Metastatic Castration-resistant Prostate Cancer Patients Research Articles

Baseline serum testosterone and differential efficacy of bipolar androgen therapy and enzalutamide in the randomized TRANSFORMER trial.

Bipolar androgen therapy (BAT) is effective in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients. Treatment selection biomarkers are needed due to other therapies that can be equally efficacious. We performed post-hoc analysis to determine whether baseline serum testosterone (T) is a treatment selection marker in the TRANSFORMER study, a randomized trial of abiraterone-pretreated mCRPC patients assigned to BAT (n = 94) or enzalutamide (n = 101). The findings suggest that patients with poor outcomes to abiraterone and serum T ≥ 20 ng/dL may benefit preferentially from BAT over enzalutamide. Baseline testosterone could be considered in the treatment selection process when BAT is an option.

Outcomes and patterns of use of Radium-223 in metastatic castration-resistant prostate cancer

IntroductionRadium-223 dichloride (Ra-223) is recommended as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and no visceral disease, after docetaxel failure, or in patients who are not candidates to receive it. In this study, we aimed to ambispectively analyze overall survival (OS) and prognostic features in mCRPC in patients receiving Ra-223 as per clinical routine practice and identify the most suitable treatment sequence.Patients and methodsThis study is observational, multicentric, and ambispective. Eligibility criteria included mCRPC patients treated with Ra-223, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, without visceral metastases, and no more than three cm involved lymph nodes.ResultsA total of 145 patients were included; the median age was 73.97 years, and a Gleason score of more than or equal to 7 in 61 (48%) patients; 73 (81%) had previously received docetaxel. The most important benefit was reached by those patients who received Ra-223 in the second-line setting, with a median OS of 17 months (95% CI, 12–21), and by patients who received six cycles of treatment, with a median OS of 19 months (95% CI, 14–21). An alkaline phosphatase (ALP) decrease was also identified as a prognosis marker. When performing the multivariate analysis, the time to develop castration-resistant disease longer than 24 months was the most important prognostic factor to predict the evolution of the patients receiving Ra-223. Ra-223 was well tolerated, with thrombocytopenia, anemia, and diarrhea being the main adverse events.ConclusionThere is a benefit for those patients who received Ra-223 in the second-line setting, regardless of prior use of docetaxel. In addition, a survival benefit for patients presenting with a decline in ALP was observed.

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study.

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3). Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168h after injection and one SPECT/CT imaging was performed at 24h post-injection for each patient. Dosimetry evaluation was compared in both patient groups. Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively. [177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy. 177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic. gov/ct2/show/NCT05603559 .

Increase of prostate-specific antigen doubling time predicts survival in metastatic castration-resistant prostate cancer patients undergoing radium therapy.

Radium-223 (Ra-223) is an important treatment modality for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). However, there is currently a lack of effective markers to monitor treatment response during treatment. We aim to investigate the response in prostate-specific antigen doubling time (PSADT) as a potential marker for assessing Ra-223 treatment in mCRPC patients. We retrospectively collected data from mCRPC patients who underwent radium treatment at our institution between August 2020 and June 2023. Prostate-specific antigen (PSA) measurements prior to treatment and during treatment were collected. Baseline PSADT was calculated from PSA measurements prior to Ra-223 treatment; interim PSADT was calculated from PSA measurements before Ra-223 treatment and prior to the fourth course injection. Overall survival was calculated from the start of treatment to the date of death. Univariable and multivariable analysis using the Cox proportional hazards model were performed to examine the association of factors with overall survival. We included 35 patients from our institution, with a median overall survival of 13.3months. Eighteen (51.4%) completed all six courses of treatment. PSA dynamic response (interim PSADT > baseline PSADT or decreased PSA) was observed in 20 patients. Overall survival was associated with a PSA dynamic response (HR = 0.318, 95% CI 0.133-0.762, p = 0.010) when compared to patients without response. Dynamic changes in PSADT were associated with survival in mCRPC patients receiving radium therapy. Comparing interim and baseline PSADT could serve as a valuable marker for determining treatment benefits.

Favorable Response of 225Ac-PSMA in the Treatment of Castration-Resistant Prostate Cancer With High Bone Metastasis Burden.

225Ac-PSMA treatment demonstrated low hematologic toxicity for prostate cancer with diffuse red marrow infiltration. A 70-year-old man with diffuse bone metastases of castration-resistant prostate cancer received 225Ac-PSMA radiation therapy. After 1 treatment cycle, the patient's skeletal lesions demonstrated a significant response and a significant decrease in PSA. 225Ac-PSMA may be a promising therapeutic option for metastatic castration-resistant prostate cancer patients with high bone metastatic burden.

Abstract LB177: Discovery of HC-4955, a novel AR-V7-targeting PROTAC for the treatment of mCRPC

Abstract Prostate cancer is the second most commonly diagnosed cancer and the second leading cause of cancer death among men worldwide. Androgens play an important role in the development and progression of prostate cancers and targeting androgen receptor (AR) signaling axis over decades has remained a mainstay of prostate cancer therapy. Next generation hormonal agents (NHAs) enzalutamide and abiraterone have brought clinical benefits for metastatic castrate-resistant prostate cancer (mCRPC) patients, AR axis-targeted therapy resistance is inevitable due to AR gene amplification or mutations. AR-V7 is the most clinically relevant AR splice variant associated with endocrine resistance and poor prognosis. AR-V7 constitutively activates AR signaling and lacks the ligand binding domain (LBD) where hormones and AR antagonists interact, resulting in resistance to AR signaling inhibitors (ARSi). Thus, AR-V7 is a promising therapeutic target to address ARSi resistance in mCRPC. We have discovered a highly potent AR-V7 proteolysis targeting chimera (PROTAC), HC-4955 that degrades both the wild-type AR (WT-AR) and AR-V7 mutant. HC-4955 degrades AR-V7 with DC50 < 5 nM. In silico molecular docking analysis predicts the binding of HC-4955 to the N-terminal domain of AR and then the essential amino acids contributed to HC-4955 binding are validated by mutational analysis studies. HC-4955 also potently degrades mutants of AR-LBD mutations including L702H and T878A and these mutations are also associated with ARSi resistance. HC-4955 strongly inhibits proliferation of ARSi-resistant prostate cancer cell lines with IC50 < 10 nM. HC-4955 shows a robust anti-tumor activity in the AR-V7-bearing 22Rv1 cell line derived tumor xenograft (CDX) and patient-derived xenograft (PDX) mouse models, with majority of the tumors completely regressed and > 90% AR-V7 expression decreased at 1-5 mg/kg (QD, PO) in these models. The pre-clinical results support the clinical development of HC-4955 for the treatment of mCRPC. Selected pre-clinical data along with the chemical structure of HC-4955 will be presented. Citation Format: Jing Li, Zhilin Tu, Wu Du, Xi Xiang, Zeyu Wen, Yang You, Lijuan Zhao, Yin Chen, Chengcheng Yang, Hongwei Yuan, Xinghai Li. Discovery of HC-4955, a novel AR-V7-targeting PROTAC for the treatment of mCRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB177.

A phase I trial of enzalutamide plus selective glucocorticoid receptor modulator relacorilant in patients with metastatic castration resistant prostate cancer.

Majority of patients with metastatic prostate cancer who receive androgen deprivation therapy and androgen receptor (AR) signaling inhibitors progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI-resistance. This single-arm phase I trial assessed safety and pharmacokinetic feasibility of combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in metastatic castration-resistant prostate cancer (mCRPC) patients. This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in refractory mCRPC patients enrolled using 6+3 design. Enzalutamide dose was kept constant at 120 mg/day with escalating doses of relacorilant based on safety and pharmacokinetic measures in cohorts of ≥ 6 patients. Primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. Thirty-five mCRPC patients were enrolled. Twenty-three were accrued across 3 dose cohorts in the dose escalation phase and twelve enrolled at the recommended phase 2 dose. The combination was generally well-tolerated and safe and achieved desirable enzalutamide pharmacokinetics. RP2D of 120 mg/day + 150 mg/day respectively was established. Median time on study was 2.2 months with 4 patients remaining on study for longer than 11 months. Four of twelve evaluable patients had a PSA partial response. This is the first prospective trial combining an AR antagonist and a non-steroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.

Abstract 3699: Identifying novel resistance biomarkers in circulating tumor cell-expressed transcriptomes of metastatic castration-resistant prostate cancer patients treated with androgen receptor signaling inhibitors

Abstract Introduction: For individuals with metastatic castration-resistant prostate cancer (mCRPC), therapeutic options include androgen receptor signaling inhibitors (ARSIs) like abiraterone or enzalutamide, as well as taxane-based chemotherapy. Despite this, establishing the best treatment approach is still debated, with varied responses to treatments observed. Notably, around 30%-40% of mCRPC patients either do not benefit from ARSI therapy or quickly become resistant. PSMA PET/CT demonstrates prognostic significance in forecasting responses to ARSI treatments, underscoring its utility in managing mCRPC. Nevertheless, the effectiveness of blood test-measured PSMA expression levels in diagnosing and treating prostate cancer remains uncertain. Consequently, there is a crucial demand for predictive biomarkers, particularly those indicating therapeutic resistance, to customize treatments according to the unique tumor biology of individual patients. Materials and Methods: We recruited 21 healthy donors and 60 ARSI-treated metastatic castration-resistive prostate cancer patients. We isolate the circulating tumor cells (CTCs) using lateral magnetophoretic microfluidic technology. The EpCAM-labeled CTCs were specifically isolated by microfluidic technology and analyzed for cell enumeration and transcriptomic analysis. Prostate cancer and epithelial-related six genes (PSMA, PSA, AR, AR-V7, EpCAM, and KRT19) were detected by droplet digital PCR (ddPCR) method. Results: In ARSI-treated groups, the connection between transcript expression and CTC count is differentiated by the presence or absence of a PSA response. Specifically, 41.7% (25/60) of the ARSI group exhibited a PSA non-response, defined as less than a 50% reduction from the baseline level. These patients demonstrated elevated PSA, PSMA, and AR-V7 mRNA expression levels. Kaplan-Meier survival analysis indicated that patients with high PSMA, PSA, and AR-V7 expressions and a higher CTC count experienced poorer PSA-PFS, radiological-PFS, and overall survival (OS) than those with lower expression levels. This trend was echoed in the findings of the proportional hazards model. Notably, patients with higher PSMA mRNA expression faced significantly lower PSA-PFS (HR: 2.28, 95% CI: 1.20-4.33, p = 0.012), radiological-PFS (HR: 4.75, 95% CI: 2.27-9.93, p < 0.001), and OS (HR: 6.99, 95% CI: 2.93-16.73, p < 0.001) than those with lower expression. The Cox model presented analogous results for CTC count and PSA mRNA levels. However, other transcripts, such as AR, KRT19, and EpCAM, did not correlate significantly with the response to ARSI treatment. Conclusions: The study's conclusion revealed that PSMA, PSA, and AR-V7 are biomarkers resistant to ARSI treatment among the CTC-derived transcriptomic genes. Citation Format: Hyungseok Cho, Jiwon Cha, Ki-Ho Han, Jae-Seung Chung. Identifying novel resistance biomarkers in circulating tumor cell-expressed transcriptomes of metastatic castration-resistant prostate cancer patients treated with androgen receptor signaling inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3699.

Abstract 5031: Identification of predictive/prognostic biomarkers in metastatic castration-resistant prostate cancer patients using plasma cell-free total RNA-sequencing

Abstract Background Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease that is still lacking an optimal patient selection strategy and a validated sequence of therapies. Therefore, there is an urgent need to identify non-invasive biomarkers to guide treatment choice in a perspective of personalized medicine. Plasma cell-free RNA profiling has emerged as a tool to investigate potential liquid biopsy biomarkers. In this study, we aimed to evaluate a method to capture total RNA content deriving from plasma and to identify potential biomarkers for mCRPC. Methods Plasma samples of 41 mCRPC patients treated with first line Abiraterone or Enzalutamide and 7 healthy donors were collected and stored from 2015 to 2022. Plasma cell-free RNA was purified using miRNeasy Serum/Plasma Advanced Kit (Qiagen) with DNase treatment. Bioanalyzer (Agilent) was used for the evaluation of RNA content and integrity profile of the samples. Sequencing libraries were generated using SMARTer Stranded Total RNA-Seq Kit v3 - Pico Input Mammalian (Takara Bio). An average of 80 millions reads pairs were sequenced on Novaseq 6000 (Illumina) using 100 bpx2 approach. After demultiplexing, reads were trimmed and aligned on hg19. Sequencing metrics were evaluated using Picard. Kallisto was used for gene expression analysis. Results A median of 10x109 bases per sample were aligned on hg19, of which a mean of 45% were located on coding or UTR regions. Storage time was investigated as a potential variable for RNA content and sequencing metrics, but no difference related to the year of storage was found. Unsupervised principal component analysis confirmed the absence of batch effects (including storage and sequencing analysis). PC1 seemed to reflect the different tumor RNA content of each sample, in which healthy donors and cancer patients were distinguished. Higher androgen receptor (AR) gene expression was found in mCRPC patients compared to healthy donors. Conclusions Despite enormous interest in extracellular nucleic acids, RNA-sequencing methods for total RNA content outside cells are rare and not standardized. In this study, we found a method to identify plasma non-invasive RNA biomarkers in mCRPC samples, retrieving coding and non-coding RNAs. Case series enlargement and differential gene expression analyses are ongoing. Citation Format: Giorgia Gurioli, Milena Urbini, Alessandra Virga, Chiara Casadei, Emilio Francesco Giunta, Nicole Brighi, Michela Cortesi, Michele Zanoni, Sara Bravaccini, Giovanni Martinelli, Paola Ulivi, Ugo De Giorgi. Identification of predictive/prognostic biomarkers in metastatic castration-resistant prostate cancer patients using plasma cell-free total RNA-sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5031.

Evaluation of two-dimensional total bone uptake (2D-TBU) and bone scan index (BSI) extracted from active bone metastatic burden on the bone scintigraphy in patients with radium-223 treatment.

Radium-223 is a first alpha-emitting radionuclide treatment for metastatic castration-resistant prostate cancer (mCRPC) patients with bone metastases. Although the spread-based bone scan index (BSI) and novel index of the intensity-based two-dimensional total bone uptake (2D-TBU) from bone scintigraphy may provide useful input in radium-223 treatment, they have not been evaluated in detail yet. This study aimed to fill this gap by evaluating BSI and 2D-TBU in patients treated with radium-223. Twenty-seven Japanese patients with mCRPC treated with radium-223 were retrospectively analyzed. The patients were evaluated via blood tests and bone scans at baseline and 3 cycles intervals of treatment. BSI and 2D-TBU were analyzed via VSBONE BSI in terms of correlations, response to radium-223 treatment, association with treatment completion, and the Kaplan-Meier survival analysis was performed. Nineteen patients (70.4%) completed six cycles of radium-223 treatment, whereas eight patients (29.6%) did not complete the treatment regimen. A significant difference in baseline BSI and 2D-TBU was observed between these groups of patients. Both BSI and 2D-TBU were highly correlated (r = 0.96, p < 0.001). Univariate analysis showed an association between radium-223 completion in median BSI and 2D-TBU values (p = 0.015) and completion percentage differences (91.7% vs. 45.5%; p = 0.027). The Kaplan-Meier product limit estimator showed that the median overall survival was 25.2 months (95% CI 14.0-33.6 months) in the completion group and 7.5 months (95% CI 3.3-14.2 months) in the without completion group (p < 0.001). The overall survival based on median cutoff levels showed a significant difference in 2D-TBU (p = 0.007), but not in BSI (p = 0.15). The 2D-TBU may offer advantages over BSI in classifying patients towards radium-223 treatment based on the degree of progression of bone metastases. This study supports the importance of preliminary assessment of bone metastasis status using BSI and 2D-TBU extracted from VSBONE BSI for radium-223 treatment decisions.

Prognostic Performance of RECIP 1.0 Based on [18F]PSMA-1007 PET in Prostate Cancer Patients Treated with [177Lu]Lu-PSMA I&T.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.

Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes

Although germline BRCA mutations have been associated with adverse outcomes in prostate cancer (PC), understanding of the association between somatic/germline alterations in homologous recombination repair (HRR) genes and treatment outcomes in metastatic castration-resistant PC (mCRPC) is limited. The aim of this study was to investigate the prevalence and outcomes associated with somatic/germline HRR alterations, particularly BRCA1/2, in patients initiating first-line (1L) mCRPC treatment with androgen receptor signalling inhibitors (ARSi) or taxanes. Data from 729 mCRPC patients were pooled for CAPTURE from four multicentre observational studies. Eligibility required 1L treatment with ARSi or taxanes, adequate tumour samples and biomarker panel results. Patients underwent paired normal and tumour DNA analyses by next-generation sequencing using a custom gene panel including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B and RAD54L. Patients were divided into subgroups based on somatic/germline alteration(s): with BRCA1/2 mutations (BRCA); with HRR mutations except BRCA1/2 (HRR non-BRCA); and without HRR alterations (non-HRR). Patients without BRCA1/2 mutations were classified as non-BRCA. Radiographic progression-free survival (rPFS), progression-free survival 2 (PFS2) and overall survival (OS) were assessed. Of 729 patients, 96 (13.2%), 127 (17.4%) and 506 (69.4%) were in the BRCA, HRR non-BRCA and non-HRR subgroups, respectively. BRCA patients performed significantly worse for all outcomes than non-HRR or non-BRCA patients (P < 0.05), while PFS2 and OS were significantly shorter for BRCA than HRR non-BRCA patients (P < 0.05). HRR non-BRCA patients also had significantly worse rPFS, PFS2 and OS than non-HRR patients. Exploratory analyses suggested that for BRCA patients, there were no significant differences in outcomes associated with 1L treatment choice (ARSi or taxanes) or with the somatic/germline origin of the alterations. Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.

Pretherapeutic PSMA PET-Derived Semiquantitative Parameters as Predictors of PSA Response in Patients with mCRPC Receiving [177Lu]Lu-PSMA-617 Radioligand Therapy

Abstract Objective [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 radioligand therapy (RLT) shows promise for metastatic castration-resistant prostate cancer (mCRPC) patients with positive PSMA positron emission tomography (PET) imaging. Identifying high-risk patients is crucial. We evaluated pretherapeutic PSMA PET-derived parameters to predict prostate-specific antigen (PSA) response in patients undergoing [177Lu]Lu-PSMA-617 RLT. Materials and Methods We conducted a retrospective analysis among 27 patients (mean age: 71.0 ± 9.5 years; range: 52–85 years) who underwent PSMA PET/computed tomography (CT) and subsequent [177Lu]Lu-PSMA-617 RLT between March 2019 and January 2023. After excluding patients with liver metastases, the number of patients left for analysis was 21 (14 responders and 7 nonresponders). Tumors were semiautomatically delineated with calculation of total tumor volume (PSMA-TV), lesion uptake (PSMA-TLU = PSMA-TV * standardized uptake value [SUV]mean), and lesion quotient (PSMA-TLQ = PSMA-TV/SUVmean) for each patient. Semiquantitative parameters were analyzed only in patients with mCRPC and no liver metastasis. Results In total, 17/27 patients (62.96%) had a decline in PSA levels; 15/27 patients (55.56%) experienced a decline of &gt; 50%. Pretherapeutic PSMA PET/CT results revealed significant differences in PSMA-TV (p = 0.003), PSMA-TLU (p = 0.013), and PSMA-TLQ (p = 0.011) between responders and nonresponders. SUVmax was significantly correlated to the best percentage change in PSA response after 177Lu-PSMA-617 treatment (r = −0.79, p = 0.006). No association was observed between PSMA-TV (p = 0.367), PSMA-TLU (p = 0.128), and PSMA-TLQ (p = 0.556), with the best percentage change in PSA response after 177Lu-PSMA-617 therapy. Conclusion Pretherapeutic PSMA PET-derived PSMA-TV, PSMA-TLU, and PSMA-TLQ were significant negative predictors of PSA response in patients with mCRPC and no liver metastasis receiving [177Lu]Lu-PSMA-617 RLT.

Metastatic castration resistant prostate cancer patients' experience with Radium-223 treatment in Japan.

Aim: We aimed to determine Japanese metastatic castration resistant prostate cancer (CRPC) patients' Ra-223 treatment experience. Patients & methods: Patients answered the Cancer Therapy Satisfaction Questionnaire (CTSQ domains: Satisfaction with Therapy [SWT], Expectations of Therapy [ET], Feelings about Side Effects [FSE]), the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) and the FACT-Bone Pain (FACT-BP) Questionnaire at baseline, during (vists 3 and 5) and after treatment (end of observation;EOO). Results: Data from 72 patients were included. Baseline median CTSQ scores SWT: 66.1 (IQR19.7), ET: 75.0 (IQR45), and FSE 68.8 (IQR 34.4) were unchanged during vists 3 and 5, but the SWT (-3.57 [IQR17.9])and ET (-5.0 [IQR30])decreased while FSE was unchanged (0.0 [IQR31.25])at EOO. The median MAX-PC (18.0 [IQR 49])score was unchanged (0.0, IQR 6) while the median FACT BP (54.0 [IQR13])score decreased by -1.0 (IQR 8) at EOO. Conclusion: Japanese metastatic castration resistant prostate cancerpatients' experience is stable during Ra-223 treatment.

Current status of PSMA-targeted imaging and therapy.

Currently, the incidence of prostate cancer is increasing, and it has become a great threat to men's health. The detection, staging, and follow-up of prostate cancer patients are inseparable from morphology or magnetic resonance imaging (MRI). However, these do not fully meet the needs of diagnosis and patient management. In particular, owing to the late diagnosis, metastatic castration-resistant prostate cancer (mCRPC) patients usually have poor survival and few options for further effective treatment. Prostate-specific membrane antigen (PSMA), because of its overexpression on prostate cancer cells, has gained interest due to its application in the imaging and theranostics field. Several PSMA radioligands have been developed for imaging and treating prostate cancer. Many clinical trials have assessed the efficacy and safety profiles of these radionuclide agents and show promise in patients who have exhausted other standard treatment options. To date, several small compounds for targeting PSMA have been developed, and 68Ga-PSMA-11 and 18F-DCFPyL have been approved by the United States (US) Food and Drug Administration (FDA) for imaging of prostate cancer. 111In- or 99mTc-labeled PSMA-ligand can guide surgeons searching for radioactive metastatic lymph nodes, and 177Lu- or 225Ac-labeled PSMA-ligand can be used for internal radiotherapy. Moreover, some molecules for therapeutic application are undergoing different stages of clinical trials. In this review, we present current perspectives on the use of PSMA-targeted imaging and theranostics in prostate cancer. As PSMA-targeted imaging and therapeutics are becoming the standard of care for prostate cancer patients, we emphasize the importance of integrating nuclear medicine physicians into multidisciplinary oncology teams.

Carboplatin in metastatic castration-resistant prostate cancer patients with molecular alterations of the DNA damage repair pathway: the PRO-CARBO phase II trial.

DNA damage repair genes are altered in 20-35% of metastatic castration-resistant prostate cancer (mCRPC). Poly-ADP (Adénosine Diphosphate)-ribose polymerase inhibitors (PARPi) showed significant activity for these selected tumors, especially with homologous recombination repair (HRR) deficiency. These alterations could also predict platinum sensitivity. Although carboplatin was inconclusive in unselected mCRPC, the literature suggests an anti-tumoral activity in mCRPC with HHR gene alterations. We aimed to assess the efficacy of carboplatin monotherapy in mCRPC patients with HRR deficiency. This prospective multicenter single-arm two-stage phase II addressed mCRPC men with HRR somatic and/or germline alterations, pretreated with ⩾2 taxane chemotherapy regimens and one androgen receptor pathway inhibitor. Prior PARPi treatment was allowed. Enrolled patients received intravenous carboplatin (AUC5) every 21 days for 6-9 cycles. The primary endpoint was the best response rate according to adapted PCWG3 guidelines: radiological response (RECIST 1.1 criteria) and/or biological response [⩾50% prostate-specific antigen (PSA) decline]. A total of 15 out of 16 enrolled patients started carboplatin treatment. Genomic alterations were identified for BRCA2 (n = 5), CDK12 (n = 3), ATM (n = 3) CHEK2 (n = 2), CHEK1 (n = 1), and BRCA1 (n = 1) genes. Objective response (partial biological response + stable radiological response) was achieved in one patient (6.7%), carrying a BRCA2 mutation and not pre-treated with PARPi; stable disease was observed for five patients (33.5%). Among seven patients (46.7%) with previous PARPi treatment, four patients (57.1%) had a stable disease. The median progression-free and overall survivals were 1.9 [95% confidence interval (95% CI), 1.8-9.5] and 8.6 months (95% CI, 4.3-19.5), respectively. The most common severe (grade 3-4) treatment-related toxicities were thrombocytopenia (66.7%), anemia (66.7%), and nausea (60%). Overall, 8 (53.3%) patients experienced a severe hematological event. The study was prematurely stopped as pre-planned considering the limited activity of carboplatin monotherapy in heavily pre-treated, HHR-deficient mCRPC patients. Larger experience is needed in mCRPC with BRCA alterations. NCT03652493, EudraCT ID number 2017-004764-35.

Development of PARP inhibitors in advanced prostate cancer.

The relatively high prevalence of alterations in the homologous recombination repair (HRR) pathway described in advanced prostate cancer provides a unique opportunity to develop therapeutic strategies that take advantage of the decreased tumor ability to repair DNA damage. Poly ADP-ribose polymerase (PARP) inhibitors have been demonstrated to improve the outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients with HRR defects, particularly in those with BRCA1/2 alterations. To expand the benefit of PARPi to patients without detectable HRR alterations, multiple studies are addressing potential synergies between PARP inhibition (PARPi) and androgen receptor pathway inhibitors (ARSi), radiation, radioligand therapy, chemotherapy, or immunotherapy, and these strategies are also being evaluated in the hormone-sensitive setting. In this review, we summarize the development of PARPi in prostate cancer, the potential synergies, and combinations being investigated as well as the future directions of PARPi for the management of the disease.

Multiparametric bone MRI targeting aides lesion selection for CT-guided sclerotic bone biopsies in metastatic castrate resistant prostate cancer

BackgroundBone biopsies in metastatic castrate-resistant prostate cancer (mCRPC) patients can be challenging. This study’s objective was to prospectively validate a multiparametric bone MRI (mpBMRI) algorithm to facilitate target lesion selection in mCRPC patients with sclerotic bone disease for subsequent CT-guided bone biopsies.Methods20 CT-guided bone biopsies were prospectively performed between 02/2021 and 11/2021 in 17 mCRPC patients with only sclerotic bone disease. Biopsy targets were selected based on MRI, including diffusion-weighted (DWI) and T1-weighted VIBE Dixon MR images, allowing for calculation of the apparent diffusion coefficient (ADC) and the relative fat-fraction (rFF), respectively. Bone marrow with high DWI signal, ADC < 1100 µm2/s and rFF < 20% was the preferred biopsy target. Tumor content and NGS-feasibility was assessed by a pathologist. Prognostic routine laboratory blood parameters, target lesion size, biopsy tract length, visual CT density, means of HU, ADC and rFF were compared between successful and unsuccessful biopsies (p < 0.05 = significant).ResultsOverall, 17/20 (85%) biopsies were tumor-positive and next-generation genomic sequencing (NGS) was feasible in 13/18 (72%) evaluated samples. Neither laboratory parameters, diameter, tract length nor visual CT density grading showed significant differences between a positive versus negative or NGS feasible versus non-feasible biopsy results (each p > 0.137). Lesion mean HU was 387 ± 187 HU in NGS feasible and 493 ± 218 HU in non-feasible biopsies (p = 0.521). For targets fulfilling all MRI selection algorithm criteria, 13/14 (93%) biopsies were tumor-positive and 10/12 (83%) provided NGS adequate tissue.ConclusionsMultiparametric bone MRI can facilitate target lesion selection for subsequent CT-guided bone biopsy in mCPRC patients with sclerotic metastases.Trial registrationCommittee for Clinical Research of the Royal Marsden Hospital registration number SE1220.

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH).

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival.

Stereotactic body radiation therapy to postpone systemic therapy escalation for castration-resistant prostate cancer: A multicenter retrospective analysis

PurposeTo evaluate the oncological outcome after stereotactic body radiation therapy (SBRT) for oligoprogressive metastatic castration-resistant prostate cancer (omCRPC) patients. Materials-MethodsIn this retrospective, observational, multi-institutional study, omCRPC patients (≤5 metastases) underwent SBRT. Primary endpoint was systemic therapy escalation-free survival (STE-FS) after SBRT. Local relapse (LR), distant (DP) and isolated biochemical (iBP) progressions were reported with progression-free survival (PFS) and overall survival (OS). Prognostic factors for STE-FS were investigated. Toxicity was reported. ResultsFrom 01/07 to 09/19, 50 pts with omCRPC underwent SBRT. With a MFU of 23 months [3–––100], median STE-FS was 13.1 months (95 %CI 10.8 – 36.4). Median OS was not reached and PFS was 13 months (CI95% 10.1 – 20.8). Post-SBRT PSA remained stable or decreased in 19 pts (38 %). Progression events (LR, DP, iBP) were observed in 34 pts (68 %), among whom 6 relapsed in the irradiated area (local control rate: 88 %). DP and iBP were observed in 28 pts (56 %) and 4 pts (8 %) respectively. In multivariate analysis, post-SBRT biochemical response was an independent prognostic factor for STE-FS. Grade ≥ 3 toxicity occurred in 2 pts. ConclusionWith excellent local control and tolerance, SBRT for omCRPC patients represents an acceptable approach to defer systemic therapeutic escalation and prevent its side effects. Accurate patient selection for SBRT requires more data with longer follow-up and higher numbers of patients pending the results of upcoming randomized trials.