The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription ...factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.
We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.
A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.
Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).
Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is ...unclear whether patients with low-volume (LV) disease benefit from early D.
To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment PRLT).
Data were accessed from two independent phase III trials of ADT alone or ADT+D—GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized.
The primary end point was OS.
Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval CI) 0.68 (95% CI 0.56; 0.82, p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached NR and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials.
There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients.
Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits.
The aggregate data of two phase 3 trials show that patients with a high volume of metastatic castrate naive prostate cancer have poorer overall survival (OS) and benefit from androgen deprivation therapy (ADT)+docetaxel. Low-volume patients have longer OS with ADT alone and no clear benefit with adding docetaxel.
Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and ...enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v -) and AR-V7 detection (+ v -) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC-, CTC+/AR-V7- and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients, intermediate for CTC+/AR-V7- patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC-, CTC+/AR-V7-, and CTC+/AR-V7+.
Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in ...longer overall survival than that with ADT alone.
We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone.
A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval CI, 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%.
Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.).
Purpose
Prostate-specific membrane antigen (PSMA) is a recognized target for imaging prostate cancer. Here we present initial safety, biodistribution, and radiation dosimetry results with
18
...FDCFPyL, a second-generation fluorine-18-labeled small-molecule PSMA inhibitor, in patients with prostate cancer.
Procedures
Biodistribution was evaluated using sequential positron-emission tomography (PET) scans in nine patients with prostate cancer. Time-activity curves from the most avid tumor foci were determined. The radiation dose to selected organs was estimated using OLINDA/EXM.
Results
No major radiotracer-specific adverse events were observed. Physiologic accumulation was observed in known sites of PSMA expression. Accumulation in putative sites of prostate cancer was observed (SUV
max
up to >100, and tumor-to-blood ratios up to >50). The effective radiation dose from
18
FDCFPyL was 0.0139 mGy/MBq or 5 mGy (0.5 rem) from an injected dose of 370 MBq (10 mCi).
Conclusions
18
FDCFPyL is safe with biodistribution as expected, and its accumulation is high in presumed primary and metastatic foci. The radiation dose from
18
FDCFPyL is similar to that from other PET radiotracers.
Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes ...of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m
for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio HR, 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.
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.
Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).
To determine if stereotactic ablative ...radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer.
The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized.
Patients were randomized in a 2:1 ratio to receive SABR or observation.
The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography in the identification of metastatic disease.
In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03).
Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates.
ClinicalTrials.gov Identifier: NCT02680587.
Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in ...homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown.
To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations.
This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA.
The proportion of patients achieving a ≥50% decline in prostate-specific antigen (PSA50 response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test.
The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA50 responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p=0.002). Patients with BRCA1/2 mutations had median PFS of 12.3mo versus 2.4mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05–0.57; p=0.004). Limitations include the retrospective design and relatively small sample size.
Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations.
Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.
In this retrospective review of 23 patients with BRCA1/2 or ATM mutations treated with olaparib, we found that none of six men with ATM mutations achieved a 50% decline in prostate-specific antigen, compared to 13/17 men with BRCA1/2 mutations. Patients with BRCA1/2 mutations also had longer progression-free survival on olaparib treatment. Men with metastatic castration-resistant prostate cancer harboring ATM mutations may not respond to PARP inhibitors as well as men with BRCA1/2 mutations and may require alternative therapies.
MSH2 Loss in Primary Prostate Cancer Guedes, Liana B; Antonarakis, Emmanuel S; Schweizer, Michael T ...
Clinical cancer research,
11/2017, Volume:
23, Issue:
22
Journal Article
Peer reviewed
Open access
Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.
A total of 1,133 primary ...prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).
Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (
< 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed
loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in
Tumors with MSH2 loss had a higher density of infiltrating CD8
lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm
;
= 0.008), and CD8
density was correlated with mutation burden among cases with MSH2 loss (
= 0.72,
= 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.
Loss of MSH2 protein is correlated with
inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
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