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Background/objectives: Unfortunately, not all metastatic castration resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing in prostate cancer., Subjects/methods: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science., Results/conclusion: We argue for the widespread adoption of germline testing in all patients with prostate cancer and for somatic mutations testing in patients at the time of recurrent/metastatic disease. In this first part, we review how genomic testing is performed. We also review how to overcome certain barriers to integrate genetic and biomarker testing into clinical practice., (© 2024. The Author(s).)

Introduction: Lurbinectedin is FDA approved for treatment of metastatic small cell lung cancer (SCLC) following progression on or after platinum-based chemotherapy. Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) behaves like SCLC; however, no safety or efficacy data for lurbinectedin in SC/NEPC exists., Patients and Methods: All SC/NEPC patients treated with lurbinectedin across 4 academic oncology centers were identified. Baseline patient data and lurbinectedin outcomes including radiographic responses (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), progression free survival (PFS), overall survival (OS), and treatment-related adverse events (trAEs) were described. Clinical benefit rate (CBR) included CR, PR, or SD on imaging. Descriptive statistics were performed., Results: At first lurbinectedin dose, all 18 patients had metastatic disease. Median age was 63.5 (Range: 53-84), number of prior systemic therapies was 4 (Range: 2-7), and lurbinectedin cycles completed was 5 (Range: 1-10). ADT was administered during lurbinectedin treatment in 9/18 patients. CBR was 9/16 (56%). The most common trAEs were fatigue and anemia. Median OS and PFS were 6.01 (0.23-16.69) and 3.35 (0.16-7.79) months., Conclusions: Lurbinectedin showed modest but significant clinical benefit in some patients with SC/NEPC and demonstrated an acceptable toxicity profile with no hospitalizations from trAEs. SC/NEPC is an aggressive disease with a poor prognosis for which more treatment options are needed. Evidence for subsequent treatments after platinum-based chemotherapy is lacking. Lurbinectedin is an active treatment option for SC/NEPC; however, larger confirmatory studies are needed., Competing Interests: Disclosures Haley M Meyer. No Relationships to Disclose, Rajitha Sunkara, No Relationships to Disclose, Himisha Beltran, Consulting or Advisory Role - Amgen; AstraZeneca; Bayer; Blue Earth Diagnostics; Curie Therapeutics; Daicchi Sankyo; Foundation Medicine; Janssen Oncology; Loxo/Lilly; Merck; Novartis; Pfizer; Sanofi, Research Funding - Abbvie/Stemcentrx (Inst); Bristol Myers Squibb Foundation (Inst); Daiichi Sankyo (Inst); Janssen (Inst). Travel, Accommodations, Expenses - Janssen Oncology, Emily Rothmann, No Relationships to Disclose, Kevin Dale Courtney. Consulting or Advisory Role - Novartis, Research Funding - Amgen (Inst); Astellas Pharma (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Celgene/Bristol-Myers Squibb (Inst); Clovis Oncology (Inst); Exelixis (Inst); Harpoon therapeutics (Inst); Lilly (Inst); Myovant Sciences (Inst); Novartis (Inst); Pfizer (Inst); Stemline Therapeutics (Inst); Surface Oncology (Inst), Patents, Royalties, Other Intellectual Property - My spouse receives patent royalties from Athena Diagnostics, Inc. (I) Andrew J. Armstrong. Consulting or Advisory Role - Astellas Scientific and Medical Affairs Inc; AstraZeneca; Bayer; Bristol-Myers Squibb; Epic Sciences; Exelixis; GoodRx; Janssen; Merck; Myovant Sciences; Novartis; Pfizer; ZAlpha, Research Funding - Amgen (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Bayer (Inst); BeiGene (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Constellation Pharmaceuticals (Inst); FORMA Therapeutics (Inst); Gilead Sciences (Inst); Janssen Oncology (Inst); Merck (Inst); Novartis (Inst); Pfizer (Inst); Roche/Genentech (Inst), Patents, Royalties, Other Intellectual Property - Circulating tumor cell novel capture technology (Inst), Travel, Accommodations, Expenses - Astellas Scientific and Medical Affairs Inc, Alan Haruo Bryce, Honoraria - Advanced Accelerator Applications/Novartis; Astellas Pharma; Astellas Pharma; AstraZeneca; Bayer; Bayer; Bayer; Castle Biosciences; Horizon CME; Janssen; Janssen Oncology; Lilly; Myovant Sciences; Myovant Sciences; Novartis; Novartis; Pfizer; Pfizer; Pfizer; Research to Practice; Research to Practice; Verity Pharmaceuticals; Verity Pharmaceuticals, Consulting or Advisory Role - Astellas Pharma, Research Funding - Janssen Oncology (Inst). Travel, Accommodations, Expenses - Bayer; Clovis Oncology (Inst); Pfizer; Pfizer (Inst); Phosplatin Therapeutics (Inst), Andrea Lippucci, Andrea Lippucci is currently a Genitourinary Oncology medical science liaison for Johnson and Johnson. The content production and involvement with this research project and manuscript were completed prior to her employment with Johnson and Johnson. This publication in no way reflects the viewpoint of Johnson and Johnson nor is it an endorsement of a particular treatment approach. Melissa L. Stanton, Consulting or Advisory Role - PAREXEL, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy., Objective: We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial., Design, Setting, and Participants: PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml., Outcome Measurements and Statistical Analysis: A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated., Results and Limitations: A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point., Conclusions: The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients., Patient Summary: A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The objective of this study was to evaluate the prognostic value of early PSA decline following initiation of second-generation hormone therapy (2nd HT), namely abiraterone acetate or enzalutamide, in patients with taxane-refractory metastatic castrate-resistant prostate cancer (mCRPC) and evaluate utility of this metric in informing intensified surveillance/imaging protocols., Methods: We retrospectively identified 75 mCRPC patients treated with 2nd HT following docetaxel failure (defined as PSA rise and radiographic progression). Patients were categorized patients into two cohorts based on the first PSA within 3 months after initiation of therapy: PSA reduction ≥50% (Group A) and PSA reduction <50% (Group B). The primary endpoint was cancer-specific mortality (CSM). The secondary endpoint was radiographic disease progression (rDP) on 2nd HT. In univariate and multivariate analyses, we investigated factors associated with rPD and CSM., Results: We included 75 patients (52 in Group A, 23 in Group B) in the analytic cohort. Baseline clinico-demographic characteristics, including median age, primary Gleason score risk group, median pre-treatment PSA, disease burden, site of metastases, and pre-treatment ECOG score were not statistically different between the two groups. Median follow up time was 30 months and the median time to radiographic disease progression was 28.1 and 12.5 months (p = 0.002) in cohorts A and B, respectively. On univariate and multivariate analyses, both PSA reduction ≥50% and volume of metastatic disease were significantly associated with a decreased risk of radiographic disease progression (HR 0.41, 95% CI 0.21-0.80, p = 0.0113) as well as a decreased risk of cancer-specific mortality (HR 0.29, 95% CI 0.09-0.87, p = 0.0325)., Conclusion: PSA reduction ≥50% within 3 months of starting 2nd HT was associated with significantly improved radiographic disease progression-free survival and 3-year cancer-specific mortality. This suggests using PSA 50%-decline metric in surveillance patients with on 2nd HT and identifies patients who require further evaluation with imaging., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose of Review: Low-volume prostate cancer is an established prognostic category of metastatic hormone-sensitive prostate cancer. However, the term is often loosely used to reflect the low burden of disease across different prostate cancer states. This review explores the definitions of low-volume prostate cancer, biology, and current evidence for treatment. We also explore future directions, including the impact of advanced imaging modalities, particularly prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scans, on refining patient subgroups and treatment strategies for patients with low-volume prostate cancer., Recent Findings: Recent investigations have attempted to redefine low-volume disease, incorporating factors beyond metastatic burden. Advanced imaging, especially PSMA PET, offers enhanced accuracy in detecting metastases, potentially challenging the conventional definition of low volume. The prognosis and treatment of low-volume prostate cancer may vary by the timing of metastatic presentation. Biomarker-directed consolidative therapy, metastases-directed therapy, and de-escalation of systemic therapies will be increasingly important, especially in patients with metachronous low-volume disease., Summary: In the absence of validated biomarkers, the management of low-volume prostate cancer as defined by CHAARTED criteria may be guided by the timing of metastatic presentation. For metachronous low-volume disease, we recommend novel hormonal therapy (NHT) doublets with or without consolidative metastasis-directed therapy (MDT), and for synchronous low-volume disease, NHT doublets with or without consolidative MDT and prostate-directed radiation. Docetaxel triplets may be a reasonable alternative in some patients with synchronous presentation. There is no clear role of docetaxel doublets in patients with low-volume disease. In the future, a small subset of low-volume diseases with oligometastases selected by genomics and advanced imaging like PSMA PET may achieve long-term remission with MDT with no systemic therapy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: CONFLICTS OF INTEREST The authors declare the following competing interests: Alan H. Bryce has received compensation for a consulting or advisory role from Merck, Janssen, Astellas, AstraZeneca, Pfizer, Myovant, and Lantheus; and grant funding from Janssen. Andrew J. Armstrong has received compensation for a consulting or advisory role from Astellas, Epic Sciences, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Clovis, Exact Sciences, Myovant, Exelixis, GoodRx, and Novartis; and his institution has received research funding from Astellas, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Amgen, and Novartis. AI has received compensation for a consulting or advisory role from Alpha9Tx, Clarity Pharmaceuticals, Novartis, Progenics, Radionetics, RayzeBio, and Telix; and research/grant funding from GE Healthcare and Novartis. Ana M. Aparicio has received compensation for a consulting or advisory role from Pfizer, Janssen, and Bristol Myers Squibb. Alicia K. Morgans has received compensation for a consulting or advisory role from Astellas, AstraZeneca, AAA, Bayer, Janssen, Exelixis, Myovant, Myriad Genetics, Lantheus, Novartis, Merck, Pfizer, Telix, and Sanofi; and research funding from Bayer, Astellas, Myovant, Pfzer, Sanofi, and Janssen. Brian F. Chapin has received compensation for a consulting or advisory role from Blue Earth Diagnostics, Astellas, Pfizer, and Janssen; and is a clinical trial investigator for Regeneron and Blue Earth Therapeutics. Daniel P. Petrylak has received compensation for a consulting or advisory role from Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Ipsen, Janssen, Merck & Company Inc, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Sanofi Aventis Pharmaceuticals, Seattle Genetics, and Urogen; has received grant support from Ada Cap (Advanced Accelerator Applications), Agensys Inc, Arvinas, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo Company Limited, Eisai, Eli Lilly, Endocyte, Ferring, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, and Seattle Genetics; and has owned stock in Bellicum and Tyme. Daniel E. Spratt has received compensation for a consulting or advisory role from AstraZeneca, Bayer, Boston Scientific, Elekta, Janssen, Novartis, Pfizer, and Varian. Emmanuel S. Antonarakis has received compensation for a consulting or advisory role from Sanofi, Dendreon, Janssen Biotech, ESSA, Merck, AstraZeneca, Clovis Oncology, Lilly, Bayer, Amgen, Astellas Pharma, Blue Earth Diagnostics, Bristol Myers Squibb/Celgene, Constellation Pharmaceuticals, Curium Pharma, Exact Sciences, Foundation Medicine, GlaxoSmithKline, InVitae, Ismar Health Care, Medivation, Tempus, Orion, and Alkido Pharma; he has received research funding from Celgene and Clovis Oncology; his institution has received research funding from Janssen Biotech, Johnson & Johnson, Sanofi, Dendreon, Aragon Pharmaceuticals, Exelixis, Millennium, Genentech, Novartis, Astellas Pharma, Tokai Pharmaceuticals, Merck, AstraZeneca, Clovis Oncology, Constellation Pharmaceuticals, Celgene, and Clovis Oncology; and he is co-inventor of a biomarker technology that has been licensed to Qiagen. E. David Crawford has received compensation for a consulting or advisory role from Janssen, Bayer, MDx, Tolmar, Pfizer, and Astellas; has received research/grant funding from the NIH and University of Colorado Cancer Center; and has received compensation for a leadership position from Carden Jennings. Eric Small has received compensation for a consulting or advisory role from Janssen, Fortis, and Deciphera; received honoraria from Janssen and Johnson & Johnson; and owns stock/stock options in Fortis, Harpoon, and Teon. Evan Y. Yu has received compensation for a consulting or advisory role from Aadi Bioscience, Advanced Accelerator Applications, Bayer, Janssen, Merck, and Oncternal; and his institution has received research funding from Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Lantheus, Merck, Seagen, Surface, Taiho, and Tyra. Felix Y. Feng has received compensation for a consulting or advisory role from Astellas, Bayer, Blue Earth Diagnostics, Janssen, Myovant, Novartis, Roivant, Sanofi, Tempus, Artera, BMS (Tumor Microenvironment Group), ClearNote, and Serimmune, Himisha Beltran has received compensation for a consulting or advisory role from Janssen, Merck, Pfizer, Foundation Medicine, Blue Earth Diagnostics, Amgen, Bayer, Oncorus, LOXO, Daicchi Sankyo, Sanofi, Curie Therapeutics, Fusion Pharma, Astra Zeneca, and Novartis; and her institution has received research funding from Janssen, Bristol Myers Squibb, Circle Pharma, Daicchi Sankyo, and Novartis. Jeremie Calais has received compensation for a consulting, advisory, or blinded image reading role from Advanced Accelerator Applications, Amgen, Astellas, Bayer, Blue Earth Diagnostics Inc., Curium Pharma, DS Pharma, GE Healthcare, Isoray, IBA RadioPharma, Janssen Pharmaceuticals, Monrol, Lightpointmedical, Lantheus, Novartis, Pfizer, POINT biopharma, Progenics, Radiomedix, Sanofi, Siemens-Varian, SOFIE, and Telix Pharmaceuticals; and grant funding from the Prostate Cancer Foundation. John W. Davis has received research funding from Janssen. Katie S. Murray has received compensation for a consulting or advisory role from Curium and Urogen Pharma. Michael S. Cookson has received compensation for a consulting or advisory role from LynxDx, Natera, Bayer, Consulting JW, Remedica Medical Education & Publishing, Pfizer, Lantheus, Nonagen Bioscience Corp, MJH LifeSciences, Pacific Edge Diagnostics USA Ltd, Janssen, Prokarium, BioPharm Communications, Myovant, Merck, Clinical Education Alliance, TesoRx Pharma; and has received research support from Ferring Pharmaceuticald and MDXHealth. Maha H. Hussain has received compensation for a consulting or advisory role from GSK, Novartis, and Bayer; honoraria for educational event or lecture from Merck, Mubarak Mahdi Almansour (Chairman, International Genitourinary Cancer Conference), MJH, and Academic CME; her institution has received research/grant funding from AstraZeneca and Arvinas. Michael Morris has received compensation for a consulting or advisory role from AstraZeneca, Lantheus, Daiichi, Convergent Therapeutics, Pfizer, ITM Isotope Technologies, Clarity Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Telix, and Z-Alpha; he is an uncompensated advisor to Bayer and Novartis; his institution has received research funding from Bayer, Corcept, Roche, Janssen, Celgene, Novartis, and Astellas. Matthew B. Rettig has received compensation for a consulting or advisory role from Myovant, INmune Bio, Bayer, and Johnson & Johnson; is a member of the Speakers’ Bureau for Johnson & Johnson and Bayer; and has received grants/research support from Merck, Lantheus, Progenics, Clovis, ORIC, Pfizer, Novartis, Amgen. Neeraj Agarwal has received compensation for a consulting or advisory role from Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; his institution has received research funding from Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Neal Shore has received compensation for a consulting or advisory role from AbbVie, Alessa Therapeutics, Akido, Amgen, Arquer, Asieris, Astellas, Astra Zeneca, Bayer, BMS, Boston Scientific, Clarity, Clovis, Cold Genesys, Dendreon, Exact Images, Exact Sciences, FerGene, FIZE Medical, GConcology, GenesisCare, Genetech, Guardant, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX, Merck, Minomic, Myovant, Myriad, NGM, Nonagen, Novartis, NYMOX, Pacific Edge, Photocure, Pfizer, PlatformQ, Profound, Promaxo, Propella, Protara, Sanofi, SesenBio, Speciality Networks, Telix, Tolmar, Urogen, Vaxiion, and Vessi; received payment for expert testimony from Ferring; and is on the board of Photocure. Oliver Sartor has received compensation for a consulting or advisory role from Advanced Accelerator Applications, Amgen, ART BioScience, Astellas Pharma, AstraZeneca, Bayer, Clarity Pharmaceuticals, EMD Serono, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, MacroGenics, Novartis, Pfizer, Point Biopharma, Ratio, Sanofi, Telix Pharmaceuticals, and TeneoBio; he has stock or other ownership interested with AbbVie, Cardinal Health, Clarity Pharmaceuticals, Convergent, Eli Lilly, Fusion Pharmaceuticals, Point Biopharma, Ratio, Telix, and United Health Group; he has patents for Saposin C and receptors as targets for treatment of benign and malignant disorders (U.S. patent awarded January 23, 2007; patent no. 7,166,691); he has provided expert testimony for Sanofi; he has received reimbursement for travel, accommodations, or expenses from AstraZeneca, Bayer, Lantheus, and Sanofi; and his institution has received research/grant funding from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, InVitae, Janssen, Lantheus, Merck, and Sanofi. Phillip J. Koo has received compensation for a consulting or advisory role from Lantheus, Blue Earth Diagnostics, Merck, Janssen, Pfizer, Astellas, AstraZeneca, Bayer, Novartis, Sanofi, Telix, and Curium. Scott E. Eggener has received compensation for a consulting or advisory role Candel Therapeutics, A3P Biomedical, Cellvax, MetasTx, Optum-Health, and Janssen. Sandy Srinivas has received compensation for a consulting or advisory role from Novartis and Janssen. Scott T. Tagawa has received compensation for a consulting or advisory role from Sanofi, Medivation, Astellas, Dendreon, Janssen, Genentech, Bayer, Endocyte, Eisai, Immunomedics, Karyopharm, Abbvie, Tolmar, Seattle Genetics, Amgen, Clovis, QED, Pfizer, AAA/Novartis, Clarity, Genomic Health, POINT Biopharma, Blue Earth, AIkido Pharma, Telix Pharma, Convergent Therapeutics, EMD Serono, Myovant, Merck, Daiichi Sankyo, TransThera, and Regeneron; he is an unpaid consultant for Atlab Pharma, Phosplatin Therapeutics, Amgen, and Ambrx; he and his institution hold patents for biomarkers for sacituzumab govitecan therapy (Immunomedics/Gilead); and his institution has received research funding from Sanofi, Medivation, Astellas, Janssen, Amgen, Progenics, Dendreon, Lilly, Genentech, Newlink, BMS, Inovio, AstraZeneca, Immunomedics, Aveo, Rexahn, Atlab, Boehringer Ingelheim, Millennium, Bayer, Merck, Abbvie, Karyopharm, Endocyte, Clovis, Seattle Genetics, Novartis, Gilead, POINT Biopharma, Ambrx, Clarity. Thomas P. Boike has received compensation for a consulting or advisory role from Lantheus, Myovant, Novartis, Pfizer, Janssen, Astellas, Blue Earth, AstraZeneca, Palette Life Sciences, and Boston Scientific. Tanya Dorff has received compensation for a consulting or advisory role from AstraZeneca, Bayer, Janssen, and Sanofi. Tian Zhang has received compensation for a consulting or advisory role from Merck, Exelixis, Sanofi-Aventis, Janssen, Astra Zeneca, Pfizer, Amgen, BMS, Dendreon, SeaGen, Eisai, Aveo, Bayer, and Eli Lilly; honoraria from MJH Associates, Vaniam, Aptitude Health, PlatformQ, IntegrityCE, PeerView, and WJ Weiser; and her institution has received research funding from Novartis, Merck, Janssen, Astra Zeneca, Pfizer, Tempus, and Eli Lilly. Wendy Poage is an employee of Servier Pharmaceuticals; and she has ownership interests in 3D biopsy.

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., Competing Interests: CONFLICTS OF INTEREST The authors declare the following competing interests: Alan H. Bryce has received compensation for a consulting or advisory role from Merck, Janssen, Astellas, AstraZeneca, Pfizer, Myovant, and Lantheus; and grant funding from Janssen. Andrew J. Armstrong has received compensation for a consulting or advisory role from Astellas, Epic Sciences, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Clovis, Exact Sciences, Myovant, Exelixis, GoodRx, and Novartis; and his institution has received research funding from Astellas, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Amgen, and Novartis. Andrei Iagaru has received compensation for a consulting or advisory role from Alpha9Tx, Clarity Pharmaceuticals, Novartis, Progenics, Radionetics, RayzeBio, and Telix; and research/grant funding from GE Healthcare and Novartis. Ana M. Aparicio has received compensation for a consulting or advisory role from Pfizer, Janssen, and Bristol Myers Squibb. Alicia K. Morgans has received compensation for a consulting or advisory role from Astellas, AstraZeneca, AAA, Bayer, Janssen, Exelixis, Myovant, Myriad Genetics, Lantheus, Novartis, Merck, Pfizer, Telix, and Sanofi; and research funding from Bayer, Astellas, Myovant, Pfzer, Sanofi, and Janssen. Brian F. Chapin has received compensation for a consulting or advisory role from Blue Earth Diagnostics, Astellas, Pfizer, and Janssen; and is a clinical trial investigator for Regeneron and Blue Earth Therapeutics. Daniel P. Petrylak has received compensation for a consulting or advisory role from Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Ipsen, Janssen, Merck & Company Inc, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Sanofi Aventis Pharmaceuticals, Seattle Genetics, and Urogen; has received grant support from Ada Cap (Advanced Accelerator Applications), Agensys Inc, Arvinas, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo Company Limited, Eisai, Eli Lilly, Endocyte, Ferring, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, and Seattle Genetics; and has owned stock in Bellicum and Tyme. Daniel E. Spratt has received compensation for a consulting or advisory role from AstraZeneca, Bayer, Boston Scientific, Elekta, Janssen, Novartis, Pfizer, and Varian. Emmanuel S. Antonarakis has received compensation for a consulting or advisory role from Sanofi, Dendreon, Janssen Biotech, ESSA, Merck, AstraZeneca, Clovis Oncology, Lilly, Bayer, Amgen, Astellas Pharma, Blue Earth Diagnostics, Bristol Myers Squibb/Celgene, Constellation Pharmaceuticals, Curium Pharma, Exact Sciences, Foundation Medicine, GlaxoSmithKline, InVitae, Ismar Health Care, Medivation, Tempus, Orion, and Alkido Pharma; he has received research funding from Celgene and Clovis Oncology; his institution has received research funding from Janssen Biotech, Johnson & Johnson, Sanofi, Dendreon, Aragon Pharmaceuticals, Exelixis, Millennium, Genentech, Novartis, Astellas Pharma, Tokai Pharmaceuticals, Merck, AstraZeneca, Clovis Oncology, Constellation Pharmaceuticals, Celgene, and Clovis Oncology; and he is co-inventor of a biomarker technology that has been licensed to Qiagen. E. David Crawford has received compensation for a consulting or advisory role from Janssen, Bayer, MDx, Tolmar, Pfizer, and Astellas; has received research/grant funding from the NIH and University of Colorado Cancer Center; and has received compensation for a leadership position from Carden Jennings. Eric Small has received compensation for a consulting or advisory role from Janssen, Fortis, and Deciphera; received honoraria from Janssen and Johnson & Johnson; and owns stock/stock options in Fortis, Harpoon, and Teon. Evan Y. Yu has received compensation for a consulting or advisory role from Aadi Bioscience, Advanced Accelerator Applications, Bayer, Janssen, Merck, and Oncternal; and his institution has received research funding from Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Lantheus, Merck, Seagen, Surface, Taiho, and Tyra. Felix Y. Feng has received compensation for a consulting or advisory role from Astellas, Bayer, Blue Earth Diagnostics, Janssen, Myovant, Novartis, Roivant, Sanofi, Tempus, Artera, BMS (Tumor Microenvironment Group), ClearNote, and Serimmune, Himisha Beltran has received compensation for a consulting or advisory role from Janssen, Merck, Pfizer, Foundation Medicine, Blue Earth Diagnostics, Amgen, Bayer, Oncorus, LOXO, Daicchi Sankyo, Sanofi, Curie Therapeutics, Fusion Pharma, Astra Zeneca, and Novartis; and her institution has received research funding from Janssen, Bristol Myers Squibb, Circle Pharma, Daicchi Sankyo, and Novartis. Jeremie Calais has received compensation for a consulting, advisory, or blinded image reading role from Advanced Accelerator Applications, Amgen, Astellas, Bayer, Blue Earth Diagnostics Inc, Curium Pharma, DS Pharma, GE Healthcare, Isoray, IBA RadioPharma, Janssen Pharmaceuticals, Monrol, Lightpointmedical, Lantheus, Novartis, Pfizer, POINT biopharma, Progenics, Radiomedix, Sanofi, Siemens-Varian, SOFIE, and Telix Pharmaceuticals; and grant funding from the Prostate Cancer Foundation. John W. Davis has received research funding from Janssen. Katie S. Murray has received compensation for a consulting or advisory role from Curium and Urogen Pharma. Michael S. Cookson has received compensation for a consulting or advisory role from LynxDx, Natera, Bayer, Consulting JW, Remedica Medical Education & Publishing, Pfizer, Lantheus, Nonagen Bioscience Corp, MJH LifeSciences, Pacific Edge Diagnostics USA Ltd, Janssen, Prokarium, BioPharm Communications, Myovant, Merck, Clinical Education Alliance, TesoRx Pharma; and has received research support from Ferring Pharmaceuticald and MDXHealth. Maha H. Hussain has received compensation for a consulting or advisory role from GSK, Novartis, and Bayer; honoraria for educational event or lecture from Merck, Mubarak Mahdi Almansour (Chairman, International Genitourinary Cancer Conference), MJH, and Academic CME; her institution has received research/grant funding from AstraZeneca and Arvinas. Michael Morris has received compensation for a consulting or advisory role from AstraZeneca, Lantheus, Daiichi, Convergent Therapeutics, Pfizer, ITM Isotope Technologies, Clarity Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Telix, and Z-Alpha; he is an uncompensated advisor to Bayer and Novartis; his institution has received research funding from Bayer, Corcept, Roche, Janssen, Celgene, Novartis, and Astellas. Matthew B. Rettig has received compensation for a consulting or advisory role from Myovant, INmune Bio, Bayer, and Johnson & Johnson; is a member of the Speakers’ Bureau for Johnson & Johnson and Bayer; and has received grants/research support from Merck, Lantheus, Progenics, Clovis, ORIC, Pfizer, Novartis, Amgen. Neeraj Agarwal has received compensation for a consulting or advisory role from Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; his institution has received research funding from Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Neal Shore has received compensation for a consulting or advisory role from AbbVie, Alessa Therapeutics, Akido, Amgen, Arquer, Asieris, Astellas, Astra Zeneca, Bayer, BMS, Boston Scientific, Clarity, Clovis, Cold Genesys, Dendreon, Exact Images, Exact Sciences, FerGene, FIZE Medical, GConcology, GenesisCare, Genetech, Guardant, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX, Merck, Minomic, Myovant, Myriad, NGM, Nonagen, Novartis, NYMOX, Pacific Edge, Photocure, Pfizer, PlatformQ, Profound, Promaxo, Propella, Protara, Sanofi, SesenBio, Speciality Networks, Telix, Tolmar, Urogen, Vaxiion, and Vessi; received payment for expert testimony from Ferring; and is on the board of Photocure. Oliver Sartor has received compensation for a consulting or advisory role from Advanced Accelerator Applications, Amgen, ART BioScience, Astellas Pharma, AstraZeneca, Bayer, Clarity Pharmaceuticals, EMD Serono, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, MacroGenics, Novartis, Pfizer, Point Biopharma, Ratio, Sanofi, Telix Pharmaceuticals, and TeneoBio; he has stock or other ownership interested with AbbVie, Cardinal Health, Clarity Pharmaceuticals, Convergent, Eli Lilly, Fusion Pharmaceuticals, Point Biopharma, Ratio, Telix, and United Health Group; he has patents for Saposin C and receptors as targets for treatment of benign and malignant disorders (U.S. patent awarded January 23, 2007; patent no. 7,166,691); he has provided expert testimony for Sanofi; he has received reimbursement for travel, accommodations, or expenses from AstraZeneca, Bayer, Lantheus, and Sanofi; and his institution has received research/grant funding from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, InVitae, Janssen, Lantheus, Merck, and Sanofi. Phillip J. Koo has received compensation for a consulting or advisory role from Lantheus, Blue Earth Diagnostics, Merck, Janssen, Pfizer, Astellas, AstraZeneca, Bayer, Novartis, Sanofi, Telix, and Curium. Scott E. Eggener has received compensation for a consulting or advisory role Candel Therapeutics, A3P Biomedical, Cellvax, MetasTx, OptumHealth, and Janssen. Sandy Srinivas has received compensation for a consulting or advisory role from Novartis and Janssen. Scott T. Tagawa has received compensation for a consulting or advisory role from Sanofi, Medivation, Astellas, Dendreon, Janssen, Genentech, Bayer, Endocyte, Eisai, Immunomedics, Karyopharm, Abbvie, Tolmar, Seattle Genetics, Amgen, Clovis, QED, Pfizer, AAA/Novartis, Clarity, Genomic Health, POINT Biopharma, Blue Earth, AIkido Pharma, Telix Pharma, Convergent Therapeutics, EMD Serono, Myovant, Merck, Daiichi Sankyo, TransThera, and Regeneron; he is an unpaid consultant for Atlab Pharma, Phosplatin Therapeutics, Amgen, and Ambrx; he and his institution hold patents for biomarkers for sacituzumab govitecan therapy (Immunomedics/Gilead); and his institution has received research funding from Sanofi, Medivation, Astellas, Janssen, Amgen, Progenics, Dendreon, Lilly, Genentech, Newlink, BMS, Inovio, AstraZeneca, Immunomedics, Aveo, Rexahn, Atlab, Boehringer Ingelheim, Millennium, Bayer, Merck, Abbvie, Karyopharm, Endocyte, Clovis, Seattle Genetics, Novartis, Gilead, POINT Biopharma, Ambrx, Clarity. Thomas P. Boike has received compensation for a consulting or advisory role from Lantheus, Myovant, Novartis, Pfizer, Janssen, Astellas, Blue Earth, AstraZeneca, Palette Life Sciences, and Boston Scientific. Tanya Dorff has received compensation for a consulting or advisory role from AstraZeneca, Bayer, Janssen, and Sanofi. Tian Zhang has received compensation for a consulting or advisory role from Merck, Exelixis, Sanofi-Aventis, Janssen, Astra Zeneca, Pfizer, Amgen, BMS, Dendreon, SeaGen, Eisai, Aveo, Bayer, and Eli Lilly; honoraria from MJH Associates, Vaniam, Aptitude Health, PlatformQ, IntegrityCE, PeerView, and WJ Weiser; and her institution has received research funding from Novartis, Merck, Janssen, Astra Zeneca, Pfizer, Tempus, and Eli Lilly. Wendy Poage is an employee of Servier Pharmaceuticals; and she has ownership interests in 3D biopsy.

Background: With the availability of second-generation androgen receptor inhibitors (SGARIs), the treatment landscape has changed dramatically for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). In clinical trials, the SGARIs (apalutamide, enzalutamide, darolutamide) increased metastasis-free survival (MFS), overall survival (OS), and patient quality of life compared to placebo. These drugs were subsequently integrated into nmCRPC clinical practice guidelines. With advances in radiographic imaging, disease assessment, and patient monitoring, nmCRPC strategies are evolving to address limitations related to tracking disease progression using prostate-specific antigen (PSA) kinetics., Methods: A panel of 10 multidisciplinary experts in prostate cancer conducted reviews and discussions of unmet needs in the management and monitoring of patients with nmCRPC in order to develop consensus recommendations., Results: Across the SGARI literature, patient MFS and OS are generally comparable for all treatments, but important distinctions exist regarding short- and long-term drug safety profiles and drug-drug interactions. With respect to disease monitoring, a substantial proportion of patients using SGARIs may experience disease progression without rising PSA levels, suggesting a need for enhanced radiographic imaging in addition to PSA monitoring. Recent data also indicate that novel prostate-specific membrane antigen positron emission tomography radiotracers provide enhanced accuracy for disease detection, as compared to conventional imaging., Conclusions: Clinical decision-making in nmCRPC has become more complex, with new opportunities to apply precision medicine to patient care. Multidisciplinary teams can ensure that patients with nmCRPC receive optimal and individualized disease management., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients (mCRPC) when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy., Methods: A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria., Results: Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for a MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR)., Conclusions: Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration., Objective: To present the final data from TRITON2., Design, Setting, and Participants: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy., Outcome Measurements and Statistical Analysis: The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint., Results and Limitations: As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35-57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40-100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5-57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46-61%), 55% (23-83%), 3.4% (0.4-12), 6.7% (0.2-32%), 14% (0.4-58%), and 23% (5.0-54%), respectively., Conclusions: The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene., Patient Summary: Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Background: De novo neuroendocrine prostate cancer (NEPC) and treatment-emergent neuroendocrine prostate cancer (T-NEPC) are rare diseases with a poor prognosis. After first-line platinum chemotherapy, there is no consensus on second-line treatments., Patients and Methods: Patients with a pathologic diagnosis of de novo NEPC or T-NEPC between 2000 and 2020 who received first-line platinum and any second-line systemic therapy were selected and standardized clinical data was collected via the electronic health record at each institution. The primary endpoint was overall survival (OS) based on second-line therapy. Secondary endpoints included objective response rate (ORR) to second-line therapy, PSA response, and time on treatment., Results: Fifty-eight patients (32 de novo NEPC, 26 T-NEPC) from 8 institutions were included. At de novo NEPC or T-NEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 59.2-70.3) and median PSA of 3.0 ng/dL (IQR 0.6-17.9). Following first-line platinum chemotherapy, 21 patients (36.2%) received platinum chemotherapy, 10 (17.2%) taxane monotherapy, 11 (19.0%) immunotherapy, 10 (17.2%) other chemotherapy, and 6 (16.2%) other systemic therapy. Among 41 evaluable patients, the ORR was 23.5%. The mOS after start of second-line therapy was 7.4 months (95% CI 6.1-11.9)., Conclusions: In this retrospective study, patients with de novo NEPC or T-NEPC who received second-line therapy were treated with wide variety of treatment regimens, reflecting the lack of consensus in this setting. Most patients received chemotherapy-based treatments. Overall prognosis was poor and ORR was low in the second line regardless of treatment choice., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose of Review: Prostate cancer (PCa) is amongst the most common cancers in men worldwide. Cardiovascular (CV) risk factors and CV disease (CVD) are common comorbidities in this patient population, posing a challenge for PCa-directed therapies which can cause or worsen CVRFs and CVDs. Herein, we summarize the approaches to prevent and manage CVD in patients with PCa receiving therapy., Recent Findings: While patients with locally advanced and metastatic PCa benefit from hormonal therapy, these treatments can potentially cause CV toxicity. Androgen receptor targeting therapies, such as androgen deprivation therapy (ADT), can induce metabolic changes and directly impact cardiovascular function, thereby reducing cardiorespiratory fitness and increasing CV mortality. Moreover, more than half of the PCa patients have poorly controlled CV risk factors at baseline. Hence, there is an urgent need to address gaps in preventing and managing CVD in PCa patients. Screening and optimizing CV risk factors and CVD in patients undergoing ADT are essential to reduce CV mortality, the leading non-cancer cause of death in PCa survivors. The risk of CV morbidity and mortality can be further mitigated by considering the patient's cardiovascular risk profile when deciding the choice and duration of ADT. A multidisciplinary team-based approach is crucial to achieve the best outcomes for PCa patients undergoing therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: A multi-cancer detection test using a targeted methylation assay and machine learning classifiers was validated and optimized for screening in prospective, case-controlled Circulating Cell-free Genome Atlas (ClinicalTrials.gov identifier: NCT02889978) substudy 3. Here, we report test performance in a subgroup of participants with symptoms suspicious for cancer to assess the test's ability to potentially facilitate efficient diagnostic evaluation in symptomatic individuals., Methods: We evaluated test performance (sensitivity, specificity, and accuracy of cancer signal origin [CSO] prediction accuracy) in participants with clinically presenting cancers (CPCs) and noncancer with underlying medical conditions and among two subgroups (65 years and older and GI cancers). Overall survival (OS) of participants who had a cancer signal detected/not detected was compared with SEER-based expected survival., Results: A total of 2,036 cancer and 1,472 noncancer participants were included. Specificity was high in all noncancer participants (99.5% [95% CI, 98.4 to 99.8]). In participants with CPCs, the overall sensitivity was 64.3% (95% CI, 62.2 to 66.4) and the overall accuracy of CSO prediction in true positives was 90.3%. For GI cancers, the overall sensitivity was 84.1% (95% CI, 80.6 to 87.1). In participants 65 years and older, test performance was similar to that of all participants. Individuals with cancers not detected had a significantly better OS than that expected from SEER ( P < .01)., Conclusion: This test detected a cancer signal with high specificity and CSO prediction accuracy and moderate sensitivity in symptomatic individuals, with especially high performance in participants with GI cancers. The survival analysis implied that the cancers not detected were less clinically aggressive than cancers detected by the test, providing prognostic insights to physicians. This multi-cancer detection test could facilitate efficient workup and stratify cancer risk in symptomatic individuals.

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.

Importance: The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown., Objective: To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups., Data Sources: For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available., Study Selection: Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC., Data Extraction and Synthesis: Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022., Main Outcomes and Measures: Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life., Results: This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT., Conclusions and Relevance: The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Background: Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population., Methods: Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation., Results: Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients., Conclusions: Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Steven Schild, MD has served as an author and editor of UpToDate, Inc. Alan Bryce, MD discloses participation on a Data Safety Monitoring Board or Advisory Board at Clovis Oncology as well as payment/honoraria by Merck & Co., Inc., Astellas Pharma Inc., and Pfizer Inc. for lectures, presentations, speakers’ bureaus, manuscript writing or educational events. Terence Sio, MD, MS provides strategic and scientific recommendations as a member of the Advisory Board and speaker for Novocure, Inc., which is not in any way associated with the content or disease site as presented in this manuscript., (© The Author(s) 2023.)

Accurate clinical staging of bladder cancer aids in optimizing the process of clinical decision-making, thereby tailoring the effective treatment and management of patients. While several radiomics approaches have been developed to facilitate the process of clinical diagnosis and staging of bladder cancer using grayscale computed tomography (CT) scans, the performances of these models have been low, with little validation and no clear consensus on specific imaging signatures. We propose a hybrid framework comprising pre-trained deep neural networks for feature extraction, in combination with statistical machine learning techniques for classification, which is capable of performing the following classification tasks: (1) bladder cancer tissue vs. normal tissue, (2) muscle-invasive bladder cancer (MIBC) vs. non-muscle-invasive bladder cancer (NMIBC), and (3) post-treatment changes (PTC) vs. MIBC.

Background: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown., Objective: To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib., Design, Setting, and Participants: Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS)., Outcome Measurements and Statistical Analysis: The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib., Results and Limitations: No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively)., Conclusions: These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance., Patient Summary: Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study., Methods: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1 , BRCA2 , or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review., Results: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea., Conclusions: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.)., (Copyright © 2023 Massachusetts Medical Society.)

Importance: Prostate cancer (PCa) is marked by disparities in clinical outcomes by race, ethnicity, and age. Equitable enrollment in clinical trials is fundamental to promoting health equity., Objective: To evaluate disparities in the inclusion of racial and ethnic minority groups and older adults across PCa clinical trials., Data Sources: MEDLINE, Embase, and ClinicalTrials.gov were searched to identify primary trial reports from each database's inception through February 2021. Global incidence in age subgroups and US population-based incidence in racial and ethnic subgroups were acquired from the Global Burden of Disease and Surveillance, Epidemiology, and End Results 21 incidence databases respectively., Study Selection: All phase 2/3 randomized PCa clinical trials were eligible for age disparity analyses. Trials recruiting exclusively from the US were eligible for primary racial and ethnic disparity analyses., Data Extraction and Synthesis: This study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were pooled using a random-effects model., Main Outcomes and Measures: Enrollment incidence ratios (EIRs), trial proportions (TPs) of participants 65 years or older or members of a racial and ethnic subgroup divided by global incidence in the corresponding age group, or US population-based incidence in the corresponding racial and ethnic subgroup, were calculated. Meta-regression was used to explore associations between trial characteristics and EIRs and trends in EIRs during the past 3 decades., Results: Of 9552 participants among trials reporting race, 954 (10.8%) were African American/Black, 80 (1.5%) were Asian/Pacific Islander, and 8518 (78.5) were White. Of 65 US trials, 45 (69.2%) reported race and only 9 (13.8%) reported data on all 5 US racial categories. Of 286 global trials, 75 (26.2%) reported the enrollment proportion of older adults. Outcomes by race and age were reported in 2 (3.1%) and 41 (15.0%) trials, respectively. Black (EIR, 0.70; 95% CI, 0.59-0.83) and Hispanic (EIR, 0.70; 95% CI, 0.59-0.83) patients were significantly underrepresented in US trials. There was no disparity in older adult representation (TP, 21 143 [71.1%]; EIR, 1.00; 95% CI, 0.95-1.05). The representation of Black patients was lower in larger trials (meta-regression coefficient, -0.06; 95% CI, -0.10 to -0.02; P = .002)., Conclusions and Relevance: The results of this meta-analysis suggest that Black and Hispanic men are underrepresented in trials compared with their share of PCa incidence. The representation of Black patients has consistently remained low during the past 2 decades.

Background: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions., Methods: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy., Results: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35)., Conclusions: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy., (© 2022 The Authors. The Prostate published by Wiley Periodicals LLC.)

We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study., We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC)., At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4-4.5) or long-term (median 29 months; range 23.5-41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders., Implications: Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K&#95;AKT&#95;MTOR pathways., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: This randomized phase 2 study sought to assess the treatment effect of a finite duration of apalutamide with and without androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BCR PC) . Materials and Methods . Patients with BCR PC after primary definitive therapy and prostate-specific antigen (PSA) doubling time ≤12 months were randomized to open-label apalutamide (240 mg/d) alone, apalutamide plus ADT, or ADT alone (1 : 1:1 ratio) for 12 months followed by a 12-month observation period (NCT01790126). Mean changes from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) at 12 months (primary endpoint) and other prespecified assessments of health-related quality of life (HRQoL), PSA nadir, time to PSA progression, time to testosterone recovery, recovered testosterone >150 ng/dL without PSA progression at 24 months, and molecular markers were evaluated., Results: In 90 enrolled patients (apalutamide plus ADT ( n  = 31), apalutamide ( n  = 29), ADT ( n  = 30)), FACT-P at 12 months was not significantly different between apalutamide, ADT and apalutamide, and ADT groups. Addition of apalutamide to ADT prolonged time to PSA progression but this change did not reach statistical significance (hazard ratio (HR): 0.56, 95% confidence interval (CI): 0.23-1.36, P =0.196); time to testosterone recovery was similar in the ADT-containing groups. In apalutamide plus ADT, apalutamide, and ADT groups, 37.9%, 37.0%, and 19.2% of patients, respectively, had testosterone >150 ng/dL at 24 months without confirmed PSA progression. Of the few biomarkers expressed in blood, EPHA3 was significantly associated with shorter time to PSA progression ( P =0.02) in the overall population., Conclusions: HRQoL was similar in patients treated with apalutamide alone, ADT alone, or their combination, although apalutamide plus ADT did not demonstrate statistically significant noninferiority in change from baseline in overall HRQoL. The aggregated efficacy and safety outcomes support further evaluation of apalutamide plus ADT in BCR PC., Competing Interests: RA declares honoraria from Clovis Oncology; advisory roles for AstraZeneca, Dendreon, and Janssen; research funding from AbbVie, Amgen, Cancer Targeted Technology, Janssen, Merck, Novartis, Xynomic Pharmaceuticals, and Zenith Epigenetics; and compensation for travel, accommodations, and expenses from Xynomic Pharmaceuticals. JJA declares consultancy for Janssen Biotech, Dendreon, and Merck; honoraria from Astellas; and research funding from Aragon Pharmaceuticals, Astellas, Gilead Sciences, Janssen, and Zenith Epigenetics. RZS declares advisory roles for AbbVie, Amgen, Astellas Pharma, AstraZeneca, Exelixis, Janssen Oncology, Merk, Pfizer, and Sanofi; honoraria from Astellas Pharma; research funding from AbbVie, Astellas Pharma, Incyte, Janssen Oncology, and Macrogenics; and holds a patent licensed by the University of Chicago as a co-inventor of Corcept Therapeutics. CSH declares personal fees from Astellas, Bayer, Blue Earth Diagnostics, Carrick Therapeutics, Clovis, Dendreon, Ferring, Genentech, Hinova, Janssen, Merck, Novartis, Orion, Pfizer, and Tolmar, and research funding from Aptevo, Aragon, Astellas, AstraZeneca, Clovis, Dendreon, eFFECTOR Therapeutics, Emergent, Ferring, Genentech, Hoffman-Laroche, Medivation, and Pfizer. AHB declares honoraria from Astellas Pharma, Bayer, and Merck. EJS declares advisory roles for Fortis and Janssen Oncology; compensation for travel from Janssen; stock and interest in Fortis and Harpoon Therapeutics; honoraria from Janssen; and research funding from Janssen and Merck Sharp & Dohme. AL-G, SAM, BM, KM, ST, and KZ are current or former employees of Janssen Research & Development and may hold stock in Johnson & Johnson., (Copyright © 2022 Rahul Aggarwal et al.)

Background: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP-ribose polymerase inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics., Methods: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment., Results: One hundred and twenty-seven mCRPC patients treated with Ra-223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra-223 treatment was 61.0 and 68.6 years, respectively. Seventy-nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2-ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2-ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0-NR) versus 26.8 months (95% CI 20.9-35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28-NR) versus 9.0 months (95% CI 7.3-11.1) and a lower OS 13.9 months (95% CI 5.2-NR) versus 26.5 months (95% CI 19.8-33.8)., Conclusions: Among mCRPC patients treated with Ra-223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2-ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra-223., (© 2022 Wiley Periodicals LLC.)

Background: Altered tumor suppressor genes (TSG-alt) in prostate cancer are associated with worse outcomes. The prognostic value of TSG-alt in metastatic, hormone-sensitive prostate cancer (M1-HSPC) is unknown. We evaluated the effects of TSG-alt on outcomes in M1-HSPC and their prognostic impact by first-line treatment., Methods: We retrospectively identified patients with M1-HSPC at our institution treated with first-line androgen deprivation therapy plus docetaxel (ADT + D) or abiraterone acetate (ADT + A). TSG-alt was defined as any alteration in one or more TSG. The main outcomes were Kaplan-Meier-estimated progression-free survival (PFS) and overall survival, analyzed with the log-rank test. Clinical characteristics were compared with the χ 2 test and Kruskal-Wallis rank sum test. Cox regression was used for univariate and multivariable analyses., Results: We identified 97 patients with M1-HSPC: 48 (49%) with ADT + A and 49 (51%) with ADT + D. Of 96 patients with data available, 33 (34%) had 1 TSG-alt, 16 (17%) had 2 TSG-alt, and 2 (2%) had 3 TSG-alt. The most common alterations were in TP53 (36%) and PTEN (31%); 6% had RB1 alterations. Median PFS was 13.1 (95% CI, 10.3-26.0) months for patients with normal TSGs (TSG-normal) vs. 7.8 (95% CI, 5.8-10.5) months for TSG-alt (P = 0.005). Median PFS was lower for patients with TSG-alt vs TSG-normal for those with ADT + A (TSG-alt: 8.0 [95% CI, 5.8-13.8] months vs. TSG-normal: 23.2 [95% CI, 13.1-not estimated] months), but not with ADT + D (TSG-alt: 7.8 [95% CI, 5.7-12.9] months vs. TSG-normal: 9.5 [95% CI, 4.8-24.7] months). On multivariable analysis, only TSG-alt predicted worse PFS (hazard ratio, 2.37; 95% CI, 1.42-3.96; P < 0.001)., Conclusions: The presence of TSG-alt outperforms clinical criteria for predicting early progression during first-line treatment of M1-HSPC. ADT + A was less effective in patients with than without TSG-alt. Confirmation of these findings may establish the need for inclusion of molecular stratification in treatment algorithms., (© 2021. The Author(s).)

Purpose: We aim to describe reporting and representation of minority patient populations in immune checkpoint inhibitor (ICI) clinical trials and assess predictors of enrollment disparity., Methods: Trial-level data were acquired from eligible phase II and III trials. Population-based estimates were acquired from the SEER 18 and Global Burden of Disease incidence databases. Trials reporting race, age, and sex were summarized using descriptive statistics. Enrollment-incidence ratio (EIR) was used to assess representation of subgroups. Average annual percentage change (AAPC) in EIR was calculated using Joinpoint Regression Analysis. Trial-level characteristics associated with EIR were assessed using multivariable linear regression., Results: A total of 107 trials with 48,095 patients were identified. Participation of Black, White, Asian, Native American, Pacific Islander, and Hispanic participants was reported in 65 (61%), 77 (72%), 68 (64%), 40 (37%,) and 24 trials (22%), respectively. Subgroup analyses of clinical outcomes by race, age, and sex were reported in 17 (22%), 62 (78%), and 57 (57%) trials, respectively. Women (trial proportion [TP]: 32%; EIR: 0.90 [95% confidence interval [CI]: 0.84-0.96]), patients aged ≥65 years (TP: 42%; EIR: 0.78 [95% CI: 0.72-0.84]), Black participants (TP: 1.9%; EIR: 0.17 [95% CI: 0.13-0.22]) and Hispanics (TP: 5.9%; EIR: 0.67 [95% CI: 0.53-0.82]) were underrepresented. Representation of Black patients decreased significantly from 2009 to 2020 (AAPC: -23.13). Black participants were significantly underrepresented in phase III trials (P < .001)., Conclusion: The reporting of participation by racial or ethnic subgroup categories is inadequate. Women, older adults, as well as Black and Hispanic participants are significantly underrepresented in ICI clinical trials., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To assess comparative effectiveness of adjuvant therapies for renal cell carcinoma and quantify the absolute benefit of adjuvant treatments by clinicopathological risk groups., Methods: This 'living' review was conducted using Living Interactive Evidence (LIvE) synthesis framework., Results: The 'living' results are available on an interactive website. This network meta-analysis, including six RCTs with 7525 participants, showed that pembrolizumab (rank 1) significantly improved disease-free survival and overall survival compared with sunitinib but not when compared to pazopanib, and axitinib. The risk of treatment-related grade 3 or higher adverse events was increased with pembrolizumab as compared to placebo and axitinib but not when compared to sunitinib. The absolute benefit of adjuvant pembrolizumab increases substantially with larger tumor size, nodal positivity and higher Leibovich scores., Conclusion: Current evidence suggests that pembrolizumab delays disease progression compared to sunitinib. A risk-adapted strategy should be used in patients undergoing consideration for treatment with adjuvant pembrolizumab., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Approximately one-third of patients with metastatic castration-resistant prostate cancer (CRPC) exhibited primary abiraterone resistance. To identify alternative treatment for abiraterone nonresponders, we performed drug discovery analyses using the L1000 database using differentially expressed genes identified in tumor biopsies and patient-derived xenograft (PDX) tumors between abiraterone responders and nonresponders enrolled in PROMOTE trial. This approach identified 3 drugs, including topoisomerase II (TOP2) inhibitor mitoxantrone, CDK4/6 inhibitor palbociclib, and pan-CDK inhibitor PHA-793887. These drugs significantly suppressed the growth of abiraterone-resistant cell lines and PDX models. Moreover, we identified 11 genes targeted by all 3 drugs that were associated with worse outcomes in both the PROMOTE and Stand Up To Cancer cohorts. This 11-gene panel might also function as biomarkers to select the 3 alternative therapies for this subgroup of patients with CRPC, warranting further clinical investigation., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: PT-112, the first pyrophosphate-platinum conjugate, causes immunogenic cell death in experimental models, leading to recruitment of tumour-infiltrating lymphocytes. PT-112 also associates with bone (osteotropism), likely driven by its pyrophosphate moiety. This is the first-in-human study of PT-112 monotherapy, exploring its safety and efficacy in a patient population where standard of care therapies were exhausted and novel treatment options are needed., Methods: Patients with progressing, advanced solid tumours received PT-112 intravenously (1 h) on days 1, 8, 15 of a 28-day cycle in an open-label, multi-centre 3 + 3 dose-escalation trial, conducted at four US research sites. The primary objective was to assess safety and pharmacokinetics, and to identify a recommended phase 2 dose (RP2D). Eligibility criteria included: age ≥18 years, Eastern Collaborative Oncology Group (ECOG) Performance Status of 0-1, and disease evaluable by Response Evaluation Criteria in Solid Tumours (RECIST) v1·1 or by informative tumour markers. Patients receiving ≥1 dose of PT-112 were included in the safety and pharmacokinetic analyses, with the exploratory efficacy analysis including patients receiving ≥1 dose at 125 mg/m 2 . This study is registered at ClinicalTrials.gov, number NCT02266745, with the dose-escalation portion of the study closed., Findings: Between July 7th, 2014 and September 18th, 2018, 66 heavily pre-treated patients (median 4 prior lines, IQR 2-6) were enrolled and treated across 11 doses (12-420 mg/m 2 ). Treatment-related adverse events included fatigue (23 patients, 35%), nausea (16 patients, 24%), and peripheral neuropathy (14 patients, 21%). Grade 3 events were experienced by 18 patients (27%), with no grade 4-5 events observed. The recommended phase 2 dose was determined to be 360 mg/m 2 . Nine (17%) of the 54 efficacy evaluable patients achieved progression-free survival ≥6 months. Durable partial responses were induced in non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and thymoma. Radiographic and serum marker reductions were observed among ten patients with metastatic castration resistant prostate cancer, four of whom survived two years or longer., Interpretation: PT-112 is safe and well-tolerated in a heavily pre-treated population. Prolonged responses were noted against thymoma and lung cancer, along with radiographic and serum marker improvement in prostate cancer. Given the heterogeneous patient population, subsequent studies will be needed to characterize the risk/benefit ratio in more homogenous settings. Further development of PT-112 is ongoing, as single-agent and in combination with immune checkpoint inhibition., Funding: Funding was provided by Promontory Therapeutics Inc., Competing Interests: Promontory Therapeutics, as the study sponsor, paid for most aspects of the trial outside those billable to patient insurance and provided study drug (all authors). Promontory in the past has covered meeting and travel expenses for TA, MP, JJ, and DK. TA and MP are employees of Promontory Therapeutics and are paid by/own equity in Promontory. JJ and DK have non-remunerated roles on Promontory's Scientific Advisory Board. JJ is a former employee of and owns shares in Promontory, currently a full-time employee of PharmaMar, and owns stock options for Pangaea Oncology. AB has served on an advisory board for and/or received speaking fees from Astellas, Bayer, and Merck. DK was the recipient of a grant from the National Center for Accelerating Translational Science, received royalties and/or license fees from book sales from “Handbook of Targeted Cancer Therapy & Immunotherapy”, and received consulting fees from Black Belt Life Sciences. JI is currently an employee of Janssen Oncology. RC has no conflicts to report., (© 2022 Published by Elsevier Ltd.)

Purpose: The US Food and Drug Administration has recently granted accelerated approval of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib as treatment for men with metastatic castration-resistant prostate cancer (mCRPC) associated with a deleterious germline or somatic BRCA1 or BRCA2 (BRCA) alteration. As the safety profile of this new addition to the mCRPC treatment landscape may be unfamiliar to clinicians and patients, we summarize the data from the literature and provide practical guidelines for the management of treatment-emergent adverse events (TEAEs) that may occur during rucaparib treatment., Materials and Methods: Safety data were identified from PubMed and congress publications of trials involving men with mCRPC treated with oral rucaparib monotherapy (600 mg twice daily). Management guidelines for TEAEs were developed based on trial protocols, prescribing information, oncology association guidance, and the authors' clinical experience., Results: In clinical trials of men with mCRPC who received rucaparib (n = 193), TEAEs observed were consistent with that of other PARP inhibitors. The most frequent any-grade TEAEs included gastrointestinal events, asthenia/fatigue, anemia, increased alanine/aspartate aminotransferase, rash, and thrombocytopenia; the most frequent grade ≥3 TEAE was anemia. The majority of TEAEs were self-limiting and did not require treatment modification or interruption. Here, we provide recommendations on management of the most common TEAEs reported with rucaparib as well as other TEAEs of interest., Conclusion: Rucaparib's recent approval for treatment of BRCA-mutant mCRPC is practice changing. Proper management of TEAEs will allow maximum treatment benefit for patients receiving rucaparib., Competing Interests: BW Labadie has nothing to disclose. DS Morris has served in a consulting/advisory role for and received research funding from Clovis Oncology, AstraZeneca, Astellas, Bayer, Dendreon, Merck, Janssen, and Pfizer. AH Bryce has received honoraria from Astellas and Bayer; personal fees from Merck and Castle Biosciences, outside the submitted work. R Given has served in a consulting or advisory role and/or on speakers bureaus for Janssen, Bayer, and Myovant and has received research funding from Clovis, Janssen, Bayer, and Merck. J Zhang has served in a consulting or advisory role and/or on speakers bureaus for Clovis Oncology, AstraZeneca, Bayer, Dendreon, Merck, Sanofi, and Seattle Genetics and received research funding from Astellas Pharma, AstraZeneca, and Bayer. W Abida has served in a consulting or advisory role for Clovis Oncology, Daiichi Sankyo, Janssen Pharmaceuticals, MORE Health, and ORIC Pharmaceuticals; has received financial support for travel and/or accommodation from Clovis Oncology and ORIC Pharmaceuticals; has received personal fees from Roche, Medscape, and Onclive, outside the submitted work; and his institution has received research funding from Clovis Oncology, AstraZeneca, and Zenith Epigenetics. He is funded by National Cancer Institute (NCI) Cancer Center Support Grant P30 CA 008748, NCI Prostate Specialized Program of Research Excellence (SPORE) grant P50 CA092629-16, Department of Defense Prostate Cancer Research Program grant W81XWH-17-1-0124, and a Prostate Cancer Foundation Young Investigator Award. S Chowdhury has served in a consulting or advisory role and/or on speakers bureaus for Clovis Oncology, Astellas, Bayer, BeiGene, Janssen, and Pfizer; received honoraria from GlaxoSmithKline; received financial support for travel and accommodation from Clovis Oncology and BeiGene: and holds stock in Curve.life; grants from Sanofi; personal fees from Huma, Remedy, Telix, Novartis, and Astra Zeneca, during the conduct of the study. A Patnaik has served in a consulting or advisory role for Exelixis, Janssen, and Jounce Therapeutics; has received honoraria from Clovis Oncology, Merck, Prime Inc., and Roche; and has received research funding from Clovis Oncology, Progenics, Bristol Myers Squibb, and GlaxoSmithKline; and has received clinical trial support from Laekna and AstraZeneca outside the submitted work., (© 2022 Labadie et al.)

Objective: To maintain living, interactive evidence (LIvE) on the benefits and harms of different treatment options in adults with cancer-associated thrombosis (CAT)., Methods: We have used a novel LIvE synthesis framework to maintain this living, interactive systematic review since September 19, 2018. Randomized controlled trials evaluating the efficacy and safety of direct oral anticoagulants (DOACs) compared with low-molecular-weight heparin for CAT are included in this analysis. Details of LIvE synthesis framework are available at the website https://cat.network-meta-analysis.com., Results: The results are constantly updated as new information becomes available (https://cat.network-meta-analysis.com/CAT.html). The living, interactive systematic review currently includes 4 randomized controlled trials (N=2894). Direct comparisons show that DOACs significantly decrease recurrent venous thromboembolism (VTE) events compared with dalteparin (odds ratio [OR], 0.59; 95% CI, 0.41 to 0.86; I 2 , 25%) without significantly increasing major bleeding (OR, 1.34; 95% CI, 0.83 to 2.18; I 2 , 28%). Mixed treatment comparisons show that apixaban (OR, 0.41; 95% credible interval [CrI], 0.16 to 0.95) and rivaroxaban (OR, 0.58; 95% CrI, 0.37 to 0.90) significantly decrease VTE recurrent events compared with dalteparin. Edoxaban significantly increases major bleeding compared with dalteparin (OR, 1.73; 95% CrI, 1.04 to 3.16), and rivaroxaban significantly increases clinically relevant nonmajor bleeding compared with dalteparin and other DOACs. There are no significant differences between DOACs in terms of VTE recurrences and major bleeding., Conclusion: DOACs should be considered a standard of care for the treatment of CAT except in patients with a high risk of bleeding. Current evidence favors the use of apixaban for the treatment of CAT among other DOACs., Registration: Open Science Framework (https://osf.io/dth86)., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: We sought to assess the prognostic utility of 11C-choline positron emission tomography/computed tomography (PET/CT) in patients with metastatic castrate resistant prostate cancer (mCRPC) undergoing primary docetaxel chemotherapy., Methods: We performed a single institution retrospective analysis of 77 mCRPC patients who were treated with 6 cycles of docetaxel chemotherapy, and who also underwent 11C-choline PET/CT scans at baseline (before chemotherapy), mid-course (after 3 cycles), and posttherapy (after 6 cycles). We evaluated treatment response based on percent change in blood pool-corrected maximum standardized uptake value (SUVmax) of the target lesion on PET/CT, as well as percent change in serum prostate specific antigen (PSA). Logistic regression analysis was used to identify factors associated with complete treatment response. Progression free survival (PFS) analysis was performed using log-rank test and shown on Kaplan-Meier plot., Results: Percent change in blood pool-corrected SUVmax on mid-course scan was a significant predictor of complete response (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-0.99, p = .0003), whereas percent change in PSA was not (OR: 0.99, 95% CI: 0.99-1.01, p = .6025). 57 of 77 patients (74%) achieved ≥20% reduction in blood pool-corrected SUVmax on mid-course; these patients were 3.6 times more likely to achieve complete response after full 6 cycles of docetaxel chemotherapy, compared to patients with <20% reduction in blood pool-corrected SUVmax (OR: 3.56, 95% CI: 1.04-16.52, p = .0420). Median PFS in the complete response group was 35.1 months (95% CI: 26.0-52.7 months), compared to 9.4 months (95% CI: 6.9-13.0 months) in the incomplete response group (p = .0005)., Conclusions: Our study showed that mid-course and posttherapy 11C-choline PET/CT evaluation for mCRPC patients undergoing primary docetaxel chemotherapy can predict full course treatment response and PFS, respectively. 11C-choline PET/CT imaging may provide valuable prognostic information to guide treatment choices for patients with mCRPC., (© 2021 Wiley Periodicals LLC.)

Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA + ), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA + mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2., Patients and Methods: Patients had progressed after next-generation androgen receptor-directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized., Results: TRITON2 enrolled 115 patients with BRCA + identified by central plasma ( n = 34), central tissue ( n = 37), or local ( n = 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA + by tissue testing., Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA + mCRPC who can benefit from treatment with the PARP inhibitor rucaparib., (©2021 American Association for Cancer Research.)

Context: Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations., Objective: To maintain living evidence for contemporary first-line treatment for previously untreated mRCC., Evidence Acquisition: We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence-assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner., Evidence Synthesis: As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps., Conclusions: This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons., Patient Summary: It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The benefit of routine pre-emptive screening for severe acute respiratory syndrome coronavirus 2 infections in patients with cancer before cancer-directed therapies is unclear. Herein, we characterize the outcomes of a cohort of patients with cancer who were diagnosed with COVID-19 by routine screening (RS) in comparison with those diagnosed on the basis of clinical suspicion or exposure history (nonroutine screening [NRS])., Methods: A multisite prospective observational study was conducted at three major and five satellite campuses of the Mayo Clinic Cancer Center between March 18 and July 31, 2020. The primary outcome was COVID-19-related hospital admission. Secondary outcomes included intensive care unit admissions and all-cause mortality., Results: Five thousand four hundred fifty-two patients underwent RS in the outpatient setting only, and 44 (0.81%) were diagnosed with COVID-19. RS detected 19 additional patients from the scheduled inpatient admissions for surgical or interventional procedures or inpatient chemotherapy. One hundred sixty-one patients were diagnosed with COVID-19 on the basis of NRS. COVID-19-related hospitalization rate (17.5% v 26.7%; P = .14), intensive care unit admission (1.6% v 5.6%; P = .19), and mortality (4.8% v 3.7%; P = .72) were not significantly different between the RS and NRS groups. In the multivariable analysis, age ≥ 60 years (odds ratio, 4.4; P = .023) and an absolute lymphocyte count ≤ 1.4 × 10 9 /L (odds ratio, 9.2; P = .002) were independent predictors of COVID-19-related hospital admission., Conclusion: The COVID-19 positivity rate was low on the basis of RS. Comparing the hospital admission and mortality outcomes with the NRS cohort, there were no significant differences. The value of routine pre-emptive screening of asymptomatic patients with cancer for COVID-19 remains low., Competing Interests: Joshua PritchettPatents, Royalties, Other Intellectual Property: Novel discovery with intellectual property interests in ongoing development with Mayo Clinic Ventures, patent pending, US Patent Application No. 63/109625Uncompensated Relationships: Biofourmis Andrew BadleyEmployment: Mayo ClinicLeadership: Splissen, NferenceStock and Other Ownership Interests: ZentalisConsulting or Advisory Role: AbbVie, Flambeau Diagnostics, Corvus Pharmaceuticals, Pinetree, EquiliumSpeakers' Bureau: Medscape, ReachMDPatents, Royalties, Other Intellectual Property: Patents on Casp8p41, and TRAILshort Rami ManochakianConsulting or Advisory Role: Takeda, Guardant Health, AstraZeneca, Novocure Sikander AilawadhiHonoraria: AstraZeneca, Bristol Myers Squibb, Amgen, JanssenConsulting or Advisory Role: Takeda, Celgene, Beigene, Oncopeptides, GlaxoSmithKline, SanofiResearch Funding: Pharmacyclics, Janssen Biotech, Cellectar, Phosplatin Therapeutics, Bristol Myers Squibb, Amgen, MedImmune, Xencor Alan H. BryceHonoraria: Astellas Pharma, BayerTravel, Accommodations, Expenses: Clovis Oncology, Phosplatin Therapeutics Joleen M. HubbardConsulting or Advisory Role: Bayer, Taiho OncologyResearch Funding: Boston Biomedical, Senhwa Biosciences, Bayer, Merck, Taiho Pharmaceutical, Treos Bio, eFFECTOR Therapeutics, Hutchison MediPharma, Seattle Genetics, Trovagene, Translational Research in Oncology, Incyte Thomas E. WitzigHonoraria: Curio ScienceConsulting or Advisory Role: Karyopharm Therapeutics, Celgene, Epizyme, Cellectar, Tessa Therapeutics, Portola Pharmaceuticals, ADC TherapeuticsResearch Funding: Celgene, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm TherapeuticsPatents, Royalties, Other Intellectual Property: I am coinventor on a patent application filed by Mayo Clinic and pending on the combination of CRM1 inhibitors with salicylates. Please note—simply filed—not even close to being granted Robert R. McWilliamsStock and Other Ownership Interests: ZentalisConsulting or Advisory Role: Merrimack, Newlink Genetics, ZentalisResearch Funding: Newlink Genetics, Merck, Bristol Myers Squibb, GlaxoSmithKline/Tesaro Konstantinos LeventakosConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Targeted Oncology, OncLive, TakedaResearch Funding: AstraZeneca, Mirati Therapeutics Thorvardur R. HalfdanarsonConsulting or Advisory Role: Lexicon, Ipsen, Advanced Accelerator Applications, Curium Pharma, ScioScientific, TerumoResearch Funding: Ipsen, Agios, Thermo Fisher Scientific, Basilea, Turnstone Bio, Advanced Accelerator Applications, NovartisNo other potential conflicts of interest were reported.

Delta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma., (© 2021. The Author(s).)

Androgen receptor-positive prostate cancer (PCa) and estrogen receptor-positive luminal breast cancer (BCa) are generally less responsive to immunotherapy compared with certain tumor types such as melanoma. However, the underlying mechanisms are not fully elucidated. In this study, we found that FOXA1 overexpression inversely correlated with interferon (IFN) signature and antigen presentation gene expression in PCa and BCa patients. FOXA1 bound the STAT2 DNA-binding domain and suppressed STAT2 DNA-binding activity, IFN signaling gene expression, and cancer immune response independently of the transactivation activity of FOXA1 and its mutations detected in PCa and BCa. Increased FOXA1 expression promoted cancer immuno- and chemotherapy resistance in mice and PCa and BCa patients. These findings were also validated in bladder cancer expressing high levels of FOXA1. FOXA1 overexpression could be a prognostic factor to predict therapy resistance and a viable target to sensitize luminal PCa, BCa, and bladder cancer to immuno- and chemotherapy.

Objective: To assess the risk of venous thromboembolism (VTE) in patients treated with Janus kinase (JAK) inhibitors in clinical trials., Patients and Methods: We performed a literature search of Ovid MEDLINE and ePub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily; Ovid EMBASE; Ovid Cochrane Central Register of Controlled Trials; Ovid Cochrane Database of Systematic Reviews; and Scopus, from inception to December 4, 2019, for randomized, placebo-controlled trials with JAK inhibitors as an intervention and reported adverse events. Odds ratio with 95% CI was calculated to estimate the VTE risk using a random effects model. Two independent reviewers screened and extracted data. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to assess certainty in estimated VTE risk., Results: We included 29 trials (13,910 patients). No statistically significant association was found between use of JAK inhibitors and risk of VTE (odds ratio, 0.91; 95% CI, 0.57 to 1.47; P=.70; I 2 =0; low certainty because of serious imprecision). Results using Bayesian analysis were consistent with those of the primary analysis. Results of stratified and meta-regression analyses suggested no interaction by dose of drug, indication for treatment, or length of follow-up., Conclusion: We found insufficient evidence to support an increased risk of JAK inhibitor-associated VTE based on currently available data., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown., Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy., Design, Setting, and Participants: This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019., Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy., Main Outcomes and Measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used., Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001)., Conclusions and Relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

The identification of isochromosome 12p [i(12p)] and 12p gains have significant clinical utility in the diagnosis of germ cell tumors (GCTs). We have summarized the results of fluorescence in situ hybridization (FISH) assays to identify i(12p), performed in a Clinical Laboratory Improvement Amendments (CLIA)-validated setting for 536 specimens. In addition, the American Association for Cancer Research (AACR) Project GENIE registry and The Cancer Genome Atlas (TCGA) data sets were evaluated for chromosome 12p gains, and a limited number of cases were concurrently evaluated using FISH, single-nucleotide polymorphism (SNP) arrays and next-generation sequencing (NGS; including mate-pair sequencing). Specimens submitted for FISH testing were frequently from potential sites of metastases (male: 70.9% and female: 69.3%), and polysomy of chromosome 12 with or without concurrent i(12p) was a frequent finding, seen in 3% (16/536) and 35% (186/536) of cases, respectively. Our analysis suggests that 12p gains are likely to be present in approximately 73% of male GCT and in 32% of female GCT (AACR GENIE, n = 555). When comparing TCGA cases of testicular GCT (n = 149) to combined cases of sarcoma, colorectal, prostate, and urothelial carcinoma (n = 1754), 12p gains had a sensitivity of 77.2% and specificity of 97.3% for GCT. Some advantages of FISH over SNP arrays/NGS include relatively lower cost, rapid turnaround time, the ability to analyze biopsy material with a limited number of tumor cells (50 cells), and the ability to distinguish i(12p) from polysomy. The ability to spatially restrict the analysis to cells of interest is critical, as specimens submitted for testing often have low tumor purity. Disadvantages include false negative results due to an inability to detect segmental gains due to FISH probe design. With the availability of numerous testing modalities, including FISH, SNP arrays, and NGS-based assays, a nuanced understanding of the advantages and disadvantages of each methodology, as has been presented in this study, may inform appropriate testing strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations., Methods: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed., Results: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men., Conclusions: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only., (© 2021 The Authors. The Prostate Published by Wiley Periodicals LLC.)

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas., Competing Interests: These commercial affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Genomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer., Methods: To enrich for response to anti-PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort., Results: Nineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy. The PSA 50 response rate was 65%, and the median progression-free survival (PFS) was 24 (95% confidence interval 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment and with density of CD8+ tumor-infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort., Conclusion: Tumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity., Implications for Practice: Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti-PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Importance: Hereditary factors play a key role in the risk of developing several cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and germline testing., Objective: To examine the prevalence of pathogenic germline variants (PGVs) in patients with cancer using a universal testing approach compared with targeted testing based on clinical guidelines and the uptake of cascade family variant testing (FVT)., Design, Setting, and Participants: This prospective, multicenter cohort study assessed germline genetic alterations among patients with solid tumor cancer receiving care at Mayo Clinic cancer centers and a community practice between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer type, disease stage, family history of cancer, ethnicity, or age., Exposures: Germline sequencing using a greater than 80-gene next-generation sequencing platform., Main Outcomes and Measures: Proportion of PGVs detected with a universal strategy compared with a guideline-directed approach and uptake of cascade FVT in families., Results: A total of 2984 patients (mean [SD] age, 61.4 [12.2] years; 1582 [53.0%] male) were studied. Pathogenic germline variants were found in 397 patients (13.3%), including 282 moderate- and high-penetrance cancer susceptibility genes. Variants of uncertain significance were found in 1415 patients (47.4%). A total of 192 patients (6.4%) had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. Of those with a high-penetrance PGV, 42 patients (28.2%) had modifications in their treatment based on the finding. Only younger age of diagnosis was associated with presence of PGV. Only 70 patients (17.6%) with PGVs had family members undergoing no-cost cascade FVT., Conclusions and Relevance: This prospective, multicenter cohort study found that universal multigene panel testing among patients with solid tumor cancer was associated with an increased detection of heritable variants over the predicted yield of targeted testing based on guidelines. Nearly 30% of patients with high-penetrance variants had modifications in their treatment. Uptake of cascade FVT was low despite being offered at no cost.

Background: ECOG3805 is a randomized trial of testosterone suppression with or without docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC). Deeper prostate-specific antigen (PSA) suppression is prognostic for outcome. However, the concordance of PSA rise and radiographic progression has not been examined previously in mHSPC, whereas this has been reported in metastatic castration-resistant prostate cancer., Objective: To determine the patterns of progression by PSA and radiographic parameters in patients in ECOG3805., Design, Setting, and Participants: We conducted a retrospective analysis of all patients in ECOG3805. Patients were classified according to the PSA level at progression (whether PSA level was below 2.0 ng/mL or not) and the type of progression event in the study (either PSA progression as defined by the study with or without clinical progression, or clinical progression alone). Baseline demographics, clinical outcomes, and patterns of progression were compared between the groups., Results and Limitations: One in eight patients had clinical progression below a PSA level of 2 ng/mL, and approximately 25% developed clinical progression in the absence of confirmed PSA progression. Overall survival from randomization was shorter in patients with clinical progression without confirmed PSA progression than in patients with PSA progression alone as the first progression. Patient demographics at study entry were not predictive of the pattern of progression. Study limitations include its retrospective and post hoc nature., Conclusions: Clinical progression prior to PSA rise or at low PSA levels is a relatively frequent phenomenon in mHSPC and is associated with poorer overall survival. Further biological and clinical studies of these patients are warranted., Patient Summary: Reliance on prostate-specific antigen (PSA) alone is an inadequate strategy to monitor patients undergoing treatment for metastatic hormone-sensitive prostate cancer. Prostate cancer can get worse on scans even with low PSA and/or no or small changes in PSA. Imaging should be added to PSA testing to monitor patients with metastatic prostate cancer., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Cutaneous melanoma metastases can contribute to visual disturbances through a variety of factors, including metastasis to the vitreal fluid. The optimum management of metastatic cutaneous melanoma to the vitreal fluid is unknown, but can include radiation therapy or systemic therapy including immunotherapy. A high degree of suspicion is necessary to consider this complication while working with patients with cutaneous melanoma.