Beltran, Himisha

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.

164 Background: Lurbinectedin (L) is a novel inhibitor of oncogenic transcription that was granted accelerated approval by the Food and Drug Administration in June 2020 for the treatment of metastatic small cell lung cancer (SCLC) following disease progression on or after platinum-based chemotherapy (PBC). Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) is a high-grade, invasive malignancy that accounts for < 1% of all prostate cancers. SC/NEPC is distinct from prostatic adenocarcinoma and behaves similar to SCLC. NCCN guidelines for SC/NEPC recommend following the SCLC treatment guidelines. Using these guidelines, L may be used as a second-line treatment in patients (pts) with SC/NEPC who progress on or after PBC. We aimed to characterize the baseline characteristics, clinical course and therapeutic outcomes of pts treated with L for SC/NEPC. Methods: After IRB approval, 18 cases were gathered from 4 academic oncology centers. Baseline patient data, prior treatments and L treatment outcomes, including best radiographic and serologic responses, overall survival (OS), progression-free survival (PFS) and treatment toxicity were assessed. The Kaplan-Meier method was used to calculate OS and PFS from the L start date. Clinical benefit rate (CBR) included pts with complete response (CR), partial response (PR) and stable disease (SD) on imaging. Results: At the time of first L dose, all had metastatic disease with 2-6 distinct sites of metastases, most commonly bone (14/18, 77.8%), lymph nodes (14/18, 77.8%) and liver (13/18, 72.2%); median age was 63.5 (Range: 53-84); 11 pts (61.1%) had an ECOG 0-1; 4 pts (22.2%) had an ECOG of 2-3. The median total number of systemic therapies administered prior to L was 4 (Range: 2-7). All pts received PBC prior to L. The most common dose of L prescribed was 3.2 mg/m2 every 21 days (15/18, 83.3%). Androgen deprivation therapy was administered in conjunction with L in 9 pts (50%). The median number of cycles of L was 5 (Range: 1-10). L was discontinued due to toxicity in 1 patient (5.6%), disease progression in 10 pts (55.6%), transition to hospice in 2 pts (11.1%), 3 pts (16.7%) died while receiving treatment (not due to L toxicity), and 2 pts (11.1%) remained on L at the time of data reporting. The median OS and PFS from date of first L dose was 6.01 months (0.23 – 16.69) and 3.35 months (0.16 – 7.79), respectively. CBR was 9/16 (56.3%) with partial response in 5 pts (31.3%), stable disease in 4 pts (25%), and progressive disease in 7 pts (43.8%). Two pts did not have post-treatment imaging available to assess response. There were no hospitalizations for L treatment related adverse events (tRAE). The most common tRAE were grade I and II fatigue and anemia; 9 pts (50%) experienced no tRAE. The only grade IV toxicity was neutropenia in 3 pts (16.7%). Conclusions: L is a well-tolerated and active treatment option for patients with SC/NEPC. Prospective studies are needed to determine the role of L in the treatment of SC/NEPC.

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.

e18584 Background: Cancer progression rates following diagnosis are readily measured. However, the progression rate of cancer during the preclinical sojourn time is generally unobserved. Understanding the duration of preclinical stages (“dwell time”) would allow clinicians to better identify appropriate screening intervals for cancer. We therefore elicited estimates of progression rate during the preclinical sojourn time for a wide variety of malignancies from a panel of clinical experts. Methods: We used a validated consensus methodology (RAND/UCLA modified Delphi panel method) to elicit per-stage dwell time estimates for 20 solid cancers and lymphoma from experts. Eleven experienced oncologists (general and subspecialists) from community and academic centers reviewed literature on the natural history of disease and estimated in number of years (<1 to 9+ years) how long it would take each cancer to progress from the beginning of clinically detectable Stage I/II/III to the beginning of the next stage in untreated adults. Cancer histological subtypes were grouped and experts were asked to provide an overall rating. Ratings were completed before and after a discussion of areas of disagreement. Results: Expert estimates and range of dwell time for 21 cancer types are provided in Table. Prostate and thyroid cancer were estimated to be the slowest growing, taking approximately 7 and 5 years respectively to progress through Stage I (range 4-8), 5 years to progress through Stage II (range 3-7), and 3 and 4 (range 2-5) years respectively to progress through Stage III. Esophageal, lung, liver/intrahepatic bile-duct, gallbladder, and pancreatic cancers were estimated to progress quickly through all three stages (1-2 years per stage). Conclusions: These findings summarize practicing oncologists’ estimates of dwell time in preclinical disease. Experts agreed on dwell times although ranges were large and differences in cancer subtypes were not captured. Generally, estimates trend with published data on survival with treatment: cancers with higher survival (e.g., prostate, thyroid) were estimated to grow slower, while cancers with lower survival (e.g., pancreatic, liver/intrahepatic bile-duct, gallbladder) were estimated to grow faster. These estimates could be useful when determining screening intervals for these or any subset of these cancers. [Table: see text]

TPS4593 Background: Bone metastases are prevalent in approximately 30% of pts with advanced RCC. Pts with bone metastases have a worse prognosis compared to pts without bone metastases and are at risk of symptomatic skeletal events (SSEs). Cabozantinib, a multitargeted inhibitor of multiple kinases, including vascular endothelial growth factor (VEGF) receptor and MET, has improved survival in pts with metastatic RCC and has enhanced activity in bone. Ra-223, an alpha-emitting radioisotope with natural bone-seeking proclivity, has been shown to prolong survival in men with castration-resistant prostate cancer. We previously conducted a pilot study of Ra-223 with VEGF inhibition and demonstrated safety and declines in markers of bone formation and resorption with the combination (McKay et al, CCR 2018). Given that decreasing rates of SSEs and improving outcomes for pts with RCC with bone metastases are unmet needs in pts with RCC, we designed a randomized phase 2 study through the National Clinical Trials Network (NCTN) investigating cabozantinib with or without Ra-223 in patients with RCC with bone metastases. Methods: This is an open-label multicenter study. Eligible pts have metastatic RCC of any histology with ≥2 metastatic bone lesions untreated with prior radiation therapy and no more than 2 prior lines of systemic therapy. Pts with non-clear cell RCC are eligible and will be capped at 20% of the total accrual goal. Pts must have a Karnofsky performance status of ≥60%, have symptomatic bone pain defined as a prior SSE or need of analgesics, and be on osteoclast-targeted therapy unless otherwise contraindicated. Pts are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) Ra-223. Starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Ra-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, quality of life measures, and correlative analyses including liquid biopsy studies and tumor tissue analysis. The study has 90% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.025 significance. To ensure 191 evaluable patients, target accrual is 210 pts. This design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events (72 SSE events) have been observed. Final data analysis will occur when 143 events have been observed. The study was activated in December 2019 and accrual is currently ongoing throughout the NCTN. Clinical trial information: NCT04071223.

PURPOSE Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression–free survival (BPFS) over RP alone. PATIENTS AND METHODS Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m 2 body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS). RESULTS In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 v 0.84, respectively; 95% CI for the difference, −0.01 to 0.11; P = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone. CONCLUSION The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

3552 Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]

BackgroundThe progression of prostate cancer is a complex, multistep process that involves molecular alterations in cells of the tumor and the microenvironment, with associated interactions between the stroma and epithelium. Genomic expression analyses of stromal infiltration markers were performed to determine the significance thereof in prostate cancer.MethodsGenome‐wide expression profiles of formalin‐fixed, paraffin‐embedded radical prostatectomy samples were evaluated from a prospective registry cohort (n = 5239) and 3 retrospective institutional cohorts (n = 1135). Two independent stromal gene expression signatures implied stromal infiltration. Cox proportional hazards regression defined the association between stromal infiltration expression and metastasis‐free survival (MFS).ResultsStromal expression scores were correlated with stromal signature genes and with other key stromal markers (CAV1, VIM, and TAGLN), basal activity, and CD3 and CD4 immune biomarkers (r > 0.5 for all). The top decile of stromal expression was associated with high genomic risk scores (Decipher ≥ 0.6) , high Cancer of the Prostate Risk Assessment–Postsurgical scores, Gleason 9 to 10 disease, and a higher risk for metastasis (hazard ratio, 2.35; 95% CI, 1.37‐4.02; P = .001). A higher stromal infiltration score was also associated with decreased expression of DNA repair genes and higher radiation sensitivity genomic scores. Postoperative radiation therapy (RT) was associated with an MFS benefit for patients with high stromal scores, but not for patients with low stromal scores (Pinteraction = .02).ConclusionsExpression of stromal infiltration markers is correlated with prostate cancer aggressiveness/progression and may be predictive of a response to RT. Stromal infiltration markers should be studied and considered for incorporation into clinical prognostication and decision making.