Multi-gene mutation metastatic castrate-resistant prostate cancer

2021 ◽  
Vol 14 (7) ◽  
pp. e243124
Author(s):  
Joshua Christy ◽  
Emad Kandah ◽  
Kavitha Kesari ◽  
Trevor Singh
Keyword(s):  
Prostate Cancer ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Gene Panel ◽  
Sequencing Analysis ◽  
Dna Mutations ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Gene Panel Sequencing ◽  
Panel Sequencing

Gene panel sequencing of metastatic castrate-resistant prostate cancer (mCRPC) can assist in identifying appropriate targeted therapies. Although some studies have reported single DNA mutations, this is the first case of mCRPC with five different DNA mutations based on gene panel analysis. The patient, a 75-year-old man, initially presented with haematuria. Laboratory investigation revealed elevated prostate-specific antigen levels, and CT showed an enlarged prostate gland with metastatic lymph nodes. A 12-core biopsy revealed adenocarcinoma of the prostate. Gene panel sequencing demonstrated five different DNA mutations associated with sensitivities to olaparib and pembrolizumab. Treatment failure after hormonal therapy with leuprorelin and bicalutamide resulted in the initiation of chemotherapy with docetaxel. Over the past decade, development of genome sequencing analysis may guide us with more precise targeted therapy specific to mCRPC early on, especially with poly (ADP-ribose) polymerase inhibitors may show survival benefits.

Biomarker development trial of satraplatin in patients with metastatic castrate-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 170-170
Author(s):  
Bobby Chi-Hung Liaw ◽  
Sonia Maria Seng ◽  
Matt D. Galsky ◽  
Che-Kai Tsao ◽  
Phillip G. Febbo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Genomic Analysis ◽  
Predictive Biomarkers ◽  
Cytotoxic Agents ◽  
Fourth Generation ◽  
Tissue Samples ◽  
Castrate Resistant Prostate Cancer ◽  
Pre Treatment ◽  
Castrate Resistant

170 Background: While satraplatin, a fourth generation oral platinum analogue, failed to improve overall survival (OS) in an unselected metastatic castrate-resistant prostate cancer (mCRPC) population (Sternberg, JCO 2009), anti-tumor activity was demonstrated, suggesting a “platinum-sensitive” subset of patients. Predictive biomarkers may not only select patients most likely to benefit from novel “targeted” therapies but also from standard (even discarded) cytotoxic agents. Development of predictive biomarkers in mCRPC is hampered by the fact that PC is associated with a long natural history and evolving genetic changes, highlighting the need for immediate pre-treatment metastatic tissue samples for biomarker development. In this trial, we sought to determine the feasibility of obtaining metastatic biopsies in patients with mCRPC treated with satraplatin. Methods: Docetaxel-refractory mCRPC patients underwent image-guided biopsy of metastatic lesions prior to treatment with satraplatin 80 mg/m2 PO on days 1 to 5 of a 35-day cycle and prednisone 5 mg PO twice daily. Biopsy samples are analyzed by whole exome and RNA sequencing, and peripheral blood samples are undergoing transcriptional profiling, to facilitate biomarker development. Results: Thirteen patients were enrolled with a median age of 71 (range: 55 to 80), prostate-specific antigen (PSA) of 82 ng/ml (0.04-3057), and Gleason score 8 (7 to 9). All patients received prior docetaxel, four (31%) had more than or eqaul to two prior chemotherapies, and two (15%) received abiraterone. Drug-related grade 3/4 toxicities included leukopenia (23%), neutropenia (8%), thrombocytopenia (8%), fatigue (8%), renal failure (8%), dysphagia (17%), and diarrhea (8%). A median of four cycles of satraplatin were completed, with declines of serum PSA of greater than or equal to 30% achieved in 4 of 13 patients (31%; 95% CI, 57.3 to 85.4%). Median time to PSA progression was 12.4 weeks (95% CI, 7.2 to 29.7+ weeks). Metastatic pre-treatment biopsies were collected in all study patients; genomic analysis is ongoing. Conclusions: This study confirms that satraplatin has anti-cancer activity in a subset of patients with mCRPC. Trials that require pre-treatment metastatic tumor biopsies are feasible. Analysis of the correlation between molecular signatures and treatment response will be presented at the meeting. Clinical trial information: NCT01289067.

Characteristics and outcome of octogenarian versus young patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) treated with ketoconazole.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 256-256
Author(s):  
Victoria J. Sinibaldi ◽  
Michal Dadon-Nachum ◽  
Maya Gottfried ◽  
Natalie Maimon ◽  
Zamir Dovrish ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Partial Likelihood ◽  
Clinicopathologic Characteristics ◽  
Very Old ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Baseline Characteristics ◽  
Castrate Resistant

256 Background: Standard treatment options for patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) include docetaxel based chemotherapy, abiraterone, and radium 223. Octogenarian pts (age 80 and older) are often considered to be unfit for chemotherapy. However, recommendations for their management is limited by the paucity of clinical trials data in this population. In countries where abiraterone in the pre-chemotherapy setting has not been approved yet, or for pts who can’t afford it, the CYP 17 inhibitor ketoconazole is used as an alternative advanced hormonal tx. We aimed to study baseline characteristics and outcome of octogenarian versus young (age 60 or younger) pts with mCRPC treated with ketoconazole. Methods: We performed an international multicenter retrospective study of pts with mCRPC, who were treated with ketoconazole at four centers across two different countries. We compared baseline characteristics and outcome of octogenarian versus young pts. The effect of very old age on prostate-specific antigen (PSA) response, progression free survival (PFS), and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chi-square test and partial likelihood test from Cox model. Results: Between 2004 and 2013, 35 octogenarians (median age 83) and 33 young pts with (median age 57) mCRPC were treated with ketoconazole. The groups were balanced regarding the following baseline clinicopathologic characteristics: extent of disease (limited-axial skeleton and/or nodal versus extensive-appendicular skeleton and/or visceral), combined gleason score, pre-treatment risk category (Keizman, Oncologist 2012; based on pre-tx neutrophil to lymphocyte ratio/prostate-specific antigen doubling time, and prior response to ADT), pain intensity, ECOG performance status, alkaline phosphatase level, hemoglobin level, PSA level. In octogenarian versus young pts, PSA response (greater than or equal to 50% decline from baseline) was 40% versus 61% (OR 3.5, p=0.04), median PFS 7 versus 8 months (HR 0.91, p=0.44), and median OS 31 versus 36 months (HR 0.66, p=0.31). Conclusions: In very old vs young mCRPC patients treated with ketoconazole, PSA response was lower. Baseline clinicopathologic characteristics, PFS, and OS were not significantly different between the groups.

Sipuleucel-T to modify the B7-H3 immune checkpoint in men with castrate resistant prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 273-273
Author(s):  
Wei Phin Tan ◽  
Gregory John Barton ◽  
Andrew Chang ◽  
Smita Nair ◽  
Brant Allen Inman
Keyword(s):  
Prostate Cancer ◽  
Pearson Correlation ◽  
Costimulatory Molecule ◽  
Specific Antigen ◽  
Additive Model ◽  
Elisa Test ◽  
Biological Information ◽  
Median Serum ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

273 Background: B7-H3 is a T cell costimulatory molecule whose expression correlates with increased prostate cancer stage and mortality. We measured serum B7-H3 (sB7-H3) levels in men undergoing sipuleucel-T (sip-T) immunotherapy for castrate-resistant prostate cancer (CRPC) to determine if sip-T modified B7-H3 levels. Methods: We analyzed 41 banked serum specimens before and after sip-T treatment for CRPC. An ELISA test for sB7-H3 was used to measure serum sB7-H3 levels using a standard curve consisting of B7-H3 fusion protein, and a 4 parameter logistic model fit to back-calculate sB7-H3 levels. Each sample was measured in duplicate and the average of these two measurements used. Generalized additive and segmented regression models were used to model the relationship between sB7-H3 level and time to (and from) sip-T treatment. Results: We found that the sB7-H3 assay had a high degree of reproducibility with a Pearson correlation coefficient of 0.9 between the two measurement occasions. Importantly, sB7-H3 had no correlation with prostate specific antigen (PSA) level, indicating that sB7-H3 was providing incremental biological information not contained in the PSA level. Median PSA before sip-T treatment was 6.2 ng/mL [IQR 3.9-14.7] and median PSA post sip-T treatment was 23.4 ng/mL [IQR 9.8-107.4). Median serum sB7-H3 before sip-T treatment was 24.2 ng/dL [IQR 20.3-27.1] and median serum B7-H3 after sip-T treatment was 23.1 ng/mL [IQR 21.8-26.6]. Using a generalized additive model to measure the level of sB7-H3 from time to sip-T treatment, we found a statistically significant relationship between sB7-H3 levels and sip-T treatment, p=0.038. Using segmented linear regression, we found that sB7-H3 levels increased gradually as CRPC worsened prior to sip-T immunotherapy then, at a mean of 24 days after sip-T initiation, sB7-H3 levels started to fall. Conclusions: We found that sB7-H3 levels increased in men with CRPC and that sip-T treatment reversed this trend. Therefore, sip-T may have a positive immunological effect in CRPC irrespective of PSA change. These results suggest that one potential mechanism of action of sipuleucel-T is the reduction of sB7-H3 production by prostate cancer cells.

TNB585.001: A multicenter, phase 1, open-label, dose-escalation and expansion study of tnb-585, a bispecific T-cell engager targeting PSMA in subjects with metastatic castrate resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5092-TPS5092
Author(s):  
Ben Buelow ◽  
Pranjali Dalvi ◽  
Kevin Dang ◽  
Ashwin Patel ◽  
Kiran Johal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Specific Antigen ◽  
Outpatient Basis ◽  
Open Label ◽  
Psma Pet ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

TPS5092 Background: Prostate cancer (CaP) is the most common cancer in US men. Disseminated CaP invariably progresses to metastatic castrate-resistant prostate cancer (mCRPC). Current treatment options for mCRPC usually lead to therapeutic resistance, and novel therapies are urgently needed. PSMA is a prostate-specific antigen over-expressed on most mCRPC. Antibodies against PSMA have been used to create T-cell engaging bispecific Abs (TCEs) and chimeric antigen receptor T cells, but all such approaches to date induce frequent/severe cytokine release syndrome (CRS). We combined a high-affinity αPSMA moiety with a low-activating αCD3 binder to create TNB-585; in preclinical studies, TNB-585 showed equivalent anti-tumor efficacy but much reduced cytokine secretion compared to PSMA-targeted TCEs with a strongly activating αCD3 domain. TNB-585 also has a full length silenced Fc domain, conferring a 3-week half-life. A phase 1 study investigating the safety, pharmacokinetics (PK), anti-drug antibodies (ADA) and preliminary activity of TNB-585 in patients with mCRPC is ongoing and described. Methods: TNB585.001 (NCT04740034) is an open-label, multi-center study of TNB-585 in patients with mCRPC. The study is divided into escalation (Arm A, N=24) and expansion (Arm B, N=30) arms. Subjects who have received 2 or more prior lines of therapy are eligible. Prior exposure to PSMA-targeted therapy is permitted, as are well-controlled HBV, HCV, and HIV infection; subjects with secondary malignancies that do not interfere with the study may also be enrolled. Other key inclusion/exclusion criteria include EGFR of > 30ml/min and ECOG ≤ 2. TNB-585 is administered as an intravenous infusion every 3 weeks. Subjects must be admitted for 48 hours after their 1st dose; TNB-585 is given on an outpatient basis thereafter. Dose escalation is proceeding in Arm A via single patient cohorts until the onset of toxicity or activity; thereafter subjects enroll using a BOIN design. Arm B will start once the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) has been selected. Subjects will be treated until progression or unacceptable toxicity. In Arm A, occurrence of dose limiting toxicities (DLTs) will drive identification of the MTD (or RP2D) based on the BOIN escalation and de-escalation boundaries (λe of 0.236 and a λd of 0.358). In Arm B accrual will be suspended if more than 33% of subjects experience a DLT event. Adverse events (AEs), laboratory profiles, and vital signs will be assessed throughout the study. AEs are graded according to the NCI CTCAE, version 5.0. The activity endpoints (per PCWG3/RECIST1.1) include overall response rate, PSA50, PSA30, CTC counts, progression free survival and overall survival. The relationship between PSMA expression (via PSMA-PET) and activity will be assessed. Clinical trial information: NCT04740034.

scholarly journals Identification of subgroups of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone plus prednisone at low- vs. high-risk of radiographic progression: An analysis of COU-AA-302

2018 ◽  
Vol 13 (6) ◽  
Author(s):  
Lisa J. Martin ◽  
Shabbir M.H. Alibhai ◽  
Maria Komisarenko ◽  
Narhari Timilshina ◽  
Antonio Finelli
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Proportional Hazards ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Limited Resource ◽  
Abiraterone Acetate ◽  
Cox Proportional Hazards ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Introduction: Radiographic imaging is used to monitor disease progression for men with metastatic castrate-resistant prostate cancer (mCRPC). The optimal frequency of imaging, a costly and limited resource, is not known. Our objective was to identify predictors of radiographic progression to inform the frequency of imaging for men with mCRPC. Methods: We accessed data for men with chemotherapy-naive mCRPC in the abiraterone acetate plus prednisone (AA-P) group of a randomized trial (COU-AA-302) (n=546). We used Cox proportional hazards modelling to identify predictors of time to progression. We divided patients into groups based on the most important predictors and estimated the probability of radiographic progression-free survival (RPFS) at six and 12 months. Results: Baseline disease and change in prostate-specific antigen (PSA) at eight weeks were the strongest determinants of RPFS. The probability of RPFS for men with bone-only disease and a ≥50% fall in PSA was 93% (95% confidence interval [CI] 87–96) at six months and 80% (95% CI 72–86) at 12 months. In contrast, the probability of RPFS for men with bone and soft tissue metastasis and <50% fall in PSA was 55% (95% CI 41–67) at six months and 34% (95% CI 22–47) at 12 months. These findings should be externally validated. Conclusions: Patients with chemotherapy-naive mCRPC treated with first-line AA-P can be divided into groups with significantly different risks of radiographic progression based on a few clinically available variables, suggesting that imaging schedules could be individualized.

scholarly journals Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone

2012 ◽  
Vol 30 (6) ◽  
pp. 637-643 ◽  
Author(s):  
Eleni Efstathiou ◽  
Mark Titus ◽  
Dimitra Tsavachidou ◽  
Vassiliki Tzelepi ◽  
Sijin Wen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Bone Marrow Aspirate ◽  
Specific Antigen ◽  
Abiraterone Acetate ◽  
Open Label ◽  
Clinical Observations ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Tumor Expression

Purpose Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow–infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations. Patients and Methods This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues. Results Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression. Conclusion The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.

scholarly journals Apalutamide in the treatment of castrate-resistant prostate cancer: evidence from clinical trials

2018 ◽  
Vol 10 (12) ◽  
pp. 445-454 ◽  
Author(s):  
Vadim S. Koshkin ◽  
Eric J. Small
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Specific Antigen ◽  
The United States ◽  
Phase Iii ◽  
Metastatic Progression ◽  
Free Survival ◽  
Phase Iii Trials ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Apalutamide (ARN-509) is a second-generation androgen receptor (AR) antagonist that was developed to inhibit AR-mediated prostate cancer cell proliferation. Following the initial promising clinical efficacy results in phase I and II clinical trials of patients with metastatic castrate-resistant prostate cancer (CRPC), apalutamide has been investigated in several phase III trials. Particular interest has focused on the development of effective therapy for the prevention of disease progression in patients with nonmetastatic (nm or M0) CRPC, especially patients who have a rapid prostate-specific antigen (PSA) doubling time that is indicative of shorter bone metastasis-free survival and associated with significant morbidity and mortality. The results from the phase III SPARTAN trial were recently published and reported a significant benefit of apalutamide relative to placebo in patients with nmCRPC and a high risk of metastatic progression. The study noted marked improvement in the primary endpoint of metastasis-free survival as well as several relevant secondary clinical endpoints, including time to symptomatic progression. These results led to the United States Food and Drug Administration (US FDA) approval of apalutamide in the nmCRPC setting in February 2018. This review summarizes the clinical development of apalutamide, culminating with the pivotal SPARTAN trial as well as other phase III trials which may further expand potential indications for this agent in the near future.

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