Up to 30% of patients with metastatic castration-resistant prostate cancer have deleterious mutations in genes involved in homologous recombination repair of DNA damage. The use of the PARP inhibitor ...olaparib in such patients was associated with longer progression-free survival and a longer time to pain progression than control therapy.
Lactate dehydrogenase (LDH) levels are inversely related with response to checkpoint inhibitors. Elevated LDH levels are the product of enhanced glycolytic activity of the tumor and tumor necrosis ...due to hypoxia, the latter being associated with high tumor burden. In this review, we elucidate the effects of glycolysis and hypoxia on antitumor immunity and set forth ways to improve response to immunotherapy in cancer patients with elevated LDH levels. We discuss the current knowledge on combining immunotherapy with glycolysis inhibitors, anti-acidifying drugs, anti-angiogenic or cytoreductive therapy.
Introduction
While
177
LuLu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive ...metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of
177
LuLu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter.
Methods
Ten mHSPC patients underwent two cycles of
177
LuLu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman’s r and p-values.
Results
Kinetics of
177
LuLu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose (
p
= 0.047).
Conclusions
We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.
Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we ...present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12
and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12
and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.
Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment.
To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as ...biomarkers of patient outcome following taxane chemotherapy.
Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m2) or cabazitaxel (20 or 25mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m2) as second-line chemotherapy (PROSELICA).
Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies.
In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio HR=1.54; 95% confidence interval CI: 1.15–2.08; p=0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18–1.97; p=0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle −0.03; 95% CI: −0.044 to −0.009; p=0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA.
We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes.
In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3–9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA.
Plasma cell-free DNA comprises fragmented nucleic acids from normal and tumour cells, and has utility as a biomarker of radiological progression-free and overall survival from first- and second-line treatment with taxane in advanced prostate cancer.
Introduction
Patient eligibility for
177
LuLu-PSMA therapy remains a challenge, with only 40–60% response rate when patient selection is done based on the lesion uptake (SUV) on
68
...GaGa-PSMA-PET/CT. Prediction of absorbed dose based on this pre-treatment scan could improve patient selection and help to individualize treatment by maximizing the absorbed dose to target lesions while adhering to the threshold doses for the organs at risk (kidneys, salivary glands, and liver).
Methods
Ten patients with low-volume hormone-sensitive prostate cancer received a pre-therapeutic
68
GaGa-PSMA-11 PET/CT, followed by 3 GBq
177
LuLu-PSMA-617 therapy. Intra-therapeutically, SPECT/CT was acquired at 1, 24, 48, 72, and 168 h. Absorbed dose in organs and lesions (
n
= 22) was determined according to the MIRD scheme. Absorbed dose prediction based on
68
GaGa-PSMA-PET/CT was performed using tracer uptake at 1 h post-injection and the mean tissue effective half-life on SPECT. Predicted PET/actual SPECT absorbed dose ratios were determined for each target volume.
Results
PET/SPECT absorbed dose ratio was 1.01 ± 0.21, 1.10 ± 0.15, 1.20 ± 0.34, and 1.11 ± 0.29 for kidneys (using a 2.2 scaling factor), liver, submandibular, and parotid glands, respectively. While a large inter-patient variation in lesion kinetics was observed, PET/SPECT absorbed dose ratio was 1.3 ± 0.7 (range: 0.4–2.7, correlation coefficient
r
= 0.69,
p
< 0.01).
Conclusion
A single time point
68
GaGa-PSMA-PET scan can be used to predict the absorbed dose of
177
LuLu-PSMA therapy to organs, and (to a limited extent) to lesions. This strategy facilitates in treatment management and could increase the personalization of
177
LuLu-PSMA therapy.
Purpose
Radium-223 is a life-prolonging therapy for castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. However, validated biomarkers for response monitoring are ...lacking. The study aim was to investigate whether early alkaline phosphatase (ALP) dynamics after the first radium-223 injection can act as surrogate marker for overall survival (OS).
Methods
This retrospective multicenter study included consecutive CRPC patients treated with radium-223. Patients were divided into four subgroups based on baseline ALP level (normal/elevated) and early ALP response, defined as ≥10% ALP decrease after the first radium-223 injection. Primary endpoint was OS among the subgroups. Secondary endpoints included time to first skeletal-related event, time to ALP progression, and treatment completion rate.
Results
A total of 180 patients were included for analysis. Median OS was 13.5 months (95% confidence interval 11.5–15.5). Patients with elevated baseline ALP without ALP response after the first injection had significantly worse OS when compared to all other patients (median OS 7.9 months versus 15.7 months, hazard ratio 2.56, 95% confidence interval 1.73–3.80,
P
< 0.001). Multivariate analysis demonstrated that elevated baseline ALP without ALP response after the first injection, the number of prior systemic therapies, baseline LDH level, and baseline ECOG performance status were prognostic factors of OS. Patients with elevated baseline ALP without ALP response after the first injection had significantly shorter times to ALP progression and first skeletal-related event, and more frequently discontinued radium-223 therapy when compared to other patients.
Conclusion
Early treatment–induced changes in ALP after one radium-223 injection were associated with OS in metastatic CRPC patients.
The clinical utility of circulating tumor cells (CTC) as a non-invasive multipurpose biomarker is broadly recognized. The earliest methods for enriching CTCs from whole blood rely on antibody-based ...positive selection. The prognostic utility of CTC enumeration using positive selection with the FDA-approved CellSearch
system has been demonstrated in numerous studies. The capture of cells with specific protein phenotypes does not fully represent cancer heterogeneity and therefore does not realize the prognostic potential of CTC liquid biopsies. To avoid this selection bias, CTC enrichment based on size and deformability may provide better fidelity, i.e., facilitate the characterization of CTCs with any phenotype. In this study, the recently FDA-approved Parsortix
technology was used to enrich CTCs from prostate cancer (PCa) patients for transcriptome analysis using HyCEAD
technology. A tailored PCa gene panel allowed us to stratify metastatic castration-resistant prostate cancer (mCRPC) patients with clinical outcomes. In addition, our findings suggest that targeted CTC transcriptome profiling may be predictive of therapy response.
Late-stage cancer immunotherapy trials often lead to unusual survival curve shapes, like delayed curve separation or a plateauing curve in the treatment arm. It is critical for trial success to ...anticipate such effects in advance and adjust the design accordingly. Here, we use in silico cancer immunotherapy trials - simulated trials based on three different mathematical models - to assemble virtual patient cohorts undergoing late-stage immunotherapy, chemotherapy, or combination therapies. We find that all three simulation models predict the distinctive survival curve shapes commonly associated with immunotherapies. Considering four aspects of clinical trial design - sample size, endpoint, randomization rate, and interim analyses - we demonstrate how, by simulating various possible scenarios, the robustness of trial design choices can be scrutinized, and possible pitfalls can be identified in advance. We provide readily usable, web-based implementations of our three trial simulation models to facilitate their use by biomedical researchers, doctors, and trialists.
Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose) polymerase (PARP) ...inhibitors, all patients ultimately develop resistance to these therapies. Therefore, it is necessary to identify therapeutic regimens with a more durable efficacy. HRD tumors have been suggested to be more immunogenic and, therefore, more susceptible to treatment with checkpoint inhibitors. In this review, we describe how HRD might mechanistically affect antitumor immunity and summarize the available translational evidence for an association between HRD and antitumor immunity across multiple tumor types. In addition, we give an overview of all available clinical data on the efficacy of checkpoint inhibitors in HRD tumors and describe the evidence for using treatment strategies that combine checkpoint inhibitors with PARP inhibitors.
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