Resistant Prostate Cancer Patients Research Articles

Abiraterone, Olaparib, or Abiraterone + Olaparib in First-line Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects (BRCAAway).

Deleterious germline/somatic homologous recombination-repair mutations (HRRm) are present in ~25% of metastatic castration resistant prostate cancer (mCRPC) patients. Preclinically, PARP-Inhibition demonstrated synergism with ARP-targeted therapy. This trial evaluated efficacy of ARP-Inhibitor versus PARP-Inhibitor versus combination as first-line therapy in mCRPC patients with HRRm. BRCAAway is a biomarker pre-selected, randomized, phase-2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: Abiraterone (1000mg)/prednisone (Abi/pred) (5mg), Arm2: Olaparib (Ola) (300mg), or Arm3: Abiraterone/prednisone + Olaparib (Abi/pred+Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRm received Olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety. 61/165 eligible patients had BRCA1/2 or ATM mutations: Median age: 67 (IQR 62-73) years. Mutations: BRCA1 n=3, BRCA2 n=46, ATM n=11, multiple n= 1; 33 germline, 28 somatic. Median PFS (95% CI): Abi/pred, 8.6 months (m) (2.9, 17), Ola, 14 m (8.4, 20), Abi/pred+Ola, 39 m (22, NR). There were no G4/5 AEs. 8/19 on Abi/pred crossed over to Ola, and 8/21 vice versa: Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15); Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25), Abi/pred-after-Ola, 16 m (11, NR). 17/165 patients with other HRRm received olaparib: Median PFS (95% CI): 5.5 m (2, 11). In mCRPC patients with BRCA1/2 or ATM HRRm, abiraterone/prednisone + olaparib was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.

Genetic analysis of metastatic castration resistant prostate cancer patients treated with Lu-177 PSMA radioligand therapy.

Genetic analysis of metastatic castration resistant prostate cancer patients treated with Lu-177 PSMA radioligand therapy.

Hematological and renal toxicity in mice after three cycles of high activity [177Lu]Lu-PSMA-617 with or without human α1-microglobulin

Radioligand therapy with [177Lu]Lu-PSMA-617 can be used to prolong life and reduce tumor burden in terminally ill castration resistant prostate cancer patients. Still, accumulation in healthy tissue limits the activity that can be administered. Therefore, fractionated therapy is used to lower toxicity. However, there might be a need to reduce toxicity even further with e.g. radioprotectors. The aim of this study was to (i). establish a preclinical mouse model with fractionated high activity therapy of three consecutive doses of 200 MBq [177Lu]Lu-PSMA-617 in which we aimed to (ii). achieve measurable hematotoxicity and nephrotoxicity and to (iii). analyze the potential protective effect of co-injecting recombinant α1-microglobulin (rA1M), a human antioxidant previously shown to have radioprotective effects. In both groups, three cycles resulted in increased albuminuria for each cycle, with large individual variation. Another marker of kidney injury, serum blood urea nitrogen (BUN), was only significantly increased compared to control animals after the third cycle. The number of white and red blood cells decreased significantly and did not reach the levels of control animals during the experiment. rA1M did reduce absorbed dose to kidney but did not show significant protection here, but future studies are warranted due to the recent clinical studies showing a significant renoprotective effect in patients.

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.

Abstract 6563: PSMA-based detection and global proteome-based analysis of circulating tumor cells in castration resistant prostate cancer patients

Abstract In recent years, many new targeted and immuno-therapies have entered the cancer treatment landscape with the potential to drastically improve patient outcomes; however, selecting the optimal drug target especially as the disease progresses becomes increasingly important. Liquid biopsies show great promise in providing insights on the current disease state, but generally rely on a small number of protein markers identified through immunofluorescence staining or genomic mutations determined from cell-free DNA which limits the amount of information available to make treatment decisions. One way to better select the optimal drug target is to generate unbiased mass-spectrometry based proteomic data from the circulating tumor cells (CTCs) isolated from blood. In this study, we collaborated with Astrin Biosciences using their patented isolation technology to enrich CTCs with high purity from the blood of 57 metastatic castration resistant prostate cancer (mCRPC) patients. The CTC-enriched sample (along with a patient-matched control sample consisting primarily of white blood cells) was analyzed in real time for either PSMA protein (Lutetium-PSMA-617 study, n=32) or via mass-spectrometry (CTC proteomics study, n=25). Over 1,500 peptides corresponding to greater than 600 proteins were identified from each patient’s CTCs. These included increased epithelial cell markers in the CTC-enriched sample and increased WBC markers in the control sample. Specifically, detection of the androgen receptor protein was identified in the CTC-enriched sample which is of particular interest in mCRPC patients. Furthermore, this method is able to detect and quantify PSMA expression, which is of clear relevance in the context of PSMA-directed therapeutics. This study demonstrates the feasibility of obtaining large scale proteomic data from a liquid biopsy. Future studies will focus on cancer signaling mechanisms and biomarkers to elucidate the clinical utility of such data. As more patients are analyzed, we will compare proteomic data with known tissue proteome information when available and to correlate these with drug response to improve treatment selection and patient outcomes. Citation Format: Justin M. Drake, Ali Arafa, Alec Horrmann, Kaylee J. Kamalanathan, Catalina Galeano-Garces, Zoi Sychev, Nicholas Heller, Mahdi Ahmadi, Megan Ludwig, Olivia Hedeen, Alexa Hesch, Grant Schaap, Joel Hapke, Jeff Miller, Ivo Babris, Tuan Lee, Tony Clacko, Justin Hwang, Jiarong Hong, Badri Konety, Jayant Parthasarathy, Emmanuel Antonarakis. PSMA-based detection and global proteome-based analysis of circulating tumor cells in castration resistant prostate cancer patients [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 6563.

Abstract 5967: Blockade of Wnt5A/ROR1 signaling as cancer stem cell targeting therapy for metastatic prostate cancer

Abstract BACKGROUND– Wnt5A and its non-canonical Wnt receptor, ROR1, have emerged as a promising new signaling pathway target for lethal, metastatic prostate cancer. Wnt5A has emerged as a significant marker of poor prognosis in circulating tumor cells (CTCs) of metastatic castration resistant prostate cancer (mCRPC) patients. ROR1 is expressed in lethal types of mCRPC, especially neuroendocrine prostate cancer (NEPC). A therapeutic ROR1 antibody, Zilovertamab, has been clinically tested in chronic lymphocytic leukemia (CLL) and metastatic breast cancer and shown to be safe. We sought to investigate Zilovertamab-based therapies for metastatic prostate cancer in pre-clinical model systems. HYPOTHESIS – Wnt5A/ROR1 signaling may mediate a cancer stem cell program which makes cells resistant to therapies which target the cell cycle and proliferation. Blocking ROR1 may reveal vulnerabilities which sensitize cancer cells to chemotherapies like docetaxel. METHODS– ROR1 expression was determined using RNASeq, qRT-PCR, FACS, IHC and Western blotting. ROR1 signaling was blocked using the anti-ROR1 therapeutic antibody, Zilovertamab, or CRISPRCas9 ROR1 knock out. Cell growth was measured using an Incucyte real time imaging system. Stem cell activity was assessed in 3D organoids. Cell cycle analysis was performed in live cells in 2D cultures and 3D organoids using the Fucci2BL bicistronic Fluorescent, Ubiquitination-based Cell Cycle Indicator reporter system. PDX PCSD13 tumor growth was measured via calipers and IVIS. RNASeq was performed on tumors. RESULTS– We showed that ROR1 was expressed at high levels in mCRPC cell lines: PC3, DU145, and in the bone metastatic prostate cancer PDX: PCSD13. CRISPR/Cas9 Knock out of ROR1 in PC3 and DU145 cells showed increased sensitivity to docetaxel inhibition of proliferation in vitro in 2D real time Incucyte proliferation assays and in 3D organoids. Organoid formation was significantly reduced in ROR1 KO cells. Cells expressing the FUCCI live cell cycle tracker showed docetaxel led to G2 arrest and ROR1 signaling inhibition increased efficacy of docetaxel induced cell cycle arrest. Treatment of PCSD13 PDX in vivo with Zilovertamab plus docetaxel synergistically increased tumor growth inhibition in vivo and modulated cancer stem cell and cell cycle expression profiles. CONCLUSIONS– Cancer stem cells represent the fundamental precursors from which all diverse tumor subpopulations evolve. Thus, therapeutic targeting of these tumor initiating stem/progenitor cells may prevent the evolutionary diversification of a tumor and overcome a critical clinical barrier to cancer treatment. We showed synergistic response in our PDX and PCs cell line models to Zilovertamab plus docetaxel. We are now conducting a phase 1b clinical trial with zilovertamab plus docetaxel in patients with metastatic CRPC (CirmD, NCT05156905, PI R Mckay). Citation Format: Christina A.M. Jamieson, Jamillah Murtadha, Christopher S. Oh, Michelle T. Muldong, Niloofar Etemadfard, Evodie Koutouan, Young E. Yoon, Sanghee Lee, Oh Kwon, Jong J. Oh, Min S. Kim, Karl Willert, Nicholas A. Cacalano, Catriona H.M. Jamieson, Terry Gaasterland, Rana R. Mckay, Christopher J. Kane, Anna A. Kulidjian, Charles E. Prussak. Blockade of Wnt5A/ROR1 signaling as cancer stem cell targeting therapy for metastatic prostate cancer [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 5967.

Abstract 5359: Targeted engineering mRNA 3′UTR length enhances immunotherapy response in prostate cancer

Abstract Background: Global mRNA 3′untranslated region (3′UTR) shortening through alternative polyadenylation (APA) has been widely observed in most cancers; however, it has not been demonstrated whether targeted interference of specific oncogenic mRNA 3′UTR lengths can inhibit tumor growth and potentiate immunotherapy response in prostate cancer. Methods: DaPars algorithm was applied for de novo identification of dynamic alternative polyadenylation (APA) during prostate cancer progression to the lethal phase; 3′UTR polyadenylation site (PAS) locations and usages were identified by Poly(A)-ClickSeq (PAC-seq) and 3′RACE; APA transcripts were quantified by RHAPA assay; a 3′UTR CRISPR/dCas13 Engineering System (3′UTRCES) was developed to manipulate the length of desired 3′UTRs; RIP-qPCR and PAR-CLIP-qPCR assays were used to determine the mechanistic basis of 3′UTRCES in APA editing; RNA-seq was utilized to evaluate the off-target effects; TT3 Lipid-like nanoparticles (LLN) were applied for intratumoral delivery of 3′UTRCES RNA molecules for targeted 3′UTR therapy. Quantitative proteomics and immunoprecipitation assays were conducted to investigate how major histocompatibility complex class I (MHC-I) substrates were recognized by SPSB1-containing ubiquitin ligase complex for degradation; Flow cytometry and T cell cytotoxicity assays were performed to evaluate MHC-I level and killing of tumor cells by antigen-stimulated CD8+ T cells. Results: 3′UTR globally shortens during prostate cancer progression to castration-resistance. Through blocking the proximal PASs, 3′UTRCES efficiently and specifically reverses the 3′UTR shortening of novel APA-linked, clinically-relevant prostate cancer oncogenic mRNAs, such as SPSB1, leading to reduced SPSB1 mRNA translation and prostate cancer cell proliferation. Intratumoral injection of TT3 LLN encapsulating 3′UTRCES RNA molecules effectively and safely inhibits prostate tumor growth in engrafted and transgenic mouse models. Notably, downregulation of SPSB1 protein by 3′UTRCES disrupts the interactions of SPSB1-containing ubiquitin ligase complex, leading to compromised ubiquitination-mediated MHC-I degradation and increased stability and abundance of MHC-I protein. Consistently, 3′UTRCES enhances MHC-I-regulated antigen presentation and thereby augments CD8+ T cell-mediated cytotoxicity, which suggest the potentials of 3′UTRCES to sensitize prostate cancer to immune checkpoint therapies. Importantly, 3′UTR shortening of SPSB1 mRNA is significantly associated with decreased MHC-I expression, reduced cytotoxic T-cell infiltration and activation in castration resistant prostate cancer patients. Conclusions: Our results establish the concept of “3′UTR targeted therapy” for treatment of prostate cancer with broad applications to other cancers and other 3′UTR-related diseases. Citation Format: Furong Huang, Fuwen Yuan, Ya Cui, Lei Li, Kexin Li, Zhifen Cui, Jingyue Yan, Qiang Chen, Christopher Nicchitta, Wenbin Ye, Yuebao Zhang, William Hankey, Jeffrey Everitt, Ming Chen, Jiaoti Huang, Hongyan Wang, Xin Lu, Eric Wagner, Yizhou Dong, Wei Li, Qianben Wang. Targeted engineering mRNA 3′UTR length enhances immunotherapy response in prostate cancer [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 5359.

Combined Cabazitaxel and Carboplatin Treatment of Metastatic Castration Resistant Prostate Cancer Patients, With Innate or Acquired Resistance to Cabazitaxel Monotherapy

BackgroundThere is new interest in platinum-based treatment of patients with metastatic castration resistant prostate cancer (mCRPC), to which a subgroup responds. Although platinum sensitivity is suggested to be associated with aggressive disease features and distinct molecular profiles, identification of responders is a clinical challenge. In this study, we selected patients who displayed PSA progression during cabazitaxel monotherapy, for combined cabazitaxel and carboplatin treatment. MethodsIn this retrospective study, mCRPC patients received carboplatin and cabazitaxel after biochemical progression following at least 2 cabazitaxel monotherapy cycles. We assessed PSA response, Time to PSA Progression (TTpsa) and Time to Radiographic Progression (TTrad). For a subset of patients, mutational analysis of BRCA-1, BRCA-2, ATM, PTEN, P53 and RB1 was performed. ResultsForty-five patients were included, after a median of 4 (3-6) cycles of cabazitaxel monotherapy. Patients received a median of 3 (2-5) cycles of combined cabazitaxel and carboplatin, on which 12 (26.6%) patients had a PSA decline ≥ 50% from baseline. TTpsa was 2 (1-5) months and TTrad 3 (2-6) months. Adverse events were predominantly grade 1-2. Of the 29 (64.4%) patients evaluable for molecular signature, 6 (13.3%) had BRCA1, BRCA2 or ATM mutations and 12 (26.7%) had a PTEN, P53 or RB1 mutations. The occurrence of these mutations was not associated with any clinical outcome measure. ConclusionsIn this study we showed that patients with PSA progression during cabazitaxel monotherapy could benefit from the addition of carboplatin to cabazitaxel, while prospective identification of these patients remains a clinical challenge.

P091 - Biochemical response and overall survival rate among castrate resistant prostate cancer patients treated with docetaxel

P091 - Biochemical response and overall survival rate among castrate resistant prostate cancer patients treated with docetaxel

Natural killer cell activity in metastatic castration resistant prostate cancer patients treated with enzalutamide

Metastatic castration resistant prostate cancer (mCRPC) is still the lethal stage for the whole spectrum of prostate cancer disease. Even though different treatment options have been introduced in the last decade with a significant survival improvement for this population, a lack of more reliable prognostic and predictive markers is still one of the main clinical challenges in management of mCRPC. The aim of this study was to investigate the correlation between Natural Killer cell activity (NKA) and both treatment effect and outcomes in patients with mCRPC treated with enzalutamide. A total of 87 patients with mCRPC treated with enzalutamide as the first line treatment were enrolled. NKA was estimated at baseline and prior to each treatment cycle. Endpoints included both treatment effect with biochemical response (BR), biochemical progression (BP) and radiological progression (RP), as well as outcome data with overall survival (OS), radiologic progression free survival (rPFS), and time to next treatment (TTT). At the time of BR, interferon-gamma (IFNγ) decreased significantly compared to levels detected at baseline (z-score = 2.33, p = 0.019). Regarding outcome data, the whole cohort was divided into four groups according to the change of IFNγ level during the first 3 cycles of enzalutamide treatment. In group 1 (n = 42) the IFNγ level remained within a normal range (≥ 250 pg/mL),while in group 2 (n = 7) it increased from an abnormal (< 250 pg/mL) to a normal level. In group 3 (n = 13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n = 17). Patients in group 2 showed the worst prognosis with shorter both rPFS and TTT (HR 4.30, p = 0.037; and HR 6.82, p = 0.011, respectively). In this study inverse correlations between NKA and both treatment response and outcomes was observed in mCRPC patients receiving enzalutamide, suggesting an unfavourable role of NK cells in the late stage of PCa.

Analysis of DNA damage using the comet assay method in metastatic castration resistant prostate cancer patients receiving 177Lu-PSMA-617 radioligand therapy

Analysis of DNA damage using the comet assay method in metastatic castration resistant prostate cancer patients receiving 177Lu-PSMA-617 radioligand therapy

C reactive protein/Albumin ratio as predictor of prognosis in castration resistant metastatic prostate cancer.

To assess the association of C reactive protein/Albumin ratio (CAR) with progression free survival (PFS) and overall survival (OS) in castration resistant metastatic prostate cancer (mCRPC) patients. A transversal study was conducted, including all patients diagnosed with mCRPC within a Central Hospital Urological Oncology consultation between December 2019 and December 2021 (n = 178) and that were submitted to systemic therapy. CRP and albumin results were collected at the beginning of the systemic treatment for mCRPC in 103 patients and, in 75 patients already under treatment at the start of the study, on that occasion (December 2019). All patients were then followed. CAR was correlated with PFS and OS. OS and PFS were measured from the day the CRP and Alb were collected until the event of interest or the final date of follow-up. The sample was divided in two groups according to an optimal cutoff point found in a ROC curve. The sample showed a median age of 75.76 ± 9.17 years old. Using a cut-off point of 0.22, patients with a CAR ≤ 0.22 (63.2%) showed, compared to CAR > 0.22, longer PFS (15.92 vs. 9.46 months, r = -0.13, p < 0.05) and OS (p = < 0.05, 25,72 vs. 15.79 months, r = -0,24, p < 0.05). Better OS in patients with CAR ≤ 0.22 vs > 0.22 was detected on both the group evaluated at the beginning of systemic treatment (26.96 vs 17.63 months, p < 0.05) and the group of patients already under treatment (23.90 vs 11.54 months, p < 0.05). Dividing the sample according to the first line treatment chosen, we found OS of 26.25 vs 5.9 months (p < 0.05), 27.71 vs 22.57 months (p < 0.05) and 27.36 vs 23.75 months (p = 0.12), for docetaxel, abiraterone and enzalutamide, respectively. According to this study, higher values of CAR are associated with lower PFS and OS in mCRPC patients. We found a cut-off value of 0.22 providing the best discrimination for prognosis. CAR is a good prognosis biomarker, irrespective of the moment of evaluation and chosen treatment option.

Abstract PR013: Unlocking the proteome of metastatic prostate cancer circulating tumor cells

Abstract In recent years, liquid biopsies have emerged to provide improved insights on the current disease state of a patient, but they generally rely on a small number of protein markers from immunofluorescent staining or cell-free DNA, which provides limited information especially around drug targets. As more targeted therapies and immunotherapies enter the market, selecting the optimal drug target could improve patient outcomes drastically. One way to achieve this goal is to generate multi-omic datasets from the cancer cells in circulation, known as circulating tumor cells (CTCs). In this study, we collaborated with Astrin Biosciences and used their patented isolation technology to enrich CTCs with high purity from the blood of 15 metastatic castration resistant prostate cancer (mCRPC) patients. The enriched CTCs and a patient matched control sample consisting primarily of white blood cells were divided such that RNA and protein could be interrogated from the same patient. Label free unbiased mass spectrometry-based proteomics was used to identify the CTC-enriched proteins and marks the first time a global proteomic assessment has been performed on CTCs from cancer patients. Initial analysis identified over 1,500 peptides corresponding to greater than 500 proteins from each patients’ CTCs; including increased epithelial cell markers in the CTC-enriched sample and increased WBC markers in the control sample. Hallmarks of androgen response and detection of the androgen receptor were also identified in the CTC-enriched proteome. Overall, this study was designed to show the feasibility of obtaining large scale proteomic data from a liquid biopsy and future studies will provide more insight into the clinical utility of such data with a focus on cancer signaling mechanisms and biomarkers. Importantly, as we analyze more patients, we plan to compare the proteomic data with future RNA signatures across mCRPC patients to eventually be able to correlate them with drug response with the overall goal to improve treatment selection and patient outcomes. Citation Format: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee Judith Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy. Unlocking the proteome of metastatic prostate cancer circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR013.

Abstract B024: Nuclear size and nuclear shape instability in prostate cancer epithelial cells during metastatic progression

Abstract Very small nuclear (vsn) circulating tumor cells (CTCs) are detected in a subgroup of metastatic, castration resistant prostate cancer (mCRPC) patients who develop visceral metastasis following intensive androgen receptor suppression. In addition, we have previously observed that nuclear shape instability (characterized by the loss and/or mis-localization of the nuclear envelop protein emerin) is present in human prostate cancer tissues, and in CTCs from patients with metastatic disease. Herein, we investigated the biological and clinical implications of the vsn phenotype in prostate CTCs. Patients with vsnCTCs had poor overall survival and low PSA response to androgen receptor suppression compared with non-vsnCTC patients. The vsnCTCs exhibited a loss/downregulation of emerin (EMD) and we found a direct correlation between emerin loss and nuclear size reduction in CTC from mCRPC patients. Further, in vitro studies revealed that the vsn phenotype was characterized by high invasive capacity, enhanced cellular plasticity, and resistance to AR target therapy. Finally, depletion of EMD in prostate tumor cells resulted in the vsn phenotype. Together, these findings demonstrate that the vsnCTC phenotype is characterized by deregulation of EMD expression, and the presence of these cells result in poor clinical outcomes in prostate cancer. Citation Format: Karen Cavassani, Edwin Posadas, Pai-Chi Teng, Sadaf Pustchi Pustchi, Minhyung Kim, Neil Bhowmick, Sungyong You, Michael Freeman, Leigh Ellis, Dolores Di Vizio, Hsian-Rong Tseng, Leland W. Chung, Susan Yao, Catherine Grasso. Nuclear size and nuclear shape instability in prostate cancer epithelial cells during metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B024.

Use of poly (adp-ribose) polymerase inhibitors (PARPi) in metastatic castration resistant prostate cancer (mCRPC) patients stratified by homologous recombination repair mutations.

e17053 Background: Approval of the PARPi in May 2020 caused a paradigm shift in the treatment of mCRPC patients with homologous recombination repair (HRR) mutations. Gaps remain in the optimal prescribing of PARPi in eligible patients, with negative consequences on clinical outcomes. The goal of this study was to look at PARPi prescribing practices in patients with HRR mutations overall and by sub-mutation. Methods: The Integra Connect PQ-deidentified real-world database was used, comprising over 1 million cancer patients across 275 sites of care, of which 80% were community practices and 20% academic settings. We performed medical chart reviews and identified 261 patients with HRRm mCRPC that received therapy between 5/1/2020 to 1/24/2023. We segmented patients into BRCA-positive with or without other HRR mutations, ATM positive without BRCA mutations and with or without other HRR mutations, and other HRR mutations without BRCA or ATM mutations. We compared utilization of PARPi in HRRm patients by sub-group. Descriptive statistics were used to assess proportions of utilization of PARPi treatment among HRRm patients. Proportions were compared using the two-proportion z-test. Results: Among HRRm mCRPC patients with prior next-generation hormonal agent (NHA) treatment, the use of PARPi is 61% (158 of 261). Among HRRm mCRPC patients who received PARPi after prior NHA treatment, 76% (78 of 103) were in the BRCA positive group, 62% (48 of 78) in the ATM positive group and 40% (32 of 80) in the other HRR mutations positive group. Patients in the BRCA positive group were more likely to receive a PARPi than those in either the ATM or other HRR mutations group (p &lt; 0.01). Patients harboring ATM mutations were more likely to receive a PARPi than patients with non-BRCA HRR mutations (p &lt; 0.01). Conclusions: This real-world study shows an opportunity to increase rates of PARPi treatment in patients with HRRm mCRPC across all HRR gene mutations. mCRPC patients with BRCA and ATM mutations were more likely to receive PARPi than those with other HRR mutations.

Prevalence of intra-patient inter-metastatic heterogeneity in mCRPC patients based on triple-tracer PET imaging: The 3TMPO study.

5033 Background: Intra-patient inter-metastatic heterogeneity (IIH) has been demonstrated in metastatic castration resistant prostate cancer (mCRPC) patients based on genomic and imaging studies, most often after several lines of therapies. IIH is of utmost importance for PSMA radioligand therapy (RLT) eligibility, biopsy-based precision medicine and/or treatment intensification decision-making. The Triple-Tracer strategy against Metastatic PrOstate cancer (3TMPO) study (NCT04000776) is a prospective multicenter PET imaging study that was designed to determine the prevalence of IIH in mCRPC patients and to determine candidacy for RLT. Methods: 3TMPO is a PET-imaging trial including mCRPC patients showing at least 3 metastases on conventional imaging with evidence of biochemical or radiographic progression, at least 3 months after initiation of the last systemic therapy. 68Ga-PSMA-617 and 18F-FDG PET/CT scans were performed within 10 days and analyzed quantitatively. A third scan with 68Ga-Octreotate was done when a PSMA-/FDG+ lesion was found. For all tracers, positivity of a lesion was defined as its SUVpeak being 1.5 times higher than the SUVmean of the liver. Lesions smaller than 1 cc and likely benign foci of uptake were excluded. IIH prevalence was the primary outcome, defined as the percentage of patients having at least two lesions with discordant features on PET imaging. Results: We included 98 patients in the final analysis. Patients had a mean age of 69 years and a median PSA of 51.1 ng/mL. Number of metastases were &lt;5 in 46.9% and ≥10 in 33.7% of patients and 10.2, 20.4, 18.4 and 51.0% had received 0, 1, 2 or &gt;2 lines of systemic therapies for mCRPC, respectively. Prevalence of IIH was 83.7% based on pre-specified PET criteria. Overall, seven different combinations of lesion phenotypes were found among patients based on FDG and PSMA PETs, and at least one PSMA-/FDG+ lesion was found in 46 patients (46.9%). Of the 44 patients who underwent Octreotate PET, six (13.6%) had at least one Octreotate-positive lesion. In this FDG/PSMA/Octreotate-imaged subgroup, 11 different combinations of phenotypes were observed between metastases of individual patients. Overall, 52.0% (IC95: 41.7-62.2) of patients were found to be candidate for PSMA RLT, but none for Octreotate RLT. Conclusions: The majority of mCRPC patients showed IIH. Based on a multi-tracer approach, up to 11 lesion phenotype combinations were found amongst patients. Correlation of these imaging phenotypes with genomics and treatment response will be highly relevant for optimized precision medicine, especially with respect to PSMA-RLT. Clinical trial information: NCT04000776 . [Table: see text]

A Retrospective Multicenter Analysis of the Incidence of Bone-Only Disease at PSMA PET/CT in Castration Resistant Prostate Cancer Patients.

PSMA PET/CT has unprecedented accuracy for localization of initial or recurrent prostate cancer (PC), which can be applied in a metastasis-directed therapy approach. PSMA PET/CT (PET) also has a role in the selection of patients for metastasis-directed therapy or radioligand therapy and therapy assessment in CRPC patients. The purpose of this multicenter retrospective study was to determine the incidence of bone-only metastasis in CRPC patients who underwent PSMA PET/CT for restaging, as well as identifying potential predictors of bone-only PET positivity. The study analyzed data from 179 patients from two centers in Essen and Bologna. Results showed that 20.1% of the patients had PSMA uptake only in the bone, with the most frequent lesions located in the vertebrae, ribs, and hip bone. Half half of the patients showed oligo disease in bone and may benefit from a bone-metastasis-directed therapy. Initial positive nodal status and solitary ADT were shown to be negative predictors of osseous metastasis. The role of PSMA PET/TC in this patient population needs to be further explored in terms of its role in the evaluation and adoption of bone-specific therapies.

Abstract 2309: Unlocking the proteome of metastatic prostate cancer circulating tumor cells

Abstract In recent years, liquid biopsies have emerged to provide improved insights on the current disease state of a patient, but they generally rely on a small number of protein markers from immunofluorescent staining or cell-free DNA, which provides limited information especially around drug targets. As more targeted and immune therapies enter the market, selecting the optimal drug target could improve patient outcomes drastically. One way to achieve this goal is to generate multi-omic datasets from the cancer cells in circulation, known as circulating tumor cells (CTCs). In this study, Astrin Biosciences’ patented isolation technology was used to enrich CTCs with high purity from the blood of metastatic castration resistant prostate cancer (mCRPC) patients. The enriched CTCs and a patient matched control sample consisting primarily of white blood cells were divided such that RNA and protein could be interrogated from the same patient. Label free unbiased mass spectrometry was used to identify proteins and marks the first time a global proteomic assessment has been performed in CTCs from cancer patients. Initial analysis identified over 1,500 peptides corresponding to greater than 500 proteins with increased epithelial cell markers in the CTC-enriched sample and increased WBC markers in the control sample. Hallmarks of androgen response and detection of the androgen receptor were also identified in the CTC proteome. In addition to the proteome, RNA sequencing will also be performed to generate a multi-omic platform to detect cancer signaling mechanisms and biomarkers. Overall, this study was designed to show the feasibility of obtaining multi-omic data from a liquid biopsy and future studies will provide more insight into the clinical utility of such data. As we analyze more patients, we plan to compare the protein and RNA signatures across mCRPC patients and eventually be able to map patient outcomes and correlate them with drug response with the overall goal to improve treatment selection and patient outcomes. Citation Format: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee J. Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy. Unlocking the proteome of metastatic prostate cancer circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2309.

Abstract 4400: Machine learning (ML) on real-world data (RWD) of front-line (1L) metastatic castration resistance prostate cancer (mCRPC) patients for dynamic prediction of time to tx discontinuation (TTD)

Abstract 4400: Machine learning (ML) on real-world data (RWD) of front-line (1L) metastatic castration resistance prostate cancer (mCRPC) patients for dynamic prediction of time to tx discontinuation (TTD)

Radium– 223 Dichloride Related Toxicity in Post – Chemotherapy Castrate Resistant Prostate Cancer Patients Treated for Bone Metastases

Background: Radiation pharmacokinetics and pharmacodynamics of Radium point to bone as its site of primary uptake and action. It is therefore very important to investigate the hematological and other toxicity of the radiopharmaceutical Radium -223 dichloride in the wake of its introduction for treatment of bone metastases. Methods: Five Patients with post-chemotherapy castrate resistant prostate cancer with bone metastases received 50kBq/ kg body weight of Radium-223 Dichloride injection every 4 weeks for 5 cycles. 1. Screening 2. Treatment (including an End of Treatment Visit) 3. Follow-up Results: The ranges of measured parameters for 4 patients at the end of 5th cycle (20th week) were within normal limits: Hb : Wk 20 = 110 -126g/l, pre-treatment = 110-136g/l (normal range 120-170) Wbc: Wk 20 = 3.3-6.2x109/l, Pre-treatment=3.5-8.9x109/l (normal range 4.5-10) Platelets: Wk 20 = 156-241x109/l, pre-treatment = 206-302x109/l (normal range 150-400). Alkaline Phosphatase: Wk 20 = 43-128IU/l, Pre-treatment = 57-253IU/l (normal Range 40-120). The 5th Patient developed bone marrow failure in the 12th week, with concurrent flaring of his alkaline phosphatase value. Conclusion: The results of this study suggest that Radium-223 dichloride at dose of 50kbq/kg is safe for palliative treatment of bone pains in metastatic bone diseases. The 5th patient’s bone marrow failure cause may be attributed to several factors such as 1. Direct effect of the drug on bone tissues 2. Drug induced allergic response 3. myelosuppression worsened by concomitant radiotherapy