Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer.

BACKGROUNDAndrogen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODSTo investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTSWe confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSIONOur findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDINGNational Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.

Opposing impact of hypertension/diabetes following hormone therapy initiation and preexisting statins on castration resistant progression of nonmetastatic prostate cancer: a multicenter study.

Hormone therapy, especially androgen deprivation therapy (ADT), is effective against prostate cancer (PC), whereas long-term ADT is a risk for metabolic/cardiovascular disorders including diabetes (DM), hypertension (HT) and dyslipidemia (DL), and might result in progression to castration-resistant prostate cancer (CRPC). We thus conducted a multicenter retrospective cohort study to ask whether CRPC progression would be associated positively with HT, DM or DL and negatively with statins prescribed for treatment of DL. In this study, 1,112 nonmetastatic PC patients undergoing ADT were enrolled. Univariate statistical analyses clearly showed significant association of HT or DM developing after ADT onset, though not preexisting HT or DM, with early CRPC progression. On the other hand, preexisting DL or statin use, but not newly developed DL or started statin prescriptions following ADT, was negatively associated with CRPC progression. Multivariate analysis revealed significant independent association of the newly developed DM or HT, or preexisting statin use with CRPC progression [adjusted hazard ratios (95% confidence intervals): 3.85 (1.65-8.98), p = 0.002; 2.75 (1.36-5.59), p = 0.005; 0.25 (0.09-0.72), p = 0.010, respectively]. Together, ADT-related development of HT or DM and preexisting statin use are considered to have positive and negative impact on CRPC progression, respectively.

Circulating Tumor Cell Count and Overall Survival in Patients With Metastatic Hormone-Sensitive Prostate Cancer.

Importance: In metastatic hormone-sensitive prostate cancer (mHSPC), new first-line combination therapies have enhanced overall survival (OS), but clinical outcomes for individual patients vary greatly and are difficult to predict. Peripheral blood circulating tumor cell (CTC) count is the most extensively validated prognostic liquid biomarker in metastatic castration-resistant prostate cancer (mCRPC), and recent studies have suggested that it may also be informative in mHSPC. Objective: To examine the prognostic value of CTC count in men with mHSPC. Design, Setting, and Participants: In this prognostic study, peripheral blood was drawn at registration (baseline) and at progression to mCRPC in the S1216 study (March 1, 2013, to July 15, 2017), a phase 3, prospective, randomized clinical trial in men with mHSPC. The CTCs were enumerated using a US Food and Drug Administration-cleared isolation platform. Counts were categorized as 0, 1 to 4, or 5 or more CTCs per 7.5 mL based on the prognostic value of these cut points in prior studies. The data analysis was performed between October 28, 2022, and June 15, 2023. Exposure: Metastatic hormone-sensitive prostate cancer. Main Outcomes and Measures: Circulating tumor cell count was evaluated for an association with 3 prespecified trial end points: OS, progression-free survival, and 7-month prostate-specific antigen, after adjusting for other baseline covariates using proportional hazards and logistic regression models. Results: Of 1313 S1216 participants (median [IQR] age, 68 [44-92] years), evaluable samples from 503 (median [IQR] age, 69 [46-90] years) with newly diagnosed mHSPC were collected at baseline, and 93 samples were collected at progression. Baseline counts were 5 or more CTCs per 7.5 mL in 60 samples (11.9%), 1 to 4 CTCs per 7.5 mL in 107 samples (21.3%), and 0 CTCs per 7.5 mL in 336 samples (66.8%). Median OS for men with 5 or more CTCs per 7.5 mL was 27.9 months (95% CI, 24.1-31.2 months) compared with 56.2 months (95% CI, 45.7-69.8 months) for men with 1 to 4 CTCs per 7.5 mL and not reached at 78.0 months follow-up for men with 0 CTCs per 7.5 mL. After adjusting for baseline clinical covariates, men with 5 or more CTCs per 7.5 mL at baseline had a significantly higher hazard of death (hazard ratio, 3.22; 95% CI, 2.22-4.68) and disease progression (hazard ratio, 2.46; 95% CI, 1.76-3.43) and a lower likelihood of prostate-specific antigen complete response (odds ratio, 0.26; 95% CI, 0.12-0.54) compared with men with 0 CTCs per 7.5 mL at baseline. Adding baseline CTC count to other known prognostic factors (covariates only: area under the curve, 0.73; 95% CI, 0.67-0.79) resulted in an increased prognostic value for 3-year survival (area under the curve, 0.79; 95% CI, 0.73-0.84). Conclusions and Relevance: In this prognostic study, the findings validate CTC count as a prognostic biomarker that improved upon existing prognostic factors and estimated vastly divergent survival outcomes regardless of subsequent lines of therapy. As such, baseline CTC count in mHSPC may serve as a valuable noninvasive biomarker to identify men likely to have poor survival who may benefit from clinical trials of intensified or novel regimens.

The Efficacy of Cabazitaxel in Treating Prostate Cancer: A Systematic Review and Meta-Analysis.

Cabazitaxel, a second-generation taxane chemotherapy agent, has demonstrated efficacy in treating metastatic castration-resistant prostate cancer (mCRPC) in patients who have previously received docetaxel-based therapy. By targeting microtubule dynamics, cabazitaxel inhibits cancer cell division and induces apoptosis, thereby extending survival and delaying disease progression in this challenging patient population. A systematic review and meta-analysis were done by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tools assessment for RCTs. In the analysis, we used RevMan Cochrane software. Our research reveals significantly improved outcomes in terms of patient survival rates, both progression-free survival (PFS) and overall survival (OS), for cabazitaxel over comparative treatment (PFS HR 0.77 [0.61, 0.97]) (OS HR 0.79 [0.70, 0.88]). The treatment response rates were also favorable for cabazitaxel, reported as PSA Reduction Response of more than 50% (PRR) (odds ratio (OR) = 1.59 [0.56, 4.52]) and tumor response rate (TRR) (OR = 2.34 [1.28, 4.28]). Cabazitaxel was associated with significantly more incidence of adverse events. The risk ratio (RR) for serious adverse events was 1.64 [1.14, 2.35] for cabazitaxel compared to the current regimen. A systematic review and meta-analysis were done by searching in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tools assessment for RCTs. In the analysis, we used RevMan Cochrane software.

The Role of CENPK Splice Variant in Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer.

Most patients with metastatic prostate cancer eventually develop resistance to primary androgen deprivation therapy. To identify predictive biomarker for Abiraterone acetate/prednisone resistance, we screened alternative splice variants between responders and non-responders from the PROMOTE clinical study and pinned down the most significant variant, CENPK-delta8. Through preclinical patient-derived mouse xenograft (PDX) and 3D organoids obtained from responders and non-responders, as well as in vitro models, aberrant CENPK-delta8 expression was determined to link to drug resistance via enhanced migration and proliferation. The FLNA and FLOT1 were observed to specifically bind to CENK-delta8 rather than wild-type CENPK, underscoring the role of CENPK-delta8 in cytoskeleton organization and cell migration. Our study, leveraging data from the PROMOTE study, TCGA, and TCGA SpliceReq databases, highlights the important function of alternative splice variants in drug response and their potential to be prognostic biomarkers for improving individual therapeutic outcomes in precision medicine.

Latin American Challenges and Recommendations for Poly Adenosine Diphosphate Ribose Polymerase Inhibitor Treatment in Metastatic Castration Resistant Prostate Cancer: An Expert Overview.

In Latin America, prostate cancer is the third most common cancer overall and the most common in men, with the highest mortality rate of all cancers. In 2022, there were approximately 22,985 new prostate cancer cases and 61,056 deaths from prostate cancer in the region. Patients with metastatic disease that is resistant to cure by castration now have multiple therapeutic options, including poly-ADP ribose polymerase inhibitors. These treatment advances present new challenges, such as developing monitoring protocols for early detection of disease progression to castration resistance. The Americas Health Foundation organized a 3-day meeting with 8 regional oncologists and pathologists to create a paper on metastatic castration-resistant prostate cancer diagnosis and therapy, including the new poly-ADP ribose polymerase inhibitors. The panel examined metastatic castration-resistant prostate cancer in Latin America and recommended ways to improve patient care using published literature and their expertise. Gene mutations play an important role in prostate cancer development. Precision medicine innovations highlight the importance of genotyping DNA variants and tumor biomarkers for targeted treatment. Access to appropriate genetic testing is difficult, medications are available but expensive, and there is a lack of infrastructure and regulatory frameworks that prevent patients from benefiting from innovative therapies. The panel recommends developing a population database and biobank and creating tumor tissue collection, processing, and storage facilities. Multi-stakeholder collaboration is needed to integrate the information gathered, train staff, select target populations, improve patient accessibility, and reduce the cost burden of drugs, genetic counselors, and cancer geneticists in Latin America. Collaboration is essential among healthcare professionals, policymakers, patient advocacy groups, pharmaceutical companies, and international organizations to address these challenges and needs in Latin America.

BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity.

The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response.

Connecting Gene Variation to Treatment Outcomes in Metastatic Castration-Resistant Prostate Adenocarcinoma: Insights into Second-Generation Androgen Receptor Axis-Targeted Therapies.

Prostate cancer (PC) is one of the most commonly diagnosed tumours among men. Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone acetate (AbA) and enzalutamide (ENZ), are currently used in the management of metastatic castration-resistant PC (mCRPC). However, the treatment is challenging due to the lack of prognostic biomarkers. Meanwhile, single-nucleotide polymorphisms (SNPs) have emerged as potential prognostic indicators of mCRPC. Thus, this study evaluated the impact of relevant SNPs on the treatment outcomes of 123 mCRPC patients enrolled in a hospital-based cohort study. The CYP17A1 rs2486758 C allele was associated with a 50% reduction in the risk of developing castration resistance (hazard ratio (HR) = 0.55; p = 0.003). Among patients without metastasis at tumour diagnosis and under AbA, a marginal association between YBX1 rs10493112 and progression-free survival was detected (log-rank test, p = 0.056). In the same subgroup, significant associations of HSD3B1 rs1047303 (CC/CA vs. AA; HR = 3.41; p = 0.025), YBX1 rs12030724 (AT vs. AA; HR = 3.54; p = 0.039) and YBX1 rs10493112 (log-rank test, p = 0.041; CC vs. AA/AC; HR = 3.22; p = 0.053) with overall survival were also observed, which were confirmed by multivariate Cox analyses. Although validation with larger cohorts is required, these findings suggest that SNPs could enhance the prognosis assessment of mCRPC patients, leading to a more personalised treatment.

TMPRSS2:ERG Gene Fusion Might Predict Resistance to PARP Inhibitors in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND/AIM: The emergence of novel DNA damage repair (DDR) pathways in molecular-target therapy drugs (MTTD) has shown promising outcomes in treating patients with metastatic castration-resistant prostate cancer (mCRPC). About 25% of mCRPC patients have actionable deleterious aberrations in DDR genes, primarily in the homologous recombination (HR) pathway. However, the response rate in patients with BRCA1/2 or mutations in HRR-related genes is only 45%-55%, when exposed to poly ADP ribose polymerase (PARP) inhibitor-based therapy (PARPi). A frequent characteristic feature of prostate cancer (PC) is the occurrence of genomic rearrangement that affects the transmembrane protease serine 2 (TMPRSS2) and E26 transformation-specific (ETS)- transcription factor-related gene (ERG). MATERIALS AND METHODS: In this study, a total of 114 patients with mCRPC had their RNA and DNA sequenced using next-generation sequencing. RESULTS: Based on their genetic profile of deleterious gene alterations of BRCA1/2 or ATM, six patients were selected for PARPi. Patients with TMPRSS2:ERG gene fusion and homozygous alteration in ATM or BRCA2 (n=2) or heterozygous alterations (BRCA1 or BRCA2) and lack of TMPRSS2:ERG gene fusion (n=2) did not show clinical benefit from PARPi (treatment duration <16 weeks). In contrast, patients (n=2) without TMPRSS2:ERG gene fusion and homozygous deleterious alterations in ATM or BRCA2 all had clinical benefit from PARPi (treatment duration ≥16 weeks). CONCLUSION: The TMPRSS2:ERG transcript product might be used as a PARPi resistance biomarker.

Dosimetry at cellular level for the alpha-emitting radionuclides actinium-225, astatine-211 and radium-223 for bone metastasis cells from castration resistant prostate cancer.

Objectives.The aim of this work is to evaluate energy deposition in the nucleus and cytoplasm in targeted alpha therapy of metastatic castration-resistant prostate cancer by modeling two cell lines, PC3 (osteolytic) and LNCaP C4-2 (osteoblastic), for actinium-225, astatine-211, and radium-223 and their progeny, using Monte Carlo simulations with the GATE/Geant4 code.Approach.We developed single cell and cell clusters models to Monte Carlo simulations, performed on the GATE platform version 9.3, with the GEANT4-DNA physics list emstandard_opt3_mixed_dna for At-211, Ac-225 and Ra-223 progenies. We considered three radionuclide distributions as a sources: the nucleus, the cytoplasm and the whole cell.Main results.When the nucleus was considered as a target, theS-values (N←N) calculated for At-211, Ac-225 and Ra-223 progenies were significantly higher, within 60%-90%, thanS-values (N←Cy), demonstrating less influence of cytoplasm only internalization. When the cytoplasm was considering as a target, theS-values (Cy←Cy) calculated for At-211, Ac-225 and Ra-223 progeny were significantly higher, within 30%-90%, than theS-values (Cy←N). When no progeny migration occurs and for target nucleus , the cumulativeS-values (N←N) calculated for At-211, Ac-225 and Ra-223 were significantly higher, within 50%-70%, than theS-values (N←N) computed for At-211, Ac-225, and Ra-223. Comparing the cumulativeS-values, Ac-225 and Ra-223 therapies is more effective, in terms of deposited energy in a target, than that with At-211.Significance.The data presented in this research indicates that Ac-225 therapy may be the optimum choice due to the energy deposited in the nucleus, as long as the recoil effects and redistribution of progeny are understood. In contrast, At-211 is an alternative to avoid progeny migration. However, to completely analyze the efficacy of radionuclide therapy, other parameters must be considered, such as biological half-life, stability of the transport molecule, progeny migration, excretion pathways, and uptake in different organs.

177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial.

BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-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 177Lu-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 177Lu-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 177Lu-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 177Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177Lu-PSMA-617 cycles was 6·0 (IQR 4·0-6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177Lu-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 177Lu-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 177Lu-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 177Lu-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: 177Lu-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, 177Lu-PSMA-617 may be an effective treatment alternative. FUNDING: Novartis.

Identification of blood lipid markers of docetaxel treatment in prostate cancer patients.

Docetaxel is commonly used for treatment of castration-resistant prostate cancer. Unfortunately, many prostate cancer patients develop resistance to docetaxel. Clinical markers less invasive than biopsies, such as blood samples, would be ideal for monitoring and predicting patient treatment outcomes to docetaxel. Lipid alterations are often associated with the progression of many cancers, including prostate cancer. This study investigated the use of lipids from whole blood as clinical markers for docetaxel resistance in a small cohort of patients with prostate cancer. Qualitative lipidomics was performed by liquid chromatography-tandem mass spectrometry to assess the lipid composition of prostate cancer cells exposed to docetaxel as well as whole blood from prostate cancer patients before, during and after docetaxel treatment. Three patients had castration resistant prostate cancer, three had castration sensitive prostate cancer, and four had de novo prostate cancer during the extent of the study. Mean decrease accuracy and classical univariate receiving operating characteristic curve analyses were performed to identify potential biomarkers. In total, 245 and 221 altered lipids were identified from a second stage of mass spectrometry analysis of prostate cancer cells and clinical blood samples, respectively. Both models indicated that docetaxel treatment altered ether-linked phosphatidylcholines, lysophosphatidylcholine, diacylglycerols, ceramides, hexosylceramides, and sphingomyelins. The results also indicated several lipid changes were associated with sphingolipid signaling and metabolism, and glycerophospholipid metabolism. Collectively, these data suggest the potential usage of identified lipid species as indicators of docetaxel resistance in prostate cancer.

Talazoparib Plus Enzalutamide in Patients With HRR-Deficient mCRPC: Practical Implementation Steps for Oncology Nurses and Advanced Practice Providers.

BACKGROUND: About one-quarter of patients with advanced prostate cancer have alterations in homologous recombination repair (HRR) genes. In a global phase 3 study, talazoparib plus enzalutamide significantly improved progression-free survival in patients with HRR-deficient metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVES: This article reviews the role of oncology nurses and advanced practice providers (APPs) in administering talazoparib plus enzalutamide in patients with mCRPC. METHODS: This review and hypothetical case study illustrate the role of oncology nurses and APPs in the administration of talazoparib plus enzalutamide and the management of adverse events to ensure safe and effective use in clinical practice. FINDINGS: Oncology nurses and APPs play an important role in the dosing and administration of talazoparib plus enzalutamide and can recognize and manage adverse events in patients with HRR-deficient mCRPC.

Early treatment response assessment with [177Lu]PSMA whole-body-scintigraphy compared to interim PSMA-PET.

BACKGROUND: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is an essential tool for patient selection before radioligand therapy (RLT). Interim-staging with PSMA-PET during RLT allows for therapy monitoring. However, its added value over post-treatment imaging is poorly elucidated. The aim of this study was to compare early treatment response assessed by post-therapeutic whole-body scans (WBS) with interim-staging by PSMA-PET after 2 cycles in order to prognosticate OS. METHODS: Men with metastasized castration-resistant PC (mCRPC) who had received at least two cycles of RLT, and interim PSMA-PET were evaluated retrospectively. PROMISE V2 framework was used to categorize PSMA expression and assess response to treatment. Response was defined as either disease control rate (DCR) for responders or progression for non-responders. RESULTS: A total of 188 men with mCRPC who underwent RLT between February 2015 and December 2021 were included. The comparison of different imaging modalities revealed a strong and significant correlation with Cramer V test: e.g. response on WBS during second cycle compared to interim PET after two cycles of RLT (cφ = 0.888, P < 0.001, n = 188). The median follow-up time was 14.7 months (range: 3-63 months; 125 deaths occurred). Median overall survival (OS) time was 14.5 months (95% CI: 11.9-15.9). In terms of OS analysis, early progression during therapy revealed a significantly higher likelihood of death: e.g. second cycle WBS (15 vs. 25 months, P < 0.001) with a HR of 2.81 (P < 0.001) or at PET timepoint after 2 cycles of RLT (11 vs. 24 months, P < 0.001) with a HR of 3.5 (P < 0.001). For early biochemical response, a PSA decline of at least 50% after two cycles of RLT indicates a significantly lower likelihood of death (26 vs. 17 months, P < 0.001) with a HR of 0.5 (P < 0.001). CONCLUSION: Response assessment of RLT by WBS and interim PET after two cycles of RLT have high congruence and can identify patients at risk of poor outcome. This indicates that interim PET might be omitted for response assessment, but future trials corroborating these findings are warranted.

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer.

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Integrative identification of non-coding regulatory regions driving metastatic prostate cancer.

Large-scale sequencing efforts have been undertaken to understand the mutational landscape of the coding genome. However, the vast majority of variants occur within non-coding genomic regions. We designed an integrative computational and experimental framework to identify recurrently mutated non-coding regulatory regions that drive tumor progression. Applying this framework to sequencing data from a large prostate cancer patient cohort revealed a large set of candidate drivers. We used (1) in silico analyses, (2) massively parallel reporter assays, and (3) in vivo CRISPR interference screens to systematically validate metastatic castration-resistant prostate cancer (mCRPC) drivers. One identified enhancer region, GH22I030351, acts on a bidirectional promoter to simultaneously modulate expression of the U2-associated splicing factor SF3A1 and chromosomal protein CCDC157. SF3A1 and CCDC157 promote tumor growth in vivo. We nominated a number of transcription factors, notably SOX6, to regulate expression of SF3A1 and CCDC157. Our integrative approach enables the systematic detection of non-coding regulatory regions that drive human cancers.

Apalutamide for non-metastatic castration-resistant prostate cancer (nmCRPC): real world data of a multicenter study.

PURPOSE: Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Nevertheless real-world data are limited. The aim of this multicenter study was to generate real-world data from nmCRPC patients treated with ADT plus apalutamide. METHODS: In this observational cohort based investigator initiated trial data of nmCRPC patients receiving apalutamide plus ADT were collected focusing on patient demographic data, prostate-specific antigen (PSA) declines, safety profile including dose modification/discontinuation as well as subsequent therapy and metastasis-free survival (MFS). RESULTS: Data from a total of 31 nmCRPC patients were documented. Compared to the Phase III study Spartan real-world patients are older, showed a higher ECOG-PS and more aggressive tumors. In the cohort PSA decreased about 98.1%, 74% of patients showed a PSA decrease over 90% and 54.8% reached a PSA-level < 0.2ng/ml. Apalutamide was well tolerated in real world patients: adverse events occurred in 67.7% but were in the majority mild (≥ grade 3: 6.5%). Dose reduction was necessary in 38.7% and 32.2% discontinued apalutamide treatment. MFS was 43 months and majority of patients were subsequently treated with abiraterone. CONCLUSION: In real world more comorbid nmCRPC patients with a higher ECOG-PS and more aggressive tumors are treated with apalutamide plus ADT. Nevertheless efficacy results as well as side effects are similar in real-world compared to Spartan trial showing also a rapid, durable and deep PSA response with a median MFS of 43 months.