Morris, Michael J.

5003 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival vs change of androgen receptor pathway inhibitor (ARPI) in taxane-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). We now present health-related quality of life (HRQoL) and pain outcomes at second interim analysis. Methods: Eligible patients had mCRPC, were candidates for change of ARPI after progression on one prior ARPI, and had ≥1 PSMA-positive and no exclusionary PSMA-negative metastatic lesions by [68Ga]Ga-PSMA-11 PET/CT. Ineligible patients were candidates for PARP inhibition or had received prior systemic radiotherapy, immunotherapy or chemotherapy. Patients were randomized 1:1 to open-label 177Lu-PSMA-617 (7.4 GBq/6 weeks; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients with confirmed radiographic progression on ARPI change could cross over to 177Lu-PSMA-617. Secondary endpoints included time to worsening (TTW) in self-reported HRQoL (FACT-P, EQ-5D-5L) and pain (BPI-SF), defined as a composite of score worsening (prespecified thresholds), clinical progression (including new anti-cancer treatment) or death. Post hoc analyses of TTW in FACT-P and BPI-SF excluded clinical progression and death. The study was not powered for these endpoints and type I error was not controlled. Results: We randomized 468 patients (234/arm) with a median age of 72 years (range, 43–94). Median duration of exposure was 8.4 months for 177Lu-PSMA-617 and 6.5 months for ARPI change. 177Lu-PSMA-617 delayed TTW in FACT-P, EQ-5D-5L and BPI-SF scales and subscales vs ARPI change (Table). Results were similar in non-composite analyses. Incidence of grade ≥3 adverse events (AEs), serious AEs and AEs leading to discontinuation for 177Lu-PSMA-617 and ARPI change were 34% vs 44%, 20% vs 28% and 5.7% vs 5.2%, respectively. Conclusions: 177Lu-PSMA-617 delayed TTW in self-reported pain and HRQoL vs change of ARPI in taxane-naïve patients with PSMA-positive mCRPC. Clinical trial information: NCT04689828 . [Table: see text]

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)–positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

TPS714 Background: 1st-line induction platinum-based chemotherapy followed by switch maintenance Av is the current preferred standard of care in patients (pts) with aUC who do not progress after platinum-based chemotherapy. There is an significant need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitor. We hypothesized that CABO-Av combination would improve survival vs Av alone and have an acceptable safety profile as switch maintenance therapy in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for pts with locally advanced/metastatic UC (including cN3M0 only)) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adults are randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or Av and CABO 40 mg daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of anti-PD(L)1, no CNS metastases, no major surgery within 4 wks, no uncontrolled hypertension or cardiovascular disorders. Pts are stratified based on 1) best response to 1L chemotherapy: complete vs partial response vs stable disease and 2) presence vs absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of 1-sided alpha 0.025, power 80%, median OS 21 months (mo) with Av and hazard ratio 0.75, thus hypothesizing median OS 28 mo on CABO-Av. Key secondary endpoints include progression-free survival, safety, tolerability, and efficacy of CABO-Av vs Av alone based on RECIST 1.1 and iRECIST criteria (and PD-L1 status).Quality of life (QOL) are assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-Av vs Av alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test the correlation of established and new radiomic signatures with survival, adverse events and QOL and incorporate both radiologic and biologic features to assess their potential association with outcomes. This trial would be the first to systematically address whether adding the multitargeted TKI, CABO, to Av improves survival vs Av alone as 1L maintenance therapy. https://acknowledgments.alliancefound.org . Support: U10CA180821, U10CA180882; U24CA196171, U10CA180863 (CCTG); Clinical trial information: NCT05092958 .

LBA531 Background: Muscle-invasive urothelial carcinoma (MIUC) is an aggressive disease with high relapse rates. Neoadjuvant platinum-based chemotherapy (NAC) is the standard of care in patients (pts) who are cisplatin (Cis)-eligible. However, many pts are Cis-ineligible or have persistent muscle-invasive disease after NAC and surgery. We evaluated pembrolizumab (Pembro) as adjuvant therapy in pts with high-risk MIUC following surgical resection. Methods: The AMBASSADOR study is an open-label, randomized, phase III trial that enrolled pts with histologically confirmed MIUC of the bladder, upper tract, or urethra who (1) had ≥ pT2 and/or pN+ or margins+ at surgery (radical cystectomy, nephrectomy, nephroureterectomy, or ureterectomy) following NAC or (2) ≥ pT3 and/or pN+ or margins+ at surgery without NAC and were either Cis-ineligible or declined adjuvant Cis-based therapy. Pts were registered ≥4 to 16 weeks after surgery and randomized 1:1 to receive Pembro 200 mg every 3 weeks for 1 year or observation (Obs). Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior NAC. The dual primary endpoints were disease-free survival (DFS) and overall survival (OS) with a target sample size of 739 pts and required 387 DFS and 320 OS events for final analysis. Secondary objectives included evaluation of DFS and OS in PD-L1-positive and -negative pts and assessing safety. Here we present the interim DFS and OS results. Results: Between 09/2017 and 08/2021 a total of 702 pts were randomized prior to early closure due to US FDA approval of nivolumab for MIUC pts: 354 pts to Pembro and 348 pts to Obs; 13.0% vs 21.6% withdrew from study without event in the Pembro vs Obs arms, respectively. 74 pts (21%) in the Obs arm received an immune checkpoint inhibitor. Median follow-up was 22.3 months (mos) for DFS and 36.9 mos for OS. The DFS endpoint (based on 319 events needed for interim analysis) crossed the efficacy boundary. Median DFS was 29.0 months (95% confidence interval (CI) 21.8‒not evaluable (NE)) with Pembro and 14.0 months (95% CI 9.7‒20.20) with Obs (hazard ratio (HR) 0.69 [95% CI 0.55–0.87]; p=0.0013). At the interim analysis (n = 257 events), median OS was 50.9 months (95% CI 43.9‒NE) with Pembro and 55.8 months (95% CI 53.3‒NE) with Obs (HR 0.98 [95% CI 0.76–1.26]; p=0.88). Grade 3+ adverse events occurred in 48.4% and 31.8% of pts in the Pembro and Obs arms, respectively. Conclusions: Adjuvant Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs Obs for high-risk MIUC pts after radical surgery. The OS endpoint may have been impacted by pts on the Obs arm receiving a checkpoint inhibitor. Pembro was tolerable with no new safety signals. These results support adjuvant Pembro as a new therapeutic option for pts with MIUC with high risk for recurrence. Additional follow-up is ongoing for the final DFS/OS, PD-L1 subgroups, and ctDNA analyses. Clinical trial information: NCT03244384 .

PURPOSE Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981 ). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

5077 Background: In the phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (Apa) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated the association between PSA nadir within 3 months of treatment initiation with subsequent PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months, without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + Apa, or ADT + Apa + AAP, stratified by PSADT (< 3 vs 3–9 months), with post-treatment follow-up. The association between PSA nadir within the first three months on treatment with subsequent PSA PFS was analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + Apa (N = 168) or ADT + Apa + AAP (N = 169). 463 pts were evaluable for PSA nadir at 3 months. Across the three treatment arms, a PSA nadir of less than 0.1, between 0.1 – 0.2, and ≥ 0.2 ng/mL within the first three months of treatment was observed in 86.3%, 4.4%, and 9.3% of patients, respectively. A PSA nadir of < 0.2 ng/mL was reached within 3 months of treatment initiation in 79.8%, 96.9%, and 95.0% of pts randomized to the ADT, ADT + Apa, and ADT + Apa + AAP arms, respectively. The association between time to PSA nadir and subsequent PSA PFS was -0.30 (standard error = 0.03, Kendall’s tau modified for bivariate censoring), and median time to PSA nadir was 2.0 months (interquartile range 1.12 – 4.76 months). Failure to reach a PSA nadir < 0.2 ng/mL within the first three months of treatment was associated with a significantly shorter PSA PFS compared to pts with a PSA nadir ≤ 0.1 ng/mL (median PSA PFS of 13.9 vs. 22.8 months from 3 months post-treatment initiation; hazard ratio = 5.60, 95% CI: 3.58 – 8.75, p < 0.0001). There was also a significant difference in PSA PFS in those with a three-month PSA nadir between 0.1 – 0.2 vs ≤ 0.1 ng/mL (median PSA PFS 17.4 vs 22.8 months, HR = 2.63, 95:CI: 1.49 – 4.63, p = 0.0008). Conclusions: Using a landmark analysis at 3 months, a failure to reach PSA nadir less than 0.1 ng/mL within three months following initiation of ADT in BRPC is associated with shorter time to subsequent progression following treatment discontinuation. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissues and whole blood RNA in pts with suboptimal PSA nadir to identify potential markers of relative androgen pathway inhibitor resistance. Clinical trial information: NCT03009981 .

5021 Background: Somatic mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion in a process called clonal hematopoiesis (CH). CH increases the risk of developing myeloid neoplasms and shortens overall survival (OS), primarily linked to increased cardiovascular (CV) mortality. The impact of CH in metastatic solid cancers has been conflicting, with shorter OS in a broad cancer cohort but prolonged OS in metastatic colorectal cancer, which may be influenced by prior cytotoxic therapy that can promote emergence of CH. As AR pathway inhibitors (ARPIs) are associated with CV adverse events (AE), exploring the impact of CH in patients (pts) with mCRPC is of interest. Methods: A 9 gene targeted DNA sequencing panel designed to capture common CH mutations ( DNMT3A, TET2, ASXL1, PPM1D, TP53, CHEK2, SRSF2, SF3B1, JAK2) was applied to pre-treatment peripheral blood samples of 957 pts enrolled in the Alliance A031201 phase 3 trial of enzalutamide versus enzalutamide plus abiraterone/prednisone in the first line mCRPC setting. No difference in OS was found between treatment arms. The primary endpoint was the impact of CH on OS; secondary and exploratory endpoints included progression-free survival (PFS) and associations with baseline comorbidities and AEs (hematologic and CV). Cox proportional-hazards and logit models were adjusted for treatment arm, age, and radiation therapy (RT). Results: CH was common with 57% of pts having low CH (VAF>0.5% in 1+ mutation, L-CH), 24% having standard CH (VAF>2%, CH), and 7% having high CH (VAF>10%, H-CH). 4% of pts had 2+ CH mutations and 1% had 3+ mutations. Patients with CH were older (73.1 vs 70.2) and had higher rates of prior RT (58.4% vs 55.7%) and prior chemotherapy (3.9% vs 2.2%). No differences in OS were detected in pts with L-CH, CH, or H-CH. Similarly, no differences in PFS or baseline CV comorbidities were seen in any CH group. Pts with H-CH and TET2-mutated CH had statistically higher odds of any CV event (adjusted p=0.0004 and p=0.010, respectively) There was also a difference in the occurrence of major adverse CV events (MACE) by H-CH status (5.8% vs. 1.9%, adjusted p=0.042), while there was no difference seen for CH (3.4% vs 1.8%, adjusted p=0.147). Regarding hematologic AEs, one pt with a TP53 mutation (VAF 0.94%) developed myelodysplastic syndrome. Conclusions: CH did not affect OS or PFS in pts with mCRPC treated with ARPIs in the A031201 trial. However, CH with VAF>10% and TET2-mutated CH were associated with an increased rate of all CV AEs, suggesting an additive effect of ARPI therapy and CH on adverse CV outcomes. Confirmatory studies are warranted to assess whether CH should be considered in the risk-benefit discussion for pts receiving ARPIs.

PURPOSE Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting. PATIENTS AND METHODS Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments. RESULTS In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide v 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided P = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide v 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided P = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone. CONCLUSION The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.

TPS589 Background: In patients (pts) with metastatic unresectable urothelial cancer, platinum-based chemotherapy remains the standard of care for first-line treatment followed by switch maintenance avelumab if disease control is achieved with chemotherapy. Outside of this setting, single agent immunotherapy is often used in pts that have recurrence after platinum-based chemotherapy or are platinum ineligible. Atezolizumab is a PD-L1 inhibitor currently approved for pts that have urothelial cancers expressing positive PD-L1 or pts ineligible for receiving platinum-based chemotherapy. Tumor-targeted radiotherapy can generate immune-stimulating effects without immune suppression as was previously thought. Moreover, it has become clear that radiotherapy can induce profound effects on tumor cells and the tumor microenvironment that can enhance or trigger an anticancer immune response. While numerous trials have investigated the abscopal effect, this trial will have specific parameters regarding drug type, radiation dose and administration. Methods: A032002 is a phase 2 trial addressing pts that are platinum ineligible or refractory to platinum-based chemotherapy. 144 pts will be randomized to receive either atezolizumab or atezolizumab and single site radiation therapy. The atezolizumab regimen is 1200 mg every 3 weeks. Administration of radiotherapy will occur to one non-target site (8 Gy x 3) for pts randomized to the atezolizumab + radiotherapy arm. All pts will undergo centralized PD-L1 testing (SP142 monoclonal primary antibody), which can be performed on archival tissue; a new biopsy is only required if no archival tissue is available. Key eligibility criteria include age ≥ 18 years, ECOG performance status 0-2, histologically confirmed metastatic urothelial cancer, having at least one measurable site per RECIST 1.1 to monitor for abscopal response, one site targetable for radiation, and tissue available for PD-L1 testing. The primary endpoint is tumor response within 6 months of randomization. Tumor response is defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using RECIST 1.1 criteria. For a one-sided log rank test with a type 1 error rateof 0.10, the study has 90% power to detect a 20% increase in response rate. Key secondary endpoints include tumor response using iRECIST, progression-free survival and overall survival. Quality of life assessments include EORTC QLQ-C30, QLQ-BLM30 and PROMIS-Fatigue. Tissue, urine and blood samples will be collected and biobanked for future correlative science. Enrollment to ART began in December 2021. The study is available for participation at all US NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882. Clinical trial information: NCT04936230 .