[18F]Fluorthanatrace - Positron Emission Tomography (FTT-PET) and ctDNA to Predict Response to PARP Inhibitor Therapy in Metastatic Prostate Cancer (mPC)

• 1-(4-(2-Fluoroethoxy)phenyl)-8,9-dihiydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Drug), also known as FTT, [18F]FluorThanatrace, [18F]FTT: \[18F\]fluorthanatrace (FTT) is a positron emitting radiopharmaceutical that is administered as an intravenous (IV) solution via injection at a prescribed dose of 10mCi. A lesser dose may be injected if complete imaging data could be generated.
• FTT-PET/CT (Device): A small intravenous (IV) catheter will be placed in the arm vein according to site's standard practice to allow injection of FTT. Approximately sixty minutes following administration of approximately 10 mCi of the radiotracer FTT, patients will undergo standard body PET/CT imaging.
• EnhanceAR-Seq (Diagnostic test): Patients will undergo approximately 30 mL of peripheral blood sample collection to be used for analysis. For each sample, EnhanceAR-Seq will be performed on each of these samples, with somatic genomic alteration calling performed in plasma cell-free DNA with removal of background non-tumor variants using matched plasma-depleted whole blood germline samples.

Primary outcomes

• Prediction performance of FTT-PET as measured by concordance index (C-index) [At baseline prior to PARPi therapy and post cycle 1 (estimated total time 28 days)]: Prediction performance of FTT-PET in predicting participant response to PARPi therapy will be assessed by concordance index (C-index). The C-index is mathematically calculated as the number of concordant pairs divided by the number of comparable pairs. A C-index of 1 indicates perfect ranking, values close to 0.5 indicate random prediction, and values between 0.5 and 1 suggest some predictive ability (a value below 0.5 can be reversed by switching the response's 0 and 1 labels).
• Prediction performance of FTT-PET as measured by area under the receiver operating characteristic (ROC) curve [At baseline prior to PARPi therapy and post cycle 1 (estimated total time 28 days)]: Prediction performance of FTT-PET in predicting participant response to PARPi therapy will be assessed by the area under the ROC curve. The ROC curve is a graphical plot that illustrates the performance of a model at various threshold settings and the area under the curve (AUC) is a single scalar value between 0 and 1 that summarizes the model performance. A higher AUC value indicates better performance.
• Prediction performance of EnhanceAR-Seq ctDNAas measured by concordance index (C-index) [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), 12 weeks after start of PARPi therapy, and at progression if applicable (estimated total time 6 months)]: Prediction performance of EnhanceAR-Seq ctDNA analysis in predicting participant response to PARPi therapy will be assessed by concordance index (C-index). The C-index is calculated as the number of concordant pairs divided by the number of comparable pairs. A C-index of 1 indicates perfect ranking, values close to 0.5 indicate random prediction, and values between 0.5 and 1 suggest some predictive ability (a value below 0.5 can be reversed by switching the response's 0 and 1 labels).
• Prediction performance of EnhanceAR-Seq ctDNA as measured by area under the receiver operating characteristic (ROC) curve [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), 12 weeks after start of PARPi therapy, and at progression if applicable (estimated total time 6 months)]: Prediction performance of EnhanceAR-Seq ctDNA analysis in predicting participant response to PARPi therapy will be assessed by the area under the ROC curve. The ROC curve is a graphical plot that illustrates the performance of a model at various threshold settings and the area under the curve (AUC) is a single scalar value between 0 and 1 that summarizes the model performance. A higher AUC value indicates better performance.
• Prediction performance of FTT-PET and EnhanceAR-Seq ctDNA collectively as measured by concordance index (C-index) [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), and at progression if applicable (estimated total time 6 months)]: Prediction performance of FTT-PET and EnhanceAR-Seq ctDNA analysis collectively in predicting participant response to PARPi therapy will be assessed by concordance index (C-index). The C-index is calculated as the number of concordant pairs divided by the number of comparable pairs. A C-index of 1 indicates perfect ranking, values close to 0.5 indicate random prediction, and values between 0.5 and 1 suggest some predictive ability (a value below 0.5 can be reversed by switching the response's 0 and 1 labels).
• Prediction performance of FTT-PET and EnhanceAR-Seq ctDNA collectively as measured by area under the receiver operating characteristic (ROC) curve [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), and at progression if applicable (estimated total time 6 months)]: Prediction performance of FTT-PET and EnhanceAR-Seq ctDNA analysis collectively in predicting participant response to PARPi therapy will be assessed by the area under the ROC curve. The ROC curve is a graphical plot that illustrates the performance of a model at various threshold settings and the area under the curve (AUC) is a single scalar value between 0 and 1 that summarizes model performance. A higher AUC value indicates better performance.
• Sensitivity of EnhanceAR-Seq ctDNA in identifying mPC patients who respond to PARPi therapy [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), 12 weeks after start of PARPi therapy, and at progression if applicable (estimated total time 6 months)]: Sensitivity is calculated as the proportion of true positives divided by the sum of true positives and false negatives. The area under the Receiver Operating Characteristic (ROC) curve will be calculated to identify the optimal cutpoint on the ROC corresponding to the maximized Youden index to evaluate sensitivity. The ROC curve is a graphical plot that illustrates the performance of a model at various threshold settings and the area under the curve (AUC) is a single scalar value between 0 and 1 that summarizes model performance. A higher AUC value indicates better performance.
• Specificity of EnhanceAR-Seq ctDNA in identifying mPC patients who respond to PARPi therapy [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), 12 weeks after start of PARPi therapy, and at progression if applicable (estimated total time 6 months)]: Specificity is calculated as the proportion of true negatives divided by the sum of true negatives and false positives. The area under the Receiver Operating Characteristic (ROC) curve will be calculated to identify the optimal cutpoint on the ROC corresponding to the maximized Youden index to evaluate specificity. The ROC curve is a graphical plot that illustrates the performance of a model at various threshold settings and the area under the curve (AUC) is a single scalar value between 0 and 1 that summarizes the performance of model. A higher AUC value indicates better performance.
• Positive predictive value (PPV) of EnhanceAR-Seq ctDNA in identifying mPC patients who respond to PARPi therapy [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), 12 weeks after start of PARPi therapy, and at progression if applicable (estimated total time 6 months)]: PPV is calculated as the number of true positives divided by the sum of the number of true positives and number of false positives. The area under the Receiver Operating Characteristic (ROC) curve will be calculated to identify the optimal cutpoint on the ROC corresponding to the maximized Youden index to evaluate PPV. The ROC curve is a graphical plot that illustrates the performance of a model at various threshold settings and the area under the curve (AUC) is a single scalar value between 0 and 1 that summarizes model performance. A higher AUC value indicates better performance.
• Negative predictive value (NPV) of EnhanceAR-Seq ctDNA in identifying mPC patients who respond to PARPi therapy [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), 12 weeks after start of PARPi therapy, and at progression if applicable (estimated total time 6 months)]: NPV is calculated as the number of true negatives divided by the sum of the number of true negatives and number of false negatives. The area under the Receiver Operating Characteristic (ROC) curve will be calculated to identify the optimal cutpoint on the ROC corresponding to the maximized Youden index to evaluate NPV. The ROC curve is a graphical plot that illustrates the performance of a model at various threshold settings and the area under the curve (AUC) is a single scalar value between 0 and 1 that summarizes model performance. A higher AUC value indicates better performance.
• Predictive performance improvement as measured by change in concordance index of FTT-PET and EnhanceAR-seq ctDNA compared to only FTT-PET or only EnhanceAR-seq ctDNA [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), 12 weeks after start of PARPi therapy, and at progression if applicable (estimated total time 6 months)]: Prediction performance of FTT-PET and EnhanceAR-seq ctDNA in predicting participant response to PARPi therapy will be assessed by the concordance index (C-index). The C-index is calculated as the number of concordant pairs divided by the number of comparable pairs. A C-index of 1 indicates perfect ranking, values close to 0.5 indicate random prediction, and values between 0.5 and 1 suggest some predictive ability prediction (a value below 0.5 can be reversed by switching the response's 0 and 1 labels).
• Predictive performance improvement as measured by area under the receiver operating characteristic (ROC) curve of FTT-PET and EnhanceAR-seq ctDNA compared to only FTT-PET or only EnhanceAR-seq ctDNA [At baseline prior to PARPi therapy, post cycle 1 (cycle is an estimated 28 days), 12 weeks after start of PARPi therapy, and at progression if applicable (estimated total time 6 months)]: Prediction performance of FTT-PET and EnhanceAR-seq ctDNA in predicting participant response to PARPi therapy will be assessed by the area under the ROC curve. The ROC curve is a graphical plot that illustrates the performance of a model at various threshold settings and the area under the curve (AUC) is a single scalar value between 0 and 1 that summarizes model performance. A higher AUC value indicates better performance.

Secondary outcomes

• Test-Retest Only: Lin's intra-class correlation coefficient of FTT-PET imaging [At baseline prior to PARPi therapy, at retest scan 1-14 days after baseline scan, and post-cycle 1 (estimated total time 28 days)]: Defined as concordance between a new test or measurement (Y) and a gold standard test or measurement (X). This statistic quantifies the agreement between these two measures of the same variable. Ranges from -1 to 1, with perfect agreement at 1.
• Correlation between FTT-PET imaging and tumor mutation burden (TMBddr) as assessed by Spearman or Pearson correlation coefficient [At baseline and post cycle 1 (estimated total time 28 days)]: TMBddr is the number of genetic mutation in tumor cells that can affect patient response and will be assessed through EnhanceAR-Seq ctDNA. Spearman's correlation coefficient evaluates the association and the association's direction between two ranked continuous variables. Spearman's correlation coefficient ranges from -1 to 1, with a negative number indicating a negative relationship between variables and a positive number indicating a positive relationship between variables. Values closer to zero indicate a weak relationship. Pearson's correlation coefficient is a measure that evaluates the association between two continuous variables with the assumption that the variables have a linear relationship. Pearson's correlation coefficient ranges from -1 to 1, with a negative number indicating a negative relationship between variables and a positive number indicating a positive relationship between variables. Values closer to zero indicate a weak relationship.
• Correlation between FTT-PET imaging and variant allele frequency (VAF) as assessed by Spearman or Pearson correlation coefficient [At baseline and post cycle 1 (estimated total time 28 days)]: VAF represents the fraction of variant sequencing reads within a genetic locus and will be assessed through EnhanceAR-Seq ctDNA. Spearman's correlation coefficient evaluates the association and the association's direction between two ranked continuous variables. Spearman's correlation coefficient ranges from -1 to 1, with a negative number indicating a negative relationship between variables and a positive number indicating a positive relationship between variables. Values closer to zero indicate a weak relationship. Pearson's correlation coefficient is a measure that evaluates the association between two continuous variables with the assumption that the variables have a linear relationship. Pearson's correlation coefficient ranges from -1 to 1, with a negative number indicating a negative relationship between variables and a positive number indicating a positive relationship between variables. Values closer to zero indicate a weak relationship.
• Correlation between FTT-PET imaging and dynamic changes in ctDNA levels as assessed by Spearman or Pearson correlation coefficient [At baseline and post cycle 1 (estimated total time 28 days)]: Dynamic changes in ctDNA refer to measurable changes in circulating tumor DNA in patient's blood over time and will be assessed through EnhanceAR-Seq ctDNA. Spearman's correlation coefficient evaluates the association and the association's direction between two ranked continuous variables. Spearman's correlation coefficient ranges from -1 to 1, with a negative number indicating a negative relationship between variables and a positive number indicating a positive relationship between variables. Values closer to zero indicate a weak relationship. Pearson's correlation coefficient is a measure that evaluates the association between two continuous variables with the assumption that the variables have a linear relationship. Pearson's correlation coefficient ranges from -1 to 1, with a negative number indicating a negative relationship between variables and a positive number indicating a positive relationship between variables. Values closer to zero indicate a weak relationship.
• Correlation between FTT-PET imaging and prostate-specific antigen (PSA) levels as assessed by Spearman or Pearson correlation coefficient [At baseline and post cycle 1 (estimated total time 28 days)]: Changes PSA levels in the blood over time will be assessed through EnhanceAR-Seq ctDNA. Spearman's correlation coefficient evaluates the association and the association's direction between two ranked continuous variables. Spearman's correlation coefficient ranges from -1 to 1, with a negative number indicating a negative relationship between variables and a positive number indicating a positive relationship between variables. Values closer to zero indicate a weak relationship. Pearson's correlation coefficient is a measure that evaluates the association between two continuous variables with the assumption that the variables have a linear relationship. Pearson's correlation coefficient ranges from -1 to 1, with a negative number indicating a negative relationship between variables and a positive number indicating a positive relationship between variables. Values closer to zero indicate a weak relationship.
• Correlation between FTT-PET imaging and tumor mutation burden (TMBddr) as assessed by Kappa agreement coefficient [At baseline and post cycle 1 (estimated total time 28 days)]: TMBddr is the number of genetic mutation in tumor cells that can affect patient response and will be assessed through EnhanceAR-Seq ctDNA. The Kappa agreement measure is calculated to evaluated inter-rater reliability. Kappa coefficient scores range from -1 to 1 with scores closer to 0 indicate poor or little agreement and scores of 1 or -1 indicating perfect agreement.
• Correlation between FTT-PET imaging and variant allele frequency (VAF) as assessed by Kappa agreement coefficient [At baseline and post cycle 1 (estimated total time 28 days)]: VAF represents the fraction of variant sequencing reads within a genetic locus and will be assessed through EnhanceAR-Seq ctDNA. The Kappa agreement measure is calculated to evaluate inter-rater reliability. Kappa coefficient scores range from -1 to 1, with scores closer to 0 indicating poor or little agreement and scores of 1 or -1 indicating perfect agreement.
• Correlation between FTT-PET imaging and dynamic changes in ctDNA level as assessed by Kappa agreement coefficient [At baseline and post cycle 1 (estimated total time 28 days)]: Dynamic changes in ctDNA refer to measurable changes in circulating tumor DNA in patient's blood over time and will be assessed through EnhanceAR-Seq ctDNA. The Kappa agreement measure is calculated to evaluated inter-rater reliability. Kappa coefficient scores range from -1 to 1, with scores closer to 0 indicating poor or little agreement and scores of 1 or -1 indicating perfect agreement.
• Correlation between FTT-PET imaging and prostate-specific antigen (PSA) as assessed by Kappa agreement coefficient [At baseline and post cycle 1 (estimated total time 28 days)]: Changes PSA levels in the blood over time will be assessed through EnhanceAR-Seq ctDNA. The Kappa agreement measure is calculated to evaluate inter-rater reliability. Kappa coefficient scores range from -1 to 1, with scores closer to 0 indicating poor or little agreement and scores of 1 or -1 indicating perfect agreement.
• Association of FTT-PET and EnhanceAR-Seq metrics with patient response based on relative risk [From enrollment to time of progression (estimated total time 6 months)]: Relative risk is a measure of the ratio of the risk of a certain event in an exposed group compared to the risk of the same event in a control group. A relative risk of 1.0 indicates no difference in risk between the groups, greater than 1.0 indicates increased risk in the exposed group, and less than 1.0 indicates decreased risk in the exposed group.

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Adult male patients 18 years of age or older
* mCRPC with confirmed germline or somatic HRR (such as ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C for Talazoparib/enzalutamide and ATMm, BRCA1m, BRCA2m, BARD1m, BRIP1m, CDK12m, CHEK1m, CHEK2m, FANCLm, PALB2m, RAD51Bm, RAD51Cm, RAD51Dm, RAD54Lm; gBRCA1m, gBRCA2m; ATMm, BRCA1m, BRCA2m for Olaparib +/- abiraterone) mutations who are scheduled for SOC PARPi therapy.
* Lesion size of at least 1.0 cm in longest dimension by imaging. If non-measurable, lesion needs to be clearly detected on other imaging studies such as bone scintigraphy, FDG-PET, PSMA-PET or MRI.
* On continuous androgen deprivation therapy (ADT) with appropriately suppressed castrate testosterone levels of < 50 ng/dL, or prior bilateral orchiectomy.
* Serum PSA of 2 ng/mL or greater.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Able to give informed consent

Exclusion Criteria:

* Receipt of prior PARP inhibitor therapy in any disease setting.
* Patients with other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of the other cancer that is active at the time of enrollment.
* Unable to tolerate approximately 30 min (total time) of PET/CT imaging.

• Farrokh Dehdashti, MD, Principal investigator, Washington University School of Medicine

NIH grants: R01CA306993