REVIEW, usually with weekly cisplatin). Outcomes examined included PROs and quality of life (QOL) metrics, including the MD Anderson Dysphagia Inventory (MDADI), European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (C30) and Head-and-Neck 35 (H&N35) scales, toxicity, overall survival (OS) and progression-free survival (PFS). RESULTS:The cohort included 59 patients, 29 patients treated with 60 Gy and 30 patients with 70 Gy. Comparing QOL changes at 1-year in the 60 Gy vs. 70 Gy cohort respectively, the 60 Gy cohort demonstrated improved MDADI total (mean ± SD change: +1.9 ± 12.2 vs. -5.8 ± 11.3, p=0.035), and functional (+5.5 ± 12.7 vs. -3.3 ± 12.2, p=0.023) scores. The 60 Gy cohort demonstrated significantly better outcomes at 1-year in several EORTC QOL domains: global health status, fatigue, nausea/vomiting, appetite, constipation, pain, xerostomia, sticky saliva, and coughing (all p < 0.05). Patients treated with 60 Gy had significantly lower rates of grade 2-3 dysphagia and grade 2-3 mucositis (all p < 0.05). CONCLUSION:This comparison of arms from the separate ORATOR trials suggests that de-escalation from 70 Gy to 60 Gy for p16-positive patients with early-stage OPSCC may lead to better PROs across numerous domains, and reduced toxicity. Results from direct comparisons of these two doses are awaited.

e16531 Background: Brain metastases (BM) occur in 10–20% of patients (pt) with metastatic renal cell carcinoma (mRCC) and are associated with poor prognosis. While local therapies remain standard, real-world outcomes with systemic therapy (ST) are poorly defined. We evaluated outcomes of pt with mRCC and BM according to timing of BM development, local therapy, and ST received. Methods: We conducted a retrospective cohort study using the Canadian Kidney Cancer Information System (CKCis) to identify pt with mRCC and BM diagnosed between January 2011 and September 2025. Patients were categorized as having BM prior to ST initiation (denovoBM) or after ST initiation. Baseline characteristics, treatments, and outcomes were analyzed. Overall survival (OS) was defined as time from ST initiation to death, and progression-free survival (PFS) as time from ST initiation to disease progression or death. Results: A total of 637 pt with mRCC and BM were identified (8.7%); the majority were male (74%, n=471) and had IMDC intermediate and poor risk disease (87.5%, n=464). 21% underwent BM surgery and 92% received radiation therapy. Median follow-up was 28.4 months. Overall, 255 (40%) had denovoBM, while 382 (60%) developed BM after ST initiation. De novo BM: Among pt treated with ipilimumab/nivolumab (I/N), 49.2% experienced disease progression, with 35.4% (n=23) receiving second line ST (2LST). Of those treated with immune checkpoint inhibitor plus tyrosine kinase inhibitor (IO/TKI), 50% experienced progression, with 41.3% (19) receiving 2LST. Among single agent TKI recipients, 89.6% experienced progression, with 54.2% (n=78) of them subsequently receiving 2LST. BM developing after ST initiation: In pt receiving I/N, 43.0% experienced brain progression, with 64.5% receiving 2LST, and for IO/TKI, 83.3% experienced disease progression with 55.6% (N=20) receiving 2LST. Of those receiving single agent TKI, 94.9% experienced progression, with 69.2% (n175=) receiving 2LST. Survival outcomes are shown in table 1. Conclusions: Patients with mRCC and BM have poor outcomes despite contemporary ST, highlighting the unmet need for more effective CNS-active therapies and consideration of baseline brain imaging in higher-risk pt. Survival outcomes by timing of BM relative to ST initiation. Outcome De novo BM BM after ST HR (95% CI) p value Ipilimumab/nivolumab PFS, median (95% CI) 5.49 (4.11–8.18) 4.99 (3.19–11.34) 1.20 (0.84-1.72) 0.32 OS, median (95% CI) 38.60 (30.00–48.89) 34.86 (18.60–59.76) 0.89 (0.58–1.36) 0.58 IO/TKI PFS, median (95% CI) 9.23 (2.66-16.26) 9.69 (5.42–17.25) 1.26 (0.76–2.09) 0.36 OS, median (95% CI) 26.71 (15.90–47.47) 33.05 (20.27–NR) 1.36 (0.74–2.49) 0.32 Single-agent TKI PFS, median (95% CI) 19.15 (15.57–22.31 10.81 (8.18 15.80) 0.88 (0.71–1.10) 0.26 OS, median (95% CI) 35.98 (29.27–40.84) 27.01 (21.88–34.86) 1.09 (0.86–1.38) 0.47

416 Background: Patients (pts) presenting with de novo metastatic renal cell carcinoma (mRCC) have a poor prognosis. The role of cytoreductive nephrectomy (CN) is uncertain in these pts. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an enhanced systemic anti-tumor immune response. The efficacy and safety of primary SBRT in combination with ipilimumab and nivolumab (I/N) in pts with previously untreated mRCC are unknown. Methods: A randomized phase II trial was conducted at sites in Canada (6) and Australia (1). Inclusion criteria were: previously untreated, biopsy-proven, IMDC intermediate or poor risk de novo clear cell mRCC. Pts with a primary kidney lesion > 20cm, previous abdominal radiation precluding SBRT, or with a contraindication to I/N were excluded. Randomization was 2:1 to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm), versus I/N alone. The primary endpoint was progression free survival (PFS). Target sample size was 78 pts. Secondary objectives included safety, overall survival (OS), objective response rate (ORR), health-related quality of life (QOL), and correlative biomarker analyses. Results: Pts were recruited between February 2020 and July 2024, with accrual paused for 8 months during COVID-19 pandemic. Median follow-up is 23.5 months. A total of 67 pts were randomized: 43 pts to I/N+SBRT, 24 to I/N alone. Median age was 65 years, 73% were male, IMDC risk groups were 58% intermediate and 42% poor. Pts in the experimental arm had larger renal tumours (T3/T4 stage 70% vs 46%), primary target lesion (95 mm vs 87.5 mm), and more likely to have liver sites of metastasis (23% vs 8%) compared to the I/N alone arm. Three pts died prior to any SBRT. PFS rate at 12-months was 35% (95% CI 21-49%) for I/N+SBRT vs 48% (27-66%) for I/N alone (HR 1.29, 0.69-2.40). The ORR was 33% vs 42% and 18-month OS was 59% vs 70%, for I/N+SBRT vs I/N alone. In per protocol analysis of pts who received 4 cycles of I/N +/- SBRT, 12-month PFS was 46% vs 56%, ORR was 50% vs 44%, and 18-month OS was 74% vs 79%, for I/N+SBRT (n = 24) vs I/N alone (n = 16). Grade 3/4 treatment related adverse events were 23% vs 29%, respectively, with no new safety signals related to I/N or SBRT toxicity noted. Conclusions: CYTOSHRINK is the first randomized trial testing the addition of early cytoreductive SBRT to first-line immune checkpoint blockade for patients with de novo mRCC. While 12-month PFS was not improved compared to I/N alone, there were notable baseline imbalances. The addition of SBRT to I/N was considered safe. Further follow up of OS, QOL and correlative biomarker analyses are ongoing. Clinical trial information: NCT04090710 .

Immune checkpoint inhibitors (ICIs) improve outcomes in metastatic renal cell carcinoma (mRCC) but are hindered by immune-related adverse events (irAEs). Modulation of the gut microbiome may enhance efficacy and mitigate toxicity, yet the safety and mechanisms of healthy donor fecal microbiota transplantation (FMT) in mRCC remain unexplored. In this phase 1 trial, 20 treatment-naive patients with mRCC received encapsulated healthy donor FMT (LND101) combined with ipilimumab/nivolumab (n = 16), pembrolizumab/axitinib (n = 3) or pembrolizumab/lenvatinib (n = 1). The primary endpoint was safety, defined by the incidence and severity of irAEs. Secondary endpoints included clinical response (Response Evaluation Criteria in Solid Tumors version 1.1), gut microbiome and immune correlates and patient-reported quality of life. The safety endpoint was met with 50 NCT04163289 . In a phase 1 trial testing healthy donor fecal microbial transplantation with immune checkpoint blockade in patients with previously untreated renal cell carcinoma, treatment was safe with an encouraging response signal and microbiome analyses, suggesting specific donor taxa associations with toxicity.

Abstract Background: Over two dozen histological types of salivary gland cancers are recognized comprising 3-5% of all head and neck cancers. Response to chemotherapy and actionable target expression in patients with metastatic disease vary by histological type e.g. HER2 and/or androgen receptor are often overexpressed by salivary duct carcinomas and NTRK fusions often present in secretory carcinomas. Overall results of this phase II basket trial have been previously reported (Gupta 2025). Herein we report additional data from the metastatic salivary gland cohort by histological subtype. Methods: IND.228 was a prospective multi-center, non-blinded, open-label phase II basket trial that enrolled 8 cohorts of patients with rare cancers including a salivary gland cohort. Eligible patients had incurable disease with no known life-prolonging treatment options or contraindications to immunotherapy and ECOG performance status 0 or 1. Tumor PD-L1 expression was not required and patients with adenoid cystic carcinoma were excluded. Patients received durvalumab 1500 mg IV plus tremelimumab 75 mg IV q4 weeks for 4 cycles followed by durvalumab q4 weeks until disease progression. The primary outcome was objective response by RECIST 1.1 criteria. Results: 21 patients with incurable salivary gland cancer were enrolled. Of 20 patients evaluable for response there were 6 females and 14 males, median age 61 years (range, 40-72) with a median of 3 metastatic sites (range, 1-5). Histological types were salivary duct carcinoma (8), acinic cell carcinoma (5), adenocarcinoma (3), clear cell carcinoma (2), and others (2). All had diagnosis confirmed by central pathology review. 190 cycles of treatment were given with a median of 7 cycles per patient (range, 1-40). Four patients had partial responses, 8 had stable disease, and 8 had progressive disease as best response. The proportions of response and response plus stable disease by histological type, respectively, were salivary duct carcinoma (2/8, 4/8), acinic cell carcinoma (1/5, 4/5), and adenocarcinoma (1/3, 3/3). 10/13 patients with avaialable tumor grade had high-grade cancers. Progression-free survival ranged from 7.3-59.3+ months in responding patients, and from 3.8-11.4 months in stable disease patients. One patient with salivary duct carcinoma received 40 cycles of treatment and had a response duration of over 5 years. Conclusions: Patients with salivary duct carcinoma, acinic cell carcinoma, and adenocarcinoma appeared to benefit from combined CTLA-4 and PD-L1 immune checkpoint blockade. Immune checkpoint blockade deserves further study and consideration as a treatment option in these histological types of incurable salivary gland cancer. Citation Format: Eric Winquist, John Hilton, Christian Kollmannsberger, Danielle Charpentier, Dorie-Anna Dueck, Hal Hirte, Sebastien Hotte, Rahima Jamal, Raymond Jang, Andrew Maksymiuk, Randeep Sangha, Stephanie Snow, Osama Souied, Jennifer Spratlin, Ralph Wong, Abha Gupta, Thierry Alcindor, Quincy Chu, Derek Jonker, Torsten Nielsen, Ming Tsao, Tricia Cottrell, Joana Sederias, Siwei Zhang, Wei Tu, Janet Dancey. Durvalumab and tremelimumab in patients with metastatic non-adenoid cystic salivary gland cancer treated in the CCTG IND.228 phase II basket trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A029.

Supplementary Table 1. Representativeness of Study Participants.

BACKGROUND:The optimal treatment de-escalation approach for HPV-related oropharyngeal squamous cell carcinomas (OPSCC) is unknown. The objective was to assess two de-escalation approaches: primary radiotherapy (RT) vs. transoral surgical (TOS). PATIENTS AND METHODS:Patients with T1-T2 N0-2 HPV-related OPSCC were randomly assigned to primary RT (60 Gy with concurrent weekly cisplatin in node-positive) vs. TOS + neck dissection (ND) (and adjuvant reduced-dose RT depending on pathology). The primary endpoint was 2-year OS (hypothesized to be 94 % in each arm, compared to 84 %). Secondary endpoints included comparisons of survival and quality of life between arms. The trial was stopped early due to two treatment related deaths in the surgical arm. RESULTS:Sixty-one patients were randomized (n = 30 in RT arm and n = 31 in TOS+ND arm), with a median age of 62 years (IQR: 57-68). The majority were male (n = 51) and never-smokers (n = 31). Median follow-up was 3.7 years (IQR: 3.1-4.5 years). In the RT arm, the primary endpoint for acceptability was met (p = 0.008), and two-year OS was 100 % (95 % confidence interval [CI]: 100-100 %). In the TOS+ND arm, the primary endpoint was not met (p = 0.296) and two-year OS was 90 % (95 % CI: 71-97 %), significantly worse than the RT arm (p = 0.041). Two-year progression-free survival (PFS) were 100 % (95 % CI: 100-100 %) vs. 86 % (95 % CI: 67-95 %) respectively (p = 0.012). Mean (± SD) 2-year MDADI total scores were 89 ± 13 vs. 83 ± 11, respectively (p = 0.11), and grade 2-5 toxicity rates were similar (n = 21 vs. n = 24 respectively, p = 0.51), with no additional grade 5 events. CONCLUSION:For treatment de-escalation, a primary RT approach achieved excellent oncologic and functional outcomes and should be tested in phase III de-escalation trials. TRIAL REGISTRATION:Clinicaltrials.gov NCT03210103.

5056 Background: DARO is a unique AR antagonist, with preclinical studies suggesting activity in mCRPC models resistant to abiraterone or enzalutamide due to AR amplification (amp) or ligand binding domain mutations. In this substudy (SS) of the (PC-BETS) master protocol, we explored DARO in ARPI-resistant mCRPC stratified by ctDNA AR status. Methods: Pts had mCRPC, ECOG PS 0–1, evaluable disease, biochemical or radiographic progression, prior ARPI, and no cytotoxic chemotherapy in mCRPC. Genomic screening tested plasma cell-free DNA and matched leukocyte DNA via targeted sequencing with a prostate cancer panel including the AR exons, introns, and flank. Only patients with evidence of ctDNA ≥1% were eligible. Pts were assigned to SS by molecular tumor board if biomarker (BM)+; otherwise, BM- pts were randomized to BM- SS. SS-C tested DARO 600mg od in three cohorts—AR amp (C1), AR mutation (C2), or BM- (C3) in a 2-stage design. Primary endpoint was clinical benefit rate (CBR), defined by PSA50 response, RECIST CR/PR, or SD ≥12 weeks. Results: PC-BETS Arm C opened in Jan 2018 and closed Feb 2024; 72 pts were enrolled: 27, 26, and 19 in C1, C2, and C3, respectively. Median age was 74 y (53–88), 100% ECOG PS 0-1. Sixteen pts (22%) had docetaxel for hormone-sensitive disease and none for mCRPC. Prior ARPI were abiraterone (31/72, 43%), enzalutamide (37/72, 51%), or apalutamide (4/72, 6%). Pts had bone (67/72, 93%), lung (9/72, 13%), and/or liver (5/72, 7%) metastases. Baseline PSA was 2–20 in 13/72 (18%), 20–100 in 32/72 (44%) or >100 in 27/72 (38%). CBR was more frequent in AR amp or mutated cohorts than BM– (Table 1). DARO median exposure was 4 months (range 1–29). Common related AEs were fatigue (38%), diarrhea (18%), nausea (15%), and anorexia (11%). Median ctDNA fraction of CBR vs no CBR was: C1: 5 vs 16%, p=0.059; C2: 5 vs 19%, p=0.042; C3: 13 vs 13%, p=0.944. C1 CBR was higher with SPOP mutations (3/5, 60%) and all CBR pts had >10 AR copies. C2 CBR was seen with L702H (3/7, 43%) and T878A (4/7, 57%) but not F877L, W724C/L, or V716M. By data cutoff, all had discontinued therapy (radiographic ± biochemical 61%, biochemical only 22%, symptomatic 7%). DARO was well tolerated, with only 6% discontinuing for AEs. Conclusions: DARO demonstrates modest activity for unselected mCRPC following ARPIs. ctDNA analysis enriched for pts more likely to benefit from DARO including SPOP alterations, AR amp, and AR mutations L702H and T878A. Clinical trial information: NCT03385655 . C1: AR-amp C2: AR-mutated C3: BM negative CBR 5/27 (19%) 7/26 (27%) 2/19 (11%) PSA response 3/27 (11%) 4/26 (15%) 1/19 (5%) TTP-PSA (mo) 2.8 (1.8–3.7) 2.8 (1.9–4.0) 1.9 (1.8–2.8) OS (mo) 12.9 (6.6–19.9) 16.4 (12.9–29.0) 15.5 (12.2–NR)

Although the majority of patients with nasopharyngeal carcinoma (NPC) present with early-stage or locoregional disease that can be treated with definitive radiotherapy, approximately 20% of patients experience disease recurrence, and 15% present with metastatic disease that is not amenable to curative therapy. Management of patients with recurrent or metastatic (r/m) NPC who are not candidates for local salvage therapy is challenging in Canada, as there is uncertainty in extrapolating evidence that is largely generated from Southeast China to non-endemic regions such as Canada. Currently, treatment options in Canada are limited to chemotherapy regimens that can only achieve short-term response and prolongation of survival. The addition of anti-PD-1 monoclonal antibodies to chemotherapy has been shown to extend progression-free survival in recurrent r/m NPC compared to chemotherapy alone; however, approval of PD-1 inhibitors in Canada has lagged behind other jurisdictions where NPC is non-endemic. This paper reviews the current systemic treatment landscape for r/m NPC in Canada, highlights unmet treatment needs for patients who are not candidates for curative therapy, and discusses the challenges and opportunities that lie in emerging therapies.

Background and objective:High-risk localized prostate cancer (PCa) patients may require neoadjuvant treatment (androgen deprivation therapy [ADT] plus abiraterone with or without taxane-based chemotherapy) before radical prostatectomy (RP). Intraductal carcinoma of the prostate (IDC) is an aggressive histological variant of prostate adenocarcinoma. This study aims to evaluate the association of IDC on biopsy with pathological response in such PCa patients. Methods:A retrospective analysis was conducted using the prospective trial data from 75 patients with high-risk localized/locally advanced PCa treated with 24 wk of neoadjuvant therapy comprising ADT and abiraterone, with or without taxane-based chemotherapy, followed by RP. Pathological responses, including pathological complete response (pCR), minimal residual disease (MRD), and adverse pathology outcomes (ypN1 or ≥ypT3b), were analyzed. Multivariable logistic regression identified the predictors of poor pathological response. Key findings and limitations:Among 75 patients, 35 (47%) had IDC on biopsy. Patients with IDC had worse pathological outcomes: 32 of 35 (91%) failed to achieve a favorable response (pCR or MRD) compared with 26 of 40 (65%) in those without IDC. IDC was also associated with higher rates of adverse pathology at RP, occurring in 27 of 35 patients (77%) versus nine of 40 patients (22%) without IDC. IDC independently predicted poor response (odds ratio 6.18, 95% confidence interval 1.16-32.8; p = 0.032) after adjusting for tumor volume, Gleason grade, and prostate-specific antigen (PSA). In contrast, cribriform (Crib) pattern at biopsy did not impact response significantly. Metastatic progression and survival data were unavailable. Conclusions and clinical implications:IDC, but not Crib, on biopsy predicts poor pathological response to neoadjuvant therapy (ADT plus abiraterone with or without taxane-based chemotherapy) in high-risk PCa after adjusting for tumor volume and PSA. An understanding of this treatment-resistant phenotype will improve PCa biology insights and guide novel therapeutic strategies. Patient summary:Intraductal carcinoma (IDC) is a more aggressive form of prostate cancer that does not respond well to treatment. In our study, we found that 91% of patients who had IDC detected in their biopsy before surgery did not show a good response to presurgery therapy.

471 Background: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) representing up to 15% of RCC. First line (1L) phase II trials have evaluated immunotherapy (IO) in combination with IO or tyrosine kinase inhibitors (TKI) in nccRCC, but these cohorts are heterogeneous, with few comparative results. Therefore, the specific value of IO therapy for pRCC remains unquantified. Methods: We conducted an analysis based on prospectively collected data from the Canadian Kidney Cancer information system (CKCis) database. The objective was to evaluate efficacy of 1L systemic therapy of metastatic pRCC with either IO based or VEGFR-TKI. Baseline characteristics, treatment outcome and safety were collected. Primary endpoint was time-to-treatment failure (TTF). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events requiring a change in dose/schedule (TRAEs). TTF, OS and ORR were adjusted (adj) for IMDC risk groups. Results: Between 01/2011 to 01/2024,206 pRCC pts were treated: 70 on IO single agent or in combination IO-IO/IO-TKI and 136 with TKI monotherapy. The median follow-up was 20.6 months (mo) (range: 1.6-146.1). There were no significant differences in baseline characteristics between 2 groups, described in table. The median TTF with IO was 9.8 mo (95%CI: 4.5, 15.9) versus (vs) 5.7 mo with TKI (95%CI: 4.6, 8.1) (adj HR: 0.61 [0.42-0.89] p=0.01). The median OS was 36.9 mo with IO (95%CI: 26.5, not reached (NR)) vs 21.6 mo with TKI (95%CI: 18, 27.9) (adj HR: 0.51 [0.3-0.85], p=0.009). Among the 170 evaluable pts, ORR was 37% (95% CI: 24.2-49.9) with IO and 21.5% (95% CI: 14.1-29) with TKI (adj OR: 2.4 [1.0-5.6] p=0.04). The TKI-IO subgroup had better TTF and OS compared to TKI therapy, with 16.9 mo (95%CI: 5.5-22.6) (adj HR: 0.46 [0.26-0.82] p=0.009), and NR (95%CI: 18.9-NR) (adj HR: 0.24 [0.08-0.78] p=0.02) respectively. 28% of pts discontinued treatment. TRAEs of grade 3-5 were noted in 27% in IO group and in 73% in TKI group. Conclusions: This study presents comparative data on 1L treatment metastatic pRCC. It shows an improved TTF and OS in the IO group, particularly in TKI-IO treated pts. Our findings underline the need for further clinical trials evaluating 1L IO in pts with metastatic pRCC. Baseline characteristics. Overall cohortn = 206 IO treatmentn = 70 (34%) TKI treatmentn = 136 (66%) Median age (range) 67 (30-89) 69 67 Sex Male 162 (79%) 51 (73%) 111 (82%) IMDC score Favorable Intermediate Poor Unknown 31 (20%)93 (60%)30 (19.5%)52 15 (29%)30 (58%)7 (13%)18 16 (16%)63 (62%)23 (22%)34 Prior Nephrectomy 164 (80%) 56 (80%) 108 (79%) Sarcomatoid component 12 (8%) 5 (7%) 7 (5%) Therapy Nivolumab + ipilimumab Pembrolizumab + axitinib Pembrolizumab + lenvatinib Pembrolizumab Nivolumab Sunitinib Pazopanib Cabozantinib Crizotinib Savolitinib m-Tor inhibitors 27 (13%)23 (11%)7 (3.5%)11 (5%)2 (1%) 88 (43%)20 (10%)8 (4%)3 (1.5%)7 (3.5%)9 (4.5%)