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Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) plus protocol-permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression-free survival (rPFS) versus SOC in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health-related quality of life (HRQOL)., Methods: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm ( 177 Lu-PSMA-617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and 5-level EQ-5D [EQ-5D-5L]). Correlation analyses used an iterative multiple imputation copula-based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong)., Results: In the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT-P total score and emotional and physical well-being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time-to-worsening EQ-5D-5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms., Conclusions: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of 177 Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer., Methods: In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous 177 Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to 177 Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff., Findings: Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive 177 Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177 Lu-PSMA-617 cycles was 6·0 (IQR 4·0-6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177 Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38-10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77-not estimable) in the 177 Lu-PSMA-617 group versus 5·55 months (4·04-5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29-0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24-27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30-14·19) in the 177 Lu-PSMA-617 group versus 5·59 months (4·21-5·95) in the ARPI change group (HR 0·49 [95% CI 0·39-0·61]). The incidence of grade 3-5 adverse events was lower in the 177 Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related])., Interpretation: 177 Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, 177 Lu-PSMA-617 may be an effective treatment alternative., Funding: Novartis., Competing Interests: Declaration of interests MJM declares receiving consulting or advisory fees from Amgen, AstraZeneca, Blue Earth Diagnostics, Clarity Pharmaceuticals, Convergent Therapeutics, Daiichi, ITM Isotope Technologies Munich, Lantheus Medical Imaging, Pfizer, POINT Biopharma, Progenics, Telix Pharmaceuticals, and Z-Alpha; stock and other ownership in Doximity; travel, accommodations, and expenses from APCCC, AstraZeneca, and Memorial Sloan-Kettering Cancer Center; institutional research funding from Astellas Pharma, Bayer, Celgene, Corcept Therapeutics, Janssen, Novartis, Progenics, and Roche/Genentech; patents pending with Novartis; and royalties from Telix. DC declares receiving payment or honorarium from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Exelisis, GlaxoSmithKline, Ipsen, Janssen, Lilly, MSD, Pfizer, QED Therapeutics, and Roche; travel or other expenses from Astellas, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; participation on a data safety monitoring or advisory board for Astellas, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; and other financial or non-financial interests in Spanish Oncology Genito-Urinary Group Foundation and GUARD Consortium Spanish group. KH declares receiving grants or contracts from Boston Scientific, Janssen, and Novartis; consulting fees from Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen, Merck, Molecular Partners, Novartis, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics, and Y-mAbs Therapeutics; and stock or other ownership in AdvanCell, Aktis Oncology, Convergent, NVision, Pharma 15, and Sofie Biosciences. JSdB declares receiving grants or contracts from Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Crescendo, Daiichi-Sankyo, Endocyte, Genentech/Roche, GlaxoSmithKline, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi Aventis; consulting or advisory fees from Astellas, AstraZeneca, Bayer, Daiichi-Sankyo, Genentech/Roche, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion, Pfizer, Sanofi Aventis, and Taiho; payment or honorarium from Astellas, AstraZeneca, Bayer, Cellcentric, Crecendo, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Mycrix, MSD, Orion, Pfizer, Sanofi Aventis, and Taiho; being an inventor on patent 8822438 for a method for treating cancer; participating on a data safety monitoring or advisory board for Amgen, AstraZeneca, Bayer, Bioxcel Therapeutics, Crescendo, Daiichi-Sankyo, Endocyte, Genentech/Roche, GlaxoSmithKline, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Oncternal, Pfizer, and Sanofi Aventis; and receiving institutional royalties or licences related to abiraterone, PARP inhibitor, and PI3K/AKT. NDS declares receiving support for the present manuscript from Novartis; consulting fees from AbbVie, Accord, Amgen, Antev, Arquer, Asieris, Astellas, AstraZeneca, Aura Biosciences, Bayer, Bioprotect, Bristol Myers Squibb, Clarity, Cold Genesys, Curium, Dendreon, Exact Imaging, Ferring, Fize Medical, Invitae, Janssen, Lantheus, Lilly, MDXHealth, Merck, Minomic, Myriad, Novartis, PlatformQ, Pfizer, POINT Biopharma, Preview, Promaxo, Propella, Protara, Sanofi Genzyme, Siemens, Speciality Networks, Sumitomo, Telix, Tolmar, and Urogen; having a leadership or fiduciary role for Photocure, and Alessa; and having stock or stock options with Photocure, and Alessa. KNC declares receiving grants or contracts from AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche; and consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche. MC declares receiving support for the present manuscript from Novartis; consulting fees from Astellas, AstraZeneca, Blue Earth Diagnostics, Boston Scientific, Elekta, Johnson & Johnson, Lantheus, Macrogenics, Pfizer, Profound Medical, Sumitomo, Telix, Tolmar, and Tempus; payment or honorarium from Johnson & Johnson, Pfizer, Profound Medical, and Telix; participating on an advisory board for Telix; and having a leadership or fiduciary role for the Society of Nuclear Medical and Molecular Imaging, and the American Urological Association. JMP declares receiving grants or contracts from BeiGene, Bristol Myers Squibb, Immunocore, Mirati, MSD, and Pfizer; consulting fees from Astellas, AstraZeneca, BeiGene, Bristol Myers Squibb, Clovis, Ideaya, Immunocore, Janssen, MSD, Novartis, and Pfizer; and travel expenses from AstraZeneca, Janssen, and Pfizer. AF declares receiving payment or honorarium from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck, MSD, Novartis, and Pfizer; and travel expenses from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck, SD, Novartis, and Pfizer. XXW declares receiving institutional grants or contracts from Bristol Myers Squibb; consulting fees from Dendreon and Novartis; honorarium from Novartis; travel or other expenses from Novartis; and participating on a data safety monitoring or advisory board for Dendreon and Novartis. HM declares receiving payment or honorarium from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Novartis and Pfizer; travel or other expenses from AstraZeneca, Novartis, Pfizer, Roche; and acting on a scientific steering committee for Curium. GR declares receiving grants or contracts from Bayer; and consulting fees from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, and Pfizer. HŠ declares receiving consulting fees from Astellas, Bayer, Janssen, Novartis, and Pfizer. JN declares receiving contracts or grants from ABX, and Novartis; consulting fees from Curium, and POINT Biopharma; and payment or honorarium from Bayer AG, and Pfizer. BM declares receiving grants or contracts from Astellas, Bayer, Janssen, Roche, and Sanofi; payment or honorarium from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Pfizer, Roche, and Sanofi; travel or other expenses from Ipsen, Janssen Pfizer, and Roche; and other financial or non-financial interests in Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Pfizer, Roche, and Sanofi. ÁM-P declares receiving personal fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Novartis, and Pfizer; and non-financial support from Bayer, Ipsen, Merck, and Pfizer. EK, SG, TNK, CW, and KL declare being employed by and receiving restricted stock options from Novartis. OS declares receiving support for the present manuscript from Novartis; institutional grants or contracts from Amgen, AstraZeneca, Bayer, Endocyte, Invitae, Janssen, Lantheus, Merck, Novartis, Progenics, and Tenebio; consulting fees from ARTBIO, AstraZeneca, Bayer, Blue Earth Diagnostics, Clarity Pharmaceuticals, Fusion, Isotopen Technologien Muenchen, Janssen, Merck, Myovant, Myriad, Noria Therapeutics, NorthStar, Novartis, Pfizer, POINT Biopharma, Sanofi, Telix, and Tenebio; travel and accommodation expenses from Lantheus, NorthStar, and Novartis; participation on a data safety monitoring or advisory board for AstraZeneca, Merck, and Pfizer; and stock or stock options in ARTBIO, Clarity Pharmaceuticals, Convergent, Fusion, Lilly, Pfizer, Ratio, and Telix. KF declares receiving institutional honorarium or payments to Gustave Roussy Institute from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, and Sanofi; institutional participation on data safety monitoring or advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and personal participation on a data safety monitoring or advisory board for Arvinas, CureVac, Macrogenics, Orion., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background Lutetium 177 [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). Quantitative PSMA PET/CT analysis could provide information on 177 Lu-PSMA-617 treatment benefits. Purpose To explore the association between quantitative baseline gallium 68 [ 68 Ga]Ga-PSMA-11 ( 68 Ga-PSMA-11) PET/CT parameters and treatment response and outcomes in the VISION trial. Materials and Methods This was an exploratory secondary analysis of the VISION trial. Eligible participants were randomized (June 2018 to October 2019) in a 2:1 ratio to 177 Lu-PSMA-617 therapy (7.4 GBq every 6 weeks for up to six cycles) plus standard of care (SOC) or to SOC only. Baseline 68 Ga-PSMA-11 PET parameters, including the mean and maximum standardized uptake value (SUV mean and SUV max ), PSMA-positive tumor volume, and tumor load, were extracted from five anatomic regions and the whole body. Associations of quantitative PET parameters with radiographic progression-free survival (rPFS), overall survival (OS), objective response rate, and prostate-specific antigen response were investigated using univariable and multivariable analyses (with treatment as the only other covariate). Outcomes were assessed in subgroups based on SUV mean quartiles. Results Quantitative PET parameters were well balanced between study arms for the 826 participants included. The median whole-body tumor SUV mean was 7.6 (IQR, 5.8-9.9). Whole-body tumor SUV mean was the best predictor of 177 Lu-PSMA-617 efficacy, with a hazard ratio (HR) range of 0.86-1.43 for all outcomes (all P < .001). A 1-unit whole-body tumor SUV mean increase was associated with a 12% and 10% decrease in risk of an rPFS event and death, respectively. 177 Lu-PSMA-617 plus SOC prolonged rPFS and OS in all SUV mean quartiles versus SOC only, with no identifiable optimum among participants receiving 177 Lu-PSMA-617. Higher baseline PSMA-positive tumor volume and tumor load were associated with worse rPFS (HR range, 1.44-1.53 [ P < .05] and 1.02-1.03 [ P < .001], respectively) and OS (HR range, 1.36-2.12 [ P < .006] and 1.04 [ P < .001], respectively). Conclusion Baseline 68 Ga-PSMA-11 PET/CT whole-body tumor SUV mean was the best predictor of 177 Lu-PSMA-617 efficacy in participants in the VISION trial. Improvements in rPFS and OS with 177 Lu-PSMA-617 plus SOC were greater among participants with higher whole-body tumor SUV mean , with evidence for benefit at all SUV mean levels. ClinicalTrials.gov identifier: NCT03511664 Published under a CC BY 4.0 license. Supplemental material is available for this article.

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was -0.7 (range: -9.3 to 4.7) with R223+P and 0.1 (-11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was -0.6 (-7.4 to 5.3) with R223+P and -1.3 (-3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7-11.0) and 16.9 months [12.7-not reached (NR)], respectively, with R223+P and 5.7 (2.6-NR) and 16.0 (9.0-NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [ 177 Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results., Methods: This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [ 177 Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([ 177 Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [ 177 Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [ 177 Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, NCT03511664, and is active but not recruiting., Findings: Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [ 177 Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65-75) in the [ 177 Lu]Lu-PSMA-617 group and 72·0 years (66-76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3-13·2) in the [ 177 Lu]Lu-PSMA-617 group and 6·8 months (5·2-8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40-0·62). Time to worsening was delayed in the [ 177 Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45-0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42-0·63), and EQ-5D-5L utility score (0·65, 0·54-0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [ 177 Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [ 177 Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only., Interpretation: [ 177 Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [ 177 Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment., Funding: Advanced Accelerator Applications (Novartis)., Competing Interests: Declaration of interests KF reports consultant or advisory fees from Janssen, Bayer, Astellas, Sanofi, Orion Pharma, CureVac, AstraZeneca, ESSA Pharma, Amgen, Bristol Myers Squibb, Clovis Oncology, Lilly, Novartis, Daiichi-Sankyo, Pfizer, and MSD. KH reports consultant or advisory fees from ABX, AstraZeneca, Advanced Accelerator Applications (Novartis), Aktis Oncology, Amgen, Bayer, BTG, Curium, Debiopharm, Endocyte, GE HealthCare, Janssen, Ipsen, Novartis, Pharma15, Siemens Healthineers, Sirtex Medical, SOFIE Biosciences, Theragnostics, and Y-mAbs Therapeutics. BJK reports consultant or advisory fees from Advanced Accelerator Applications (Novartis), Astellas, Bayer, Janssen, Terumo, PSFI, and Isotope Technologies Munich; and research funding from Advanced Accelerator Applications (Novartis). KR reports consulting or advisory fees from ABX-CRO, ABX, Advanced Accelerator Applications (Novartis), and Bayer. KNC reports consultant or advisory fees from AstraZeneca, ESSA Pharma, Janssen, Merck, POINT Biopharma, and Roche; and research funding from AstraZeneca, ESSA Pharma, Janssen, Merck, POINT Biopharma, Novartis, Roche, and Arvinas. MJM reports consultant or advisory fees from Exelixis, Lanctheus, AstraZeneca, Amgen, Daiichi, Convergent Therapeutics, Clarity Pharmaceuticals, Pfizer, Blue Earth Diagnostics, and Isotope Technologies Munich; and research funding from Novartis. OS reports consultant or advisory fees from Advanced Accelerator Applications (Novartis), Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis Oncology, Constellation, Dendreon, EMD Serono, Fusion, Isotope Technologies Munich, Merck, Janssen, Myovant, Myriad, Noria Therapeutics, NorthStar, Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, and Theragnostics; research funding from Bayer, Endocyte, Merck, InVitae, Constellation, Amgen, Advanced Accelerator Applications (Novartis), Arvinas, AstraZeneca, Dendreon, Janssen, Lantheus, Tenebio, and Progenics; holds an issued US patent (number 7 166 691); and owns stock in Lilly, GlaxoSmithKline, AbbVie, Cardinal Health, UnitedHealth Group, Clarity Pharmaceuticals, Noria Therapeutics, and Clovis Oncology. STT reports consultant or advisory fees from Sanofi, Medivation, Astellas, Janssen, Genentech, Bayer, Eisai, Abbvie, Tolmar, Seattle Genetics, Amgen, Clovis Oncology, Pfizer, Novartis, Clarity Pharmaceuticals, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, Aikido, Telix, Convergent Therapeutics, EMD Serono, Myovant, and Merck; research funding from Sanofi, Medivation, Astellas, Janssen, Amgen, Genentech, Newlink, Bristol-Myers Squibb, Inovio, AstraZeneca, Aveo, Rexahn, Bayer, Merck, Abbvie, Karyopharm, Endocyte, Clovis Oncology, Seattle Genetics, Novartis, Gilead, and POINT Biopharma; holds a patent pending with Gilead; and owns stock in Alkido. NV reports consultant or advisory fees from Genzyme, MSD, Janssen, Eisai, AstraZeneca, Dendreon, Pfizer, Bayer, Seagen, Clovis Oncology, Advanced Accelerator Applications (Novartis), and Amgen. JC reports consultant or advisory fees from Astellas, Blue Earth Diagnostics, Curium, DS Pharma, GE Healthcare, Isoray, Janssen, Lightpoint Medical, Lantheus, POINT Biopharma, Radiomedix, IBA RadioPharma, Monrol, Novartis, Telix, and Sanofi; and research funding from Lantheus, Novartis, and POINT Biopharma. JN reports consultant or advisory fees from Curium, POINT Biopharma, Bayer, and Pfizer; and research funding from Advanced Accelerator Applications (Novartis) and ABX. ATK and XXW report consultant or advisory fees from Advanced Accelerator Applications (Novartis). VSK reports consultant or advisory fees from Clovis Oncology, Pfizer, EMD Serono, Seagen, AstraZeneca, Janssen, Astellas, Seattle Genetics, Dendreon, Guidepoint, GLG, and ExpertConnect; and research funding from Janssen, Clovis Oncology, Nektar, Taiho, Merck, and Advanced Accelerator Applications (Novartis). JdB reports consultant or advisory fees from AstraZeneca, Astellas, Bayer, Cell Centric, Daiichi, Genentech (Roche), Endocyte, Advanced Accelerator Applications (Novartis), Pfizer, GSK, Janssen, Merck Serono, MSD, Sanofi Aventis, and Pfizer; and research funding from AstraZeneca, Bayer, CellCentric, Daiichi, GSK, Harpoon, Janssen, Merck Serono, MSD, Pfizer, Sanofi Aventis, and Genentech (Roche). RG, MD, and RAM are employees or own Novartis stocks and shares. J-MB and BC declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Sipuleucel-T has demonstrated survival benefit in phase 3 trials but is utilized in few men with metastatic castration-resistant prostate cancer (mCRPC) in part due to low rates of PSA and objective response. Given the requirement to develop immune-mediated antitumor activity as vaccine-based therapy, sipuleucel-T may have delayed clinical activity. We explored this in a cohort of men from PROCEED (NCT01306890), an FDA-requested outcomes registry, and in a separate institutional cohort of mCRPC patients treated with sipuleucel-T at Dana-Farber Cancer Institute (DFCI)., Methods: Men with mCRPC who received 3 infusions of sipuleucel-T and did not initiate a new mCRPC directed therapy for ≥6 months after completion of sipuleucel-T were included. All patients had rising PSA before starting sipuleucel-T and available post-treatment PSA measurements. Clinical outcomes of interest included: PSA 50 response rate, time to subsequent mCRPC directed therapy, and overall survival (OS)., Results: Of 1902 men with mCRPC treated in PROCEED and 255 patients treated consecutively with sipuleucel-T between 4/2010 and 4/2017 at DFCI, 171 and 28 patients were included, respectively. In the PROCEED sample, PSA 50 response was observed in 34 (19.9%) of patients at a median of 5.5 months (IQR: 3.9-9.5) since the last sipuleucel-T infusion; median time to subsequent mCRPC directed therapy was 10 months (95% CI: 9-11); and median OS was 49 months (95% CI: 43-NR). In the DFCI cohort, PSA 50 response was observed in 4 (14.3%) of patients at a median of 6.3 months (IQR: 4.7-7.0); median time to subsequent mCRPC directed therapy was 9 months (95% CI: 9-11); and median OS was 60 months (95% CI: 51-74)., Conclusions: In this analysis of mCRPC patients treated with sipuleucel-T who did not immediately initiate subsequent therapy using two datasets, delayed PSA response was observed in a subset of patients indicating delayed clinical activity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance., Patients and Methods: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing., Results: A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes ( PTEN, RB1 , and TP53 ), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression vs. 53.9% at baseline) and BRCA2 alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression., Conclusions: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC., (©2021 American Association for Cancer Research.)

Background: Tumor content in circulating cell-free DNA (cfDNA) is a promising biomarker, but longitudinal dynamics of tumor-derived and non-tumor-derived cfDNA through multiple courses of therapy have not been well described., Methods: CfDNA from 663 plasma samples from 140 patients with castration-resistant prostate cancer (CRPC) was subject to sparse whole genome sequencing. Tumor fraction (TFx) estimated using the computational tool ichorCNA was correlated with clinical features and responses to therapy., Results: TFx associated with the number of bone metastases (median TFx = 0.014 with no bone metastases, 0.047 with 1-3 bone metastases, 0.190 for 4+ bone metastases; P < 0.0001) and with visceral metastases (P < 0.0001). In multivariable analysis, TFx remained associated with metastasis location (P = 0.042); TFx was positively correlated with alkaline phosphatase (P = 0.0227) and negatively correlated with hemoglobin (Hgb) (P < 0.001), but it was not correlated with prostate specific antigen (PSA) (P = 0.75). Tumor-derived and non-tumor-derived cfDNA track together and do not increase with generalized tissue damage from chemotherapy or radiation at the time scales examined. All new treatments that led to ≥30% PSA decline at 6 weeks were associated with TFx decline when baseline TFx was >7%; however, TFx in patients being subsequently maintained on secondary hormonal therapy was quite dynamic., Conclusion: TFx correlates with clinical features associated with overall survival in CRPC, and TFx decline is a promising biomarker for initial therapeutic response., Trial Registration: Dana-Farber/Harvard Cancer Center (DF/HCC) protocol no. 18-135., Funding: Wong Family Award in Translational Oncology, Dana Farber Cancer Institute Medical Oncology grant, Gerstner Family Foundation, Janssen Pharmaceuticals Inc., and Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute (NCI).

Background: Sipuleucel-T is an autologous cell-based cancer immunotherapy for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its approval by the Food and Drug Administration was based on demonstration of an overall survival (OS) benefit in randomized placebo-controlled phase III trials. However, treatment was associated with a prostate-specific antigen (PSA) decline in only a small minority of patients. Understanding the clinical factors that are associated with OS could help guide treatment decisions, including patient selection and the timing of sipuleucel-T relative to other therapies., Patients and Methods: We retrospectively identified 94 mCRPC patients treated with sipuleucel-T from April 2010 to April 2016. The Kaplan-Meier method was used to estimate the distribution of OS. Univariate and multivariate Cox proportional hazard modeling was used to identify the prognostic factors for OS., Results: With a median follow-up of 24.9 months, the median OS was 34.9 months. On multivariate analysis, Eastern Cooperative Oncology Group performance status, pretreatment PSA doubling time, and previous abiraterone and/or enzalutamide were significant prognostic factors for OS., Conclusion: A poorer baseline performance status, faster disease pace measured by the PSA doubling time, and previous novel androgen signaling inhibitor exposure could be important prognostic considerations for the treatment of mCRPC patients with sipuleucel-T. Further studies are needed to validate these findings., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Lessons Learned: In abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate-specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post-abiraterone and/or post-enzalutamide mCRPC space., Background: Selinexor is a first-in-class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin-1 (XPO-1), leading to nuclear accumulation of tumor suppressor proteins., Methods: This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide., Results: Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m 2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow-up of 4 months, two patients (14%) had ≥50% prostate-specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment-related grade 3-4 AEs. The most common drug-related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability., Conclusion: Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti-androgenic agents., (©AlphaMed Press; the data published online to support this summary is the property of the authors.)

Purpose of Review: There are currently limited data to guide the optimal management of patients with low-volume metastatic castration-resistant prostate cancer (mCRPC). In this review, we critically assess the most relevant clinical data, and discuss opportunities for advancing therapeutic options in this patient population., Recent Findings: Over the past decade, treatment options for mCRPC have expanded beyond taxanes to include abiraterone/prednisone, enzalutamide, sipuleucel-T, and radium-223. However, only a subset of patients in the landmark phase 3 studies would meet criteria consistent with low-volume mCRPC, and optimal treatment approach for this patient population is unclear. There is emerging evidence that mCRPC patients who harbor low-volume or indolent disease may derive the most benefit from immunotherapy. Whereas prospective data are lacking, stereotactic body radiation appears to be well tolerated and effective for local control of metastases in oligometastatic CRPC., Summary: Prospective studies are needed to establish optimal therapeutic approaches in carefully selected low-volume mCRPC patients. Advances in functional imaging and molecular profiling should provide opportunities to optimize patient selection for effective treatment strategies.

Lessons Learned: The combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored., Background: Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance., Methods: This phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy., Results: Six patients ( n  = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed., Conclusion: The combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503-e43., (© AlphaMed Press; the data published online to support this summary is the property of the authors.)

Introduction: Ipilimumab is a fully human monoclonal antibody that blocks Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) to potentiate antitumor T cell response. Ipilimumab is approved for the treatment of advanced melanoma based on improved overall survival. Clinical trials of ipilimumab in patients with metastatic castrate-resistant prostate cancer (mCRPC) have demonstrated some clinical activity, but have largely been disappointing to date., Areas Covered: Results of key clinical studies of ipilimumab in the treatment of prostate cancer, including clinical efficacy and toxicities, are summarized., Expert Opinion: There is likely a clinical benefit to ipilimumab in a subset of mCRPC patients. The development of biomarkers for enrichment treatment strategies that select for patients most likely to benefit from ipilimumab is a top priority. Similarly, an understanding of the factors predictive of toxicity will be important in the development of future treatment approaches.

The management of advanced prostate cancer, specifically metastatic castrate-resistant prostate cancer (mCRPC), remains a therapeutic challenge. Sipuleucel-T (Provenge; APC8015) was approved by the FDA in 2010 for the treatment of asymptomatic or minimally symptomatic mCRPC patients, and it remains the only FDA-approved immunotherapy for prostate cancer of any indication to date. Given the continued need to improve therapeutics in patients with advanced prostate cancer, as well as recent enthusiasm for cancer immunotherapy, there is a wide range of ongoing trials evaluating combinations of sipuleucel-T with other therapeutics. Additional trials are aiming to expand the application of sipuleucel-T to prostate cancer patients beyond the mCRPC setting. Ongoing challenges include understanding the full mechanism of action of sipuleucel-T, optimizing the sequence of sipuleucel-T in relation to other therapies for mCRPC in clinical practice, and the identification of surrogate markers to predict survival benefit in clinical trials.