Publications by authors named "Ian D Davis"

173 Publications

[Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

Lancet 2021 Feb 11;397(10276):797-804. Epub 2021 Feb 11.

Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia; Eastern Health, Melbourne, VIC, Australia.

Background: Lutetium-177 [Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer.

Methods: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [Ga]Ga-PSMA-11 and 2-flourine-18[F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428.

Findings: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [Lu]Lu-PSMA-617.

Interpretation: [Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel.

Funding: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
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http://dx.doi.org/10.1016/S0140-6736(21)00237-3DOI Listing
February 2021

Opening a Scan of Worms.

Authors:
Ian D Davis

Eur Urol Oncol 2020 12 31;3(6):725-727. Epub 2020 Oct 31.

Monash University Eastern Health Clinical School, Melbourne, Australia; Eastern Health, Melbourne, Australia; ANZUP Cancer Trials Group, Sydney, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.euo.2020.10.009DOI Listing
December 2020

Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial.

J Clin Oncol 2020 Dec 14;38(34):4064-4075. Epub 2020 Oct 14.

Medical Research Council Clinical Trials Unit at University College London (UCL), Institute of Clinical Trials and Methodology, London, United Kingdom.

Purpose: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence.

Patients And Methods: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo.

Results: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib.

Conclusion: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.
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http://dx.doi.org/10.1200/JCO.20.01800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768344PMC
December 2020

First clinical study of a pegylated diabody I-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers.

Theranostics 2020 15;10(25):11404-11415. Epub 2020 Sep 15.

Avipep Pty Ltd and the Victorian Cancer Biologics Consortium, Parkville, Victoria 3052, Australia.

Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Clinical translation followed characterization of PEG-AVP0458 drug product and preclinical biodistribution and imaging assessments of Iodine-124 trace labeled PEG-AVP0458 (I-PEG-AVP0458). The primary study objective of the first-in-human study was the safety of a single protein dose of 1.0 or 10 mg/mI-PEG-AVP0458 in patients with TAG-72 positive relapsed/ metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor uptake, pharmacokinetics and immunogenicity. Patients were infused with a single-dose of I labeled PEG-AVP0458 (3-5 mCi (111-185 MBq) for positron emission tomography (PET) imaging, performed sequentially over a one-week period. Safety, pharmacokinetics, biodistribution, and immunogenicity were assessed up to 28 days after infusion. PEG-AVP0458 was radiolabeled with I and shown to retain high TAG-72 affinity and excellent targeting of TAG-72 positive xenografts by biodistribution analysis and PET imaging. In the first-in-human trial, no adverse events or toxicity attributable to I-PEG-AVP0458 were observed. Imaging was evaluable in 5 patients, with rapid and highly specific targeting of tumor and minimal normal organ uptake, leading to high tumor:blood ratios. Serum concentration values of I-PEG-AVP0458 showed consistent values between patients, and there was no significant difference in T½α and T½β between dose levels with mean (± SD) results of T½α = 5.10 ± 4.58 hours, T½β = 46.19 ± 13.06 hours. These data demonstrates the safety and feasibility of using pegylated diabodies for selective tumor imaging and potential delivery of therapeutic payloads in cancer patients.
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http://dx.doi.org/10.7150/thno.49422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545991PMC
September 2020

Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.

Lancet Oncol 2020 10;21(10):1331-1340

Auckland Hospital, Auckland, New Zealand.

Background: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy.

Methods: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652.

Findings: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; p=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]).

Interpretation: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity.

Funding: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.
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http://dx.doi.org/10.1016/S1470-2045(20)30456-3DOI Listing
October 2020

Prognostic Impact of Total Plasma Cell-free DNA Concentration in Androgen Receptor Pathway Inhibitor-treated Metastatic Castration-resistant Prostate Cancer.

Eur Urol Focus 2020 Jul 29. Epub 2020 Jul 29.

Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Electronic address:

Total plasma cell-free DNA (cfDNA) levels were recently shown to be prognostic in two large phase III trials of taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). However, whether cfDNA concentration is predictive of treatment outcomes with androgen receptor pathway inhibitors (ARPIs) is unknown. We quantified plasma cfDNA levels at baseline (n = 74) and 4 weeks on treatment (n = 56) in a prospective cohort of mCRPC patients treated with the ARPIs abiraterone acetate or enzalutamide. Elevated total cfDNA concentration (log) at both baseline (hazard ratio [HR] 5.5, p < 0.001) and week 4 (HR 7.5, p < 0.001) was a significant negative prognostic factor for overall survival (OS), a finding maintained after adjustment for plasma circulating tumour DNA fraction. Unexpectedly, a rise in cfDNA concentration from baseline to week 4 was also associated with significantly improved OS (HR 0.14, p = 0.003). Conversely, patients with ≥29.8% decrease in cfDNA from baseline (optimal cut-point) had significantly shorter median OS than the rest of the cohort (10.5 vs 25.7 mo, p = 0.03). Collectively, our findings point to the potential prognostic utility of quantifying cfDNA in mCRPC and in particular suggest that dynamic changes in total cfDNA levels may be a novel early predictive biomarker for therapeutic outcome in ARPI-treated patients. PATIENT SUMMARY: We measured the levels of total cell-free DNA (cfDNA) in the plasma of patients with metastatic prostate cancer prior to and 4 weeks after starting new hormonal drugs. We found that patients with higher levels of cfDNA or a higher proportion of tumour-derived DNA at baseline had worse outcomes on hormonal therapies. Similarly, higher levels of cfDNA at 4 weeks into therapy were also associated with worse outcomes. However, a rise in total cfDNA levels at 4 weeks compared with baseline was linked with better outcomes. Measuring changes in cfDNA concentration may be a useful and technically straightforward early way to predict how patients will respond to treatment in metastatic prostate cancer.
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http://dx.doi.org/10.1016/j.euf.2020.07.001DOI Listing
July 2020

Nursing Implications of Recent Changes in Management Practices for Metastatic Prostate Cancer.

Semin Oncol Nurs 2020 08 22;36(4):151047. Epub 2020 Jul 22.

Eastern Health, Melbourne, VIC, Australia. Electronic address:

Objective: Prostate cancer is one of the most common male cancers in the world and accounts for substantial morbidity, mortality, loss of disability-adjusted life-years, and financial burden to patients and to the community. Metastatic prostate cancer has been managed for over 70 years with androgen deprivation therapy, but further life-prolonging therapies were not available until 2004. Since then, drugs such as docetaxel, abiraterone, enzalutamide, cabazitaxel, radium-223 dichloride, and (not available in Australia) sipuleucel-T have all demonstrated efficacy in prolongation of survival in castrate-resistant prostate cancer, and improvement in cancer-related morbidity.

Data Sources: Peer-reviewed scientific publications, Australian Government agency reports, and expert opinion.

Conclusion: More recently, several of these agents have been given earlier in the treatment course to the hormone-sensitive metastatic setting, with even greater benefits in survival. These treatments have come at a cost: a literal financial cost to the community, and often to the patients and their families; and financial costs to the community to supply the drugs to those who need them. They also carry non-financial costs, including side effects of treatment, exacerbation of other co-morbidities, metabolic and bone health challenges, and psychological and social stresses, including those associated with longer survival with metastatic cancer.

Implications For Nursing Practice: The role of the nurse in management of these issues has never been more important. Nurses are often uniquely placed to educate men with prostate cancer and their families, screen for and identify adverse effects of treatment, and provide education and support not otherwise available. Nurses are central to the streamline of care coordination within the multidisciplinary team and the holistic care journey for men and their partners through the health care system. This review discusses several of these aspects to inform practice.
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http://dx.doi.org/10.1016/j.soncn.2020.151047DOI Listing
August 2020

Compliance with follow-up for patients with stage 1 testicular germ cell tumour.

ANZ J Surg 2021 01 2;91(1-2):184-186. Epub 2020 Jul 2.

Department of Urology, Eastern Health, Melbourne, Victoria, Australia.

Background: This study aimed to evaluate the compliance and loss-to-follow-up (LTFU) rate in patients with stage 1 testicular germ cell tumours (GCTs) on active surveillance protocol at a metropolitan health service in Melbourne, Australia.

Methods: Patients with stage 1 testicular GCTs diagnosed between 30 June 2012 and 30 June 2018 were identified. Compliance of surveillance programme was classified into three groups: 'adequate', 'missed appointment(s)' or 'LTFU'. The LTFU rate was assessed using Kaplan-Meier methodology. Log-rank test was used for univariate analyses.

Results: Forty-eight patients had stage 1 testicular GCTs during the 6-year period. Twenty-two (46%) of them were managed with active surveillance and 26 (54%) of them were given adjuvant therapy. Compliance with active surveillance was assessed as adequate in 12 (55%), missed appointment(s) in six (27%) and LFTU in four (18%). The LTFU rates in patients with active surveillance at 12, 24 and 36 months were 9%, 9% and 19%, respectively. The LTFU rate in patients with active surveillance was not significantly different from patients who received adjuvant therapy (hazard ratio 0.71 (95% confidence intervals 0.22, 2.30), P = 0.56). Three (14%) of the 22 patients managed with active surveillance had recurrence of disease, all of which occurred in the first 12 months, compared to two (8%) of the 26 patients who had adjuvant therapy.

Conclusion: Active surveillance is a commonly utilized management option for stage 1 testicular GCTs, but has a LTFU rate of almost 20% that may limit its effectiveness. The recurrence rate was comparable to published literature.
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http://dx.doi.org/10.1111/ans.16114DOI Listing
January 2021

Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.

Lancet 2020 05;395(10236):1547-1557

MD Anderson Cancer Center Madrid, Madrid, Spain.

Background: Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma.

Methods: In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636.

Findings: Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1-17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5-8·3) in group A and 6·3 months (6·2-7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70-0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9-18·9) in group A and 13·4 months (12·0-15·2) in group C (0·83, 0·69-1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1-17·8) for group B and 13·1 months (11·7-15·1) for group C (1·02, 0·83-1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo.

Interpretation: Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma.

Funding: F Hoffmann-La Roche and Genentech.
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http://dx.doi.org/10.1016/S0140-6736(20)30230-0DOI Listing
May 2020

Effects of estrogen receptor signaling on prostate cancer carcinogenesis.

Transl Res 2020 08 12;222:56-66. Epub 2020 May 12.

Eastern Health Clinical School, Monash University, Victoria, Australia.

Management of advanced prostate cancer remains complex, with substantial changes in treatment options emerging in recent years having implications for treatment selection and sequencing. Recognition of the importance of androgen signaling has led to life-prolonging treatments, as well as "liquid biopsy" techniques to guide these treatments in some settings. Therapies that target estrogen receptor signaling are efficacious but infrequently used options for treatment of castration-resistant prostate cancer. It is possible that nuances of estrogen receptor (ER) signaling, or selective modulation of ER signaling, might favorably influence outcomes in castration-resistant prostate cancer. Expression of ERs and their variants has been investigated in other cancers such as breast. Constitutively activating gene alterations can potentially lead to ER activation and subsequently promote cancer progression. The identification of these aberrations may help identify cancer phenotypes that are susceptible or resistant to therapies involved in ER signaling. This review outlines the current literature regarding ER signaling in prostate cancer, and provides background for exploration of potentially useful ER signaling biomarkers in advanced prostate cancer.
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http://dx.doi.org/10.1016/j.trsl.2020.04.003DOI Listing
August 2020

Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma.

J Immunother Cancer 2020 04;8(1)

Ludwig Institute for Cancer Research Austin Branch, Heidelberg, Victoria, Australia.

Background: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.

Methods: Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.

Results: The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4 and CD8 responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)/Human Leukocyte Antigen (HLA) class I double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.

Conclusions: The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.
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http://dx.doi.org/10.1136/jitc-2019-000410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204806PMC
April 2020

A Simple Clinical Tool for Stratifying Risk of Clinically Significant CKD after Nephrectomy: Development and Multinational Validation.

J Am Soc Nephrol 2020 05 1;31(5):1107-1117. Epub 2020 Apr 1.

Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Background: Clinically significant CKD following surgery for kidney cancer is associated with increased morbidity and mortality, but identifying patients at increased CKD risk remains difficult. Simple methods to stratify risk of clinically significant CKD after nephrectomy are needed.

Methods: To develop a tool for stratifying patients' risk of CKD arising after surgery for kidney cancer, we tested models in a population-based cohort of 699 patients with kidney cancer in Queensland, Australia (2012-2013). We validated these models in a population-based cohort of 423 patients from Victoria, Australia, and in patient cohorts from single centers in Queensland, Scotland, and England. Eligible patients had two functioning kidneys and a preoperative eGFR ≥60 ml/min per 1.73 m. The main outcome was incident eGFR <45 ml/min per 1.73 m at 12 months postnephrectomy. We used prespecified predictors-age ≥65 years old, diabetes mellitus, preoperative eGFR, and nephrectomy type (partial/radical)-to fit logistic regression models and grouped patients according to degree of risk of clinically significant CKD (negligible, low, moderate, or high risk).

Results: Absolute risks of stage 3b or higher CKD were <2%, 3% to 14%, 21% to 26%, and 46% to 69% across the four strata of negligible, low, moderate, and high risk, respectively. The negative predictive value of the negligible risk category was 98.9% for clinically significant CKD. The statistic for this score ranged from 0.84 to 0.88 across derivation and validation cohorts.

Conclusions: Our simple scoring system can reproducibly stratify postnephrectomy CKD risk on the basis of readily available parameters. This clinical tool's quantitative assessment of CKD risk may be weighed against other considerations when planning management of kidney tumors and help inform shared decision making between clinicians and patients.
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http://dx.doi.org/10.1681/ASN.2019121328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217412PMC
May 2020

Synchronous Versus Metachronous Metastatic Disease: Impact of Time to Metastasis on Patient Outcome-Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Eur Urol Oncol 2020 08 6;3(4):530-539. Epub 2020 Feb 6.

Tom Baker Cancer Center, Calgary, Canada.

Background: Patients with metastatic renal cell carcinoma (mRCC) may present with primary metastases (synchronous disease) or develop metastases during follow-up (metachronous disease). The impact of time to metastasis on patient outcome is poorly characterised.

Objective: To characterise overall survival (OS) and time to treatment failure (TTF) based on time to metastasis in mRCC patients treated with targeted therapy (tyrosine kinase inhibitors [TKIs]).

Design, Setting, And Participants: We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare synchronous (metastases within ≤3 mo of initial diagnosis of cancer) versus metachronous disease (evaluated by >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr intervals).

Outcome Measurements And Statistical Analysis: OS and TFF were assessed using Kaplan-Meier curves. Cox multivariable regressions analyses (MVAs) were adjusted for baseline factors.

Results And Limitations: Of 7386 patients with mRCC treated with first-line TKIs, 3906 (53%) and 3480 (47%) had synchronous and metachronous metastasis, respectively. More patients with synchronous versus metachronous disease had higher T stage (T1-2: 19% vs 34%), N1 disease (21% vs 6%), presence of sarcomatoid differentiation (15.8% vs 7.9%), Karnofsky performance status <80 (25.9% vs 15.1%), anaemia (62.5% vs 42.3%), elevated neutrophils (18.9% vs 10.9%), elevated platelets (21.6% vs 11.4%), bone metastases (40.4% vs 29.8%), and IMDC poor risk (40.6% vs 11.3%). Synchronous versus metachronous disease by intervals >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr correlated with poor TTF (5.6 mo vs 7.3, 8.0, 10.8, and 13.3 mo, p <  0.0001) and poor OS (median 16.7 mo vs 23.8, 30.2, 34.8, and 41.7 mo, p <  0.0001). In MVAs, the adjusted hazard ratios (95% confidence intervals) were 1.00 (reference), 0.98 (0.90-1.06), 0.81 (0.73-0.91), 0.74 (0.68-0.81), and 0.60 (0.54-0.67), respectively, for OS (p <  0.0001), and 1.00 (reference), 0.99 (0.92-1.06), 0.98 (0.90-1.07), 0.83 (0.77-0.89), and 0.66 (0.60-0.72), respectively, for TTF (p <  0.0001). Data were collected retrospectively.

Conclusions: Timing of metastases after initial RCC diagnosis may impact the outcomes from targeted therapy in mRCC.

Patient Summary: We looked at the impact of the timing of metastatic outbreak on survival outcomes in kidney cancer patients treated with targeted therapy. We found that the longer time to metastatic development was associated with improved outcome.
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http://dx.doi.org/10.1016/j.euo.2020.01.001DOI Listing
August 2020

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019.

Eur Urol 2020 04 27;77(4):508-547. Epub 2020 Jan 27.

University of Bern, Bern, Switzerland; Department of Medical Oncology and Haematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.

Objective: To present the results from the APCCC 2019.

Design, Setting, And Participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.

Outcome Measurements And Statistical Analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.

Results And Limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.

Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.

Patient Summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
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http://dx.doi.org/10.1016/j.eururo.2020.01.012DOI Listing
April 2020

The impact of chemotherapy on cognitive function: a multicentre prospective cohort study in testicular cancer.

Support Care Cancer 2020 Jul 23;28(7):3081-3091. Epub 2019 Oct 23.

Faculty of Health and Medical Sciences, University of Adelaide, Frome Road, Adelaide, South Australia, 5005, Australia.

Purpose: The causal link between chemotherapy and cognitive impairment is unclear. We studied testicular cancer patients' objective and subjective cognitive function longitudinally, comparing a surgery group with a surgery + chemotherapy group, addressing prior methodological issues using a computerized test to limit assessment issues, and controlling for confounding variables.

Methods: Prospectively, of 145 patients from 16 centres with sufficient data, n = 61 receiving surgery + chemotherapy (etoposide and cisplatin ± bleomycin, BEP/EP; or single agent carboplatin) were compared to n = 41 receiving surgery alone. CogHealth assessed six objective cognitive tasks. The Cognitive Failures Questionnaire assessed self-perceived cognitive dysfunction. The Functional Assessment of Chronic Illness Therapy-Fatigue and the Hospital Anxiety and Depression Scale assessed psychological influences. Linear mixed models compared changes from baseline (< 6 months post-surgery/pre-chemotherapy) to follow-up (12-18 months post-baseline), controlling covariates.

Results: There were no significant interaction effects for five objective cognitive function tasks suggesting that changes over time were not due to group membership. However, psychomotor function (controlling for age) and physical well-being were significantly worse for the chemotherapy versus the surgery group at baseline, with groups converging by follow-up. Groups showed no differences in subjective cognitive dysfunction. The chemotherapy group showed higher anxiety, poorer functional well-being and worse fatigue compared to the surgery-only group at baseline, but not by follow-up. For both groups, emotional well-being, functional well-being and anxiety significantly improved over time.

Conclusion: No substantive differences in objective or subjective cognitive dysfunction in either group persisted 12-18 months post-baseline. Patients undergoing chemotherapy for testicular cancer differ from findings in breast cancer populations.

Trial Registration: ClinicalTrials.gov Identifier: ACTRN12609000545268.
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http://dx.doi.org/10.1007/s00520-019-05095-3DOI Listing
July 2020

TheraP: a randomized phase 2 trial of Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (Clinical Trial Protocol ANZUP 1603).

BJU Int 2019 11 22;124 Suppl 1:5-13. Epub 2019 Oct 22.

Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, NSW, Australia.

Objective: To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with Lu-PSMA-617, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in men with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel treatment.

Patients And Methods: The TheraP trial (ANZUP 1603) is an open-label, randomized, stratified, two-arm multicentre phase 2 trial comparing the activity and safety of cabazitaxel chemotherapy vs Lu-PSMA-617 therapy in the treatment of men with mCRPC. Key eligibility criteria include prior docetaxel chemotherapy, rising prostate-specific antigen (PSA) level, sufficient PSMA avidity, as defined by centrally reviewed Ga-PSMA-11 and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with no discordant FDG-avid PSMA-negative sites of disease. Patients in the control group receive standard treatment with cabazitaxel (20 mg/m ) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive Lu-PSMA-617 (8.5 GBq decreasing by 0.5 GBq per cycle) i.v. every 6 weeks, for up to a maximum of six cycles. In the event of an exceptional response as defined on centrally reviewed post-therapy single-photon emission CT imaging, treatment will be suspended but can recommence on progression. The trial aims to include 200 patients who will be centrally randomized to one of the two treatment groups, in a 1:1 ratio. The primary endpoint is PSA response. Secondary endpoints are overall survival, progression-free survival (PFS), radiographic PFS, PSA PFS, objective tumour response, pain response, pain PFS, health-related quality of life, and frequency and severity of adverse events. The treatment and outcomes of patients excluded on the basis of low PSMA avidity or discordant FDG-avid disease on screening Ga-PSMA-11 and Fluorine-18 ( F)-FDG-PET/CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018.

Results And Conclusions: Lu-PSMA-617 offers a potential additional life-prolonging treatment option for men with mCRPC. The results of this trial will determine, for the first time in a randomized design, the activity and safety of Lu-PSMA-617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.
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http://dx.doi.org/10.1111/bju.14876DOI Listing
November 2019

Enzalutamide in Metastatic Prostate Cancer. Reply.

N Engl J Med 2019 10;381(15):1494-1495

Dana-Farber Cancer Institute, Boston, MA.

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http://dx.doi.org/10.1056/NEJMc1910553DOI Listing
October 2019

Body size and dietary risk factors for aggressive prostate cancer: a case-control study.

Cancer Causes Control 2019 Dec 24;30(12):1301-1312. Epub 2019 Sep 24.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.

Purpose: Diet and body size may affect the risk of aggressive prostate cancer (APC), but current evidence is inconclusive.

Methods: A case-control study was conducted in men under 75 years of age recruited from urology practices in Victoria, Australia; 1,254 with APC and 818 controls for whom the presence of prostate cancer had been excluded by biopsy. Dietary intakes were assessed using a validated food frequency questionnaire. Multivariable unconditional logistic regression estimated odds ratios and confidence intervals for hypothesized risk factors, adjusting for age, family history of prostate cancer, country of birth, socioeconomic status, smoking, and other dietary factors.

Results: Positive associations with APC (odds ratio, 95% confidence intervals, highest vs. lowest category or quintile) were observed for body mass index (1.34, 1.02-1.78, P = 0.04), and trouser size (1.54, 1.17-2.04, P = 0.001). Intakes of milk and all dairy products were inversely associated with APC risk (0.71, 9.53-0.96, P = 0.05, and 0.64, 0.48-0.87, P = 0.012, respectively), but there was little evidence of an association with other dietary variables (P > 0.05).

Conclusions: We confirmed previous evidence for a positive association between body size and risk of APC, and suggest that consumption of dairy products, and milk more specifically, is inversely associated with risk.
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http://dx.doi.org/10.1007/s10552-019-01234-7DOI Listing
December 2019

Tumor size and postoperative kidney function following radical nephrectomy.

Clin Epidemiol 2019 6;11:333-348. Epub 2019 May 6.

Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Chronic kidney disease (CKD) following nephrectomy for kidney tumors is common, and both patient and tumor characteristics may affect postoperative kidney function. Several studies have reported that surgery for large tumors is associated with a lower likelihood of postoperative CKD, but others have reported CKD to be more common before surgery in patients with large tumors. The aim of this study was to clarify inconsistencies in the literature regarding the prognostic significance of tumor size for postoperative kidney function. We analyzed data from 944 kidney cancer patients managed with radical nephrectomy between January 2012 and December 2013, and 242 living kidney donors who underwent surgery between January 2011 and December 2014 in the Australian states of Queensland and Victoria. Multivariable logistic regression was used to assess the primary outcome of CKD upstaging. Structural equation modeling was used to evaluate causal models, to delineate the influence of patient and tumor characteristics on postoperative kidney function. We determined that a significant interaction between age and tumor size (=0.03) led to the observed inverse association between large tumor size and CKD upstaging, and was accentuated by other forms of selection bias. Subgrouping patients by age and tumor size demonstrated that all patients aged ≥65 years were at increased risk of CKD upstaging, regardless of tumor size. Risk of CKD upstaging was comparable between age-matched living donors and kidney cancer patients. Larger tumors are unlikely to confer a protective effect with respect to postoperative kidney function. The reason for the previously reported inconsistency is likely a combination of the analytical approach and selection bias.
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http://dx.doi.org/10.2147/CLEP.S197968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511655PMC
May 2019

Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer.

N Engl J Med 2019 07 2;381(2):121-131. Epub 2019 Jun 2.

From Monash University (I.D.D., M.F., D.W.P.), Eastern Health (I.D.D.), Australian Urology Associates (M.F.), Monash Health (D.W.P.), and the Peter MacCallum Cancer Centre and the University of Melbourne (S.K.S., S.G.W.), Melbourne, VIC, the National Health and Medical Research Council Clinical Trials Centre, University of Sydney (A.J.M., M.R.S., X.C., W.E.H., E.T., S.Y., A.Y.Z.), the Chris O'Brien Lifehouse (M.R.S., L.G.H., A.Y.Z.), the University of Sydney (L.G.H., G.M.), Royal Prince Alfred Hospital (L.G.H.), Kinghorn Cancer Centre, St. Vincent's Hospital, and Garvan Institute of Medical Research (A.M.J.), Macquarie University (A.Y.Z.), and Western Sydney University (R.R.Z.), Sydney, Concord Cancer Centre, Concord Repatriation General Hospital, Concord, NSW (M.R.S.), Port Macquarie Base Hospital and Mid North Coast Cancer Institute Port Macquarie, Port Macquarie, NSW (S.B.), Sydney Adventist Hospital, Wahroonga, NSW (G.M.), the ANZUP Cancer Trials Group, Camperdown, NSW (M.M.), the Adelaide Cancer Centre and the University of Adelaide (F.P.) and the Royal Adelaide Hospital (T.H.T.), Adelaide, SA, and Orange Health Service, Central West Cancer Care Centre, Orange, NSW (R.R.Z.) - all in Australia; BC Cancer and the University of British Columbia, Vancouver (K.N.C.), the Cross Cancer Institute and the University of Alberta, Edmonton (S.A.N.), Canadian Cancer Trials Group, Queen's University (W.P., F.V.-B.), and the Kingston Health Sciences Center (F.V.-B.), Kingston, ON, and the University of Ottawa and the Ottawa Hospital Research Institute, Ottawa (M.N.R.) - all in Canada; Guy's and St. Thomas' NHS Foundation Trust Biomedical Research Centre, Cancer Research UK and King's College London, and Sarah Cannon Research UK, London (S.C.), and the Royal Cornwall Hospital, Truro (A. Thomson) - all in the United Kingdom; Auckland City Hospital, Auckland (N.J.L.), and the Waikato District Health Board, Hamilton (A. Tan) - both in New Zealand; Cancer Trials Ireland (J.M., R.M.), Mater Misericordiae University Hospital (J.M.), and St. Vincent's University Hospital and University College Dublin (R.M.D.) - all in Dublin; and Dana-Farber Cancer Institute and Harvard Medical School (C.J.S.) - both in Boston.

Background: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.

Methods: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.

Results: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.

Conclusions: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).
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http://dx.doi.org/10.1056/NEJMoa1903835DOI Listing
July 2019

Prognostic Utility of a Whole-blood Androgen Receptor-based Gene Signature in Metastatic Castration-resistant Prostate Cancer.

Eur Urol Focus 2019 May 15. Epub 2019 May 15.

Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address:

Background: The treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly in recent years. Identifying predictive and/or prognostic biomarkers in the context of this rapidly expanding therapeutic armamentarium remains a pressing and unmet clinical need.

Objective: To develop a prognostic whole-blood gene signature for mCRPC patients.

Design, Setting, And Participants: As part of an ongoing prospective, multicentre biomarker research study (Australian Prostate Biomarker Alliance), we enrolled 115 mCRPC patients commencing chemotherapy (n = 34) or androgen receptor (AR) pathway inhibitors therapy (n = 81) and obtained pretreatment whole-blood samples in PAXgene RNA tubes. Gene expression was assessed using reverse transcription-polymerase chain reaction.

Outcome Measurements And Statistical Analysis: Gene transcripts correlating with overall survival (OS) at p < 0.10 in univariate Cox regression models were incorporated into a multigene signature. Kaplan-Meier survival estimates and multivariate analyses were used to assess association with clinical outcomes. Prognostic strength of the signature was estimated using a concordance probability estimate (CPE).

Results And Limitations: Based on univariate analysis for OS, the following genes were incorporated into a multigene signature: AR splice variant 7 (AR-V7), and three androgen-regulated genes: GRHL2, HOXB13, and FOXA1. The number of positive transcripts clearly stratified survival outcomes (median OS: not reached vs 24.8 mo vs 16.2 mo for 0, 1, and ≥2 transcripts, respectively; p = 0.0052). Notably, this multigene signature retained prognostic significance on multivariable analysis (hazard ratio, 2.1; 95% confidence interval, 1.1-4.0; p = 0.019). Moreover, CPE for this model was 0.78, indicating strong discriminative capacity. Limitations include short follow-up time.

Conclusions: Our data demonstrate the prognostic utility of a novel whole-blood AR-based signature in mCRPC patients commencing contemporary systemic therapies. Our pragmatic assay requires minimal processing, can be performed in most hospital laboratories, and could represent a key prognostic tool for risk stratification in mCRPC.

Patient Summary: We found that expression of certain genes associated with the androgen receptor could help determine how long men with advanced prostate cancer survive after starting modern drug therapies.
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http://dx.doi.org/10.1016/j.euf.2019.04.020DOI Listing
May 2019

Circulating oestrogen receptor mutations and splice variants in advanced prostate cancer.

BJU Int 2019 11 3;124 Suppl 1:50-56. Epub 2019 Oct 3.

Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia.

Objective: To characterize circulating oestrogen receptor ( ER) mutants and splice variants in men with advanced prostate cancer.

Materials And Methods: Sequential blood samples were obtained from men with advanced prostate cancer, and from healthy controls. Blood-derived RNA samples were analysed using droplet digital PCR for the presence of six ERα mutations (E380Q, L536Q, Y537C, Y537S, Y537N and D538G), and six ERα and ERβ splice variants (ERα-66, ERα-36, ERβ1, ERβ2, ERβ4 & ERβ5).

Results: A total of 94 samples were collected from 42 men with advanced prostate cancer. Four mutations (E380Q, L536Q, Y537S and D538G) and all six splice variants were detected in patient samples. Splice variants were detectable in non-cancer control samples. The presence of ER mutations was associated with bone metastases and castration resistance. ERβ splice variant concentrations decreased after successive lines of treatment.

Conclusions: The ER mutations were detectable in plasma from patients with advanced prostate cancer. ER splice variants were frequently detected in both men with and without prostate cancer.
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http://dx.doi.org/10.1111/bju.14797DOI Listing
November 2019

Incident Chronic Kidney Disease After Radical Nephrectomy for Renal Cell Carcinoma.

Clin Genitourin Cancer 2019 06 15;17(3):e581-e591. Epub 2019 Mar 15.

QIMR Berghofer Medical Research Institute, Brisbane, Australia; University of Queensland, Brisbane, Australia.

Background: Chronic kidney disease (CKD) after surgery for kidney cancer is common, and is associated with increased morbidity and mortality. This study aimed to identify factors associated with incident CKD in patients managed with radical nephrectomy.

Patients And Methods: All patients diagnosed with renal cell carcinoma between January 2012 and December 2013 were ascertained from state-based cancer registries in Queensland and Victoria. Information on patient, tumor, and health service characteristics was obtained via chart review. Multivariable logistic regression was used to evaluate exposures associated with incident CKD (estimated glomerular filtration rate [eGFR] <60 mL per minute per 1.73 m) at 12 months after nephrectomy.

Results: Older age (adjusted odds ratio [aOR] per 5-year increase, 1.5; 95% confidence interval [CI], 1.4-1.6), male sex (aOR, 1.4; 95% CI, 1.0-2.0), obese compared with not obese (aOR, 1.8; 95% CI, 1.2-2.7), rural compared with urban place of residence (aOR, 1.8; 95% CI, 1.1-3.0) were associated with a higher risk of incident CKD. Lower preoperative eGFR was also associated with a higher risk of incident CKD. Management in private compared with public hospitals was also associated with a higher risk of CKD (aOR, 1.6; 95% CI, 1.2-2.2). Factors related to tumor size and cancer severity were also associated with worse postoperative kidney function, although it is likely this was a consequence of selection bias.

Conclusion: Patient characteristics have the strongest associations with incident CKD after radical nephrectomy. Potential risk factors were reasonably similar to recognized CKD risk factors for the general population. Patients who undergo nephrectomy who have CKD risk factors might benefit from ongoing postoperative screening for deterioration of kidney function.
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http://dx.doi.org/10.1016/j.clgc.2019.02.011DOI Listing
June 2019

The Contribution of Multiparametric Pelvic and Whole-Body MRI to Interpretation of F-Fluoromethylcholine or Ga-HBED-CC PSMA-11 PET/CT in Patients with Biochemical Failure After Radical Prostatectomy.

J Nucl Med 2019 09 22;60(9):1253-1258. Epub 2019 Mar 22.

St. Vincent's Hospital, Sydney, Australia.

Our purpose was to assess whether the addition of data from multiparametric pelvic MRI (mpMR) and whole-body MRI (wbMR) to the interpretation of F-fluoromethylcholine (F-FCH) or Ga-HBED-CC PSMA-11 (Ga-PSMA) PET/CT (=PET) improves the detection of local tumor recurrence or of nodal and distant metastases in patients after radical prostatectomy with biochemical failure. The current analysis was performed as part of a prospective, multicenter trial on F-FCH or Ga-PSMA PET, mpMR, and wbMR. Eligible men had an elevated level of prostate-specific antigen (PSA) (>0.2 ng/mL) and high-risk features (Gleason score > 7, PSA doubling time < 10 mo, or PSA > 1.0 ng/mL) with negative or equivocal conventional imaging results. PET was interpreted with mpMR and wbMR in consensus by 2 radiologists and compared with prospective interpretation of PET or MRI alone. Performance measures of each modality (PET, MRI, and PET/mpMR-wbMR) were compared for each radiotracer and each individual patient (for F-FCH, or Ga-PSMA for patients who had Ga-PSMA PET) and to a composite reference standard. There were 86 patients with PET (F-FCH [ = 76] and/or Ga-PSMA [ = 26]) who had mpMR and wbMR. Local tumor recurrence was detected in 20 of 76 (26.3%) on F-FCH PET/mpMR, versus 11 of 76 (14.5%) on F-FCH PET ( = 0.039), and in 11 of 26 (42.3%) on Ga-PSMA PET/mpMR, versus 6 of 26 (23.1%) on Ga-PSMA PET ( = 0.074). Per patient, PET/mpMR was more often positive for local tumor recurrence than PET ( = 0.039) or mpMR ( = 0.019). There were 20 of 86 patients (23.3%) with regional nodal metastases on both PET/wbMR and PET ( = 1.0) but only 12 of 86 (14%) on wbMR ( = 0.061). Similarly, there were more nonregional metastases detected on PET/wbMR than on PET ( = 0.683) or wbMR ( = 0.074), but these differences did not reach significance. Compared with the composite reference standard for the detection of disease beyond the prostatic fossa, PET/wbMR, PET, and wbMR had sensitivity of 50%, 50%, and 8.3%, respectively, and specificity of 97.1%, 97.1%, and 94.1%, respectively. Interpretation of PET/mpMR resulted in a higher detection rate for local tumor recurrence in the prostatic bed in men with biochemical failure after radical prostatectomy. However, the addition of wbMR to F-FCH or Ga-PSMA PET did not improve detection of regional or distant metastases.
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http://dx.doi.org/10.2967/jnumed.118.225185DOI Listing
September 2019

Assessment of Simplified Methods for Quantification of F-FDHT Uptake in Patients with Metastatic Castration-Resistant Prostate Cancer.

J Nucl Med 2019 09 8;60(9):1221-1227. Epub 2019 Mar 8.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

F-fluorodihydrotestosterone (F-FDHT) PET/CT potentially provides a noninvasive method for assessment of androgen receptor expression in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to assess simplified methods for quantifying F-FDHT uptake in mCRPC patients and to assess effects of tumor perfusion on these F-FDHT uptake metrics. Seventeen mCRPC patients were included in this prospective observational multicenter study. Test and retest 30-min dynamic F-FDHT PET/CT scans with venous blood sampling were performed in 14 patients. In addition, arterial blood sampling and dynamic O-HO scans were obtained in a subset of 6 patients. Several simplified methods were assessed: Patlak plots; SUV normalized to body weight (SUV), lean body mass (SUV), whole blood (SUV), parent plasma activity concentration (SUV), area under the parent plasma curve (SUV), and area under the whole-blood input curve (SUV); and SUV corrected for sex hormone-binding globulin levels (SUV). Results were correlated with parameters derived from full pharmacokinetic F-FDHT and O-HO. Finally, the repeatability of individual quantitative uptake metrics was assessed. Eighty-seven F-FDHT-avid lesions were evaluated. F-FDHT uptake was best described by an irreversible 2-tissue-compartment model. Replacing the continuous metabolite-corrected arterial plasma input function with an image-derived input function in combination with venous sample data provided similar results ( = 0.98). Patlak and SUV showed an excellent correlation ( > 0.9). SUV showed a moderate correlation to ( = 0.70, presumably due to fast F-FDHT metabolism. When calculating SUV, correlation to improved ( = 0.88). The repeatability of full kinetic modeling parameters was inferior to that of simplified methods (repeatability coefficients > 36% vs. < 28%, respectively). F-FDHT uptake showed minimal blood flow dependency. F-FDHT kinetics in mCRPC patients are best described by an irreversible 2-tissue-compartment model with blood volume parameter. SUV showed a near-perfect correlation with the irreversible 2-tissue-compartment model analysis and can be used for accurate quantification of F-FDHT uptake in whole-body PET/CT scans. In addition, SUV could potentially be used as an even simpler method to quantify F-FDHT uptake when less complex scanning protocols and accuracy are required.
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http://dx.doi.org/10.2967/jnumed.118.220111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735284PMC
September 2019

What Survival Benefits are Needed to Make Adjuvant Sorafenib Worthwhile After Resection of Intermediate- or High-Risk Renal Cell Carcinoma? Clinical Investigators' Preferences in the SORCE Trial.

Kidney Cancer 2018 Aug 1;2(2):123-131. Epub 2018 Aug 1.

NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia.

Background: Decisions about adjuvant therapy involve trade-offs between possible benefits and harms.

Objective: We sought to determine the survival benefits that clinical investigators would judge as sufficient to warrant treatment with adjuvant sorafenib in the SORCE trial after nephrectomy for apparently localised renal cell carcinoma (RCC).

Methods: A subset of clinical investigators in the SORCE trial completed a validated questionnaire that elicited the minimum survival benefits they judged sufficient to warrant one year of adjuvant sorafenib in scenarios with hypothetical baseline survival times of 5 years and 15 years, and baseline survival rates at 5 years of 65% and 85%.

Results: The 100 participating SORCE investigators had a median age of 42 years, and 74 were male. For one year of sorafenib versus no therapy, the median benefits in survival times the investigators judged sufficient to warrant treatment were an extra nine months beyond five years and an extra 12 months beyond 15 years; the median benefits in survival rates were an extra 5% beyond baseline survival rates of both 65% and 85% at five years. The patients recruited in the SORCE trial by these investigators judged smaller benefits sufficient to warrant adjuvant sorafenib for both survival rate scenarios (≤0.0001). The survival benefits the investigators judged sufficient to warrant one year of adjuvant therapy with sorafenib for RCC were similar to those of other clinicians considering three months of adjuvant chemotherapy for lung cancer, but smaller than those of clinicians considering six months of adjuvant chemotherapy for breast cancer.

Conclusion: SORCE investigators judged larger benefits necessary to warrant adjuvant sorafenib than their patients. The benefits required by the investigators were similar or smaller than those other clinicians considered sufficient to warrant adjuvant chemotherapy for other cancers. Clinicians should recognise that their patients and colleagues may have preferences that differ from their own when considering the potential benefits and harms of adjuvant treatment.
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http://dx.doi.org/10.3233/KCA-180038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364092PMC
August 2018

Identification of novel oncogenic events occurring early in prostate carcinogenesis using purified autologous malignant and non-malignant prostate epithelial cells.

BJU Int 2019 05;123 Suppl 5:27-35

Eastern Health Clinical School, Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne, Vic., Australia.

Objective: To interrogate enriched prostate cancer cells and autologous non-malignant prostate epithelial cells from men with localized prostate cancer, in order to identify early oncogenic pathways.

Patients And Methods: We collected malignant and matched non-malignant prostatectomy samples from men with adenocarcinoma involving two or more contiguous areas in only one lobe of the prostate. Tissue samples from both lobes were subjected to digestion and single-cell suspensions were prepared. Epithelial cell adhesion molecule-positive cells from cancerous and contralateral non-malignant (control) samples were isolated using magnetic beads, ensuring uniform populations were obtained for each donor. Unbiased RNA sequencing analysis was used to measure gene expression and for detection of transcribed mutations or splice variants that were over- or under-represented in malignant prostate epithelial cells relative to autologous control prostate epithelial cells.

Results: From five patient samples we identified 17 genes that were altered in prostate cancer epithelial cells, with 82% of genes being downregulated. Three genes, TDRD1, ANGTL4, and CLDN3, were consistently upregulated in malignant tissue. Malignant cells from three of the five patients showed evidence of upregulated ERG signalling, however, only one of these contained a TMPRSS2-ERG rearrangement. We did not identify mutations, gene rearrangements, or splice variants that were consistent amongst the patients.

Conclusions: Events occurring early in prostate cancer oncogenesis in these samples were characterized by a predominant downregulation of gene expression along with upregulation of TDRD1, ANGTL4 and CLDN3. No consistent mutations or splice variants were observed, but upregulation of ERG signalling was seen both in the presence and absence of the classic TMPRSS2-ERG rearrangement.
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http://dx.doi.org/10.1111/bju.14695DOI Listing
May 2019

Clinical Trials of Metastatic Castration-sensitive Prostate Cancer: Recent Progress and New Horizons.

Eur Urol Focus 2019 03 14;5(2):165-167. Epub 2018 Dec 14.

Monash University, Melbourne, Australia; Eastern Health, Melbourne, Australia.

Recent clinical trials have changed the treatment landscape for metastatic castration-sensitive prostate cancer. Ongoing and future studies using new therapeutic approaches hold the promise of further improving outcomes for patients with advanced prostate cancer.
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http://dx.doi.org/10.1016/j.euf.2018.12.001DOI Listing
March 2019

Prospective, Multisite, International Comparison of F-Fluoromethylcholine PET/CT, Multiparametric MRI, and Ga-HBED-CC PSMA-11 PET/CT in Men with High-Risk Features and Biochemical Failure After Radical Prostatectomy: Clinical Performance and Patient Outcomes.

J Nucl Med 2019 06 15;60(6):794-800. Epub 2018 Nov 15.

Olivia Newton-John Cancer Research Institute, La Trobe University, Melbourne, Australia and Austin Health, University of Melbourne, Melbourne, Australia.

A significant proportion of men with rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP) fail prostate fossa (PF) salvage radiation treatment (SRT). This study was done to assess the ability of F-fluoromethylcholine (F-FCH) PET/CT (hereafter referred to as F-FCH), Ga-HBED-CC PSMA-11 PET/CT (hereafter referred to as PSMA), and pelvic multiparametric MRI (hereafter referred to as pelvic MRI) to identify men who will best benefit from SRT. Prospective, multisite imaging studies were carried out in men who had rising PSA levels after RP, high-risk features, and negative/equivocal conventional imaging results and who were being considered for SRT. F-FCH (91/91), pelvic MRI (88/91), and PSMA (31/91) (Australia) were all performed within 2 wk. Imaging was interpreted by experienced local/central interpreters who were masked with regard to other imaging results, with consensus being reached for discordant interpretations. Expected management was documented before and after imaging, and data about all treatments and PSA levels were collected for 3 y. The treatment response to SRT was defined as a reduction in PSA levels of >50% without androgen deprivation therapy. The median Gleason score, PSA level at imaging, and PSA doubling time were 8, 0.42 (interquartile range, 0.29-0.93) ng/mL, and 5.0 (interquartile range, 3.3-7.6) months. Recurrent prostate cancer was detected in 28% (25/88) by pelvic MRI, 32% (29/91) by F-FCH, and 42% (13/31) by PSMA. This recurrence was found within the PF in 21.5% (19/88), 13% (12/91), and 19% (6/31) and at sites outside the PF (extra-PF) in 8% (7/88), 19% (17/91), and 32% (10/31) by MRI, F-FCH, and PSMA, respectively ( < 0.004). A total of 94% (16/17) of extra-PF sites on F-FCH were within the pelvic MRI field. Intrapelvic extra-PF disease was detected in 90% (9/10) by PSMA and in 31% (5/16) by MRI. F-FCH changed management in 46% (42/91), and MRI changed management in 24% (21/88). PSMA provided additional management changes over F-FCH in 23% (7/31). The treatment response to SRT was higher in men with negative results or disease confined to the PF than in men with extra-PF disease (F-FCH 73% [32/44] versus 33% [3/9] [ < 0.02], pelvic MRI 70% [32/46] versus 50% [2/4] [ was not significant], and PSMA 88% [7/8] versus 14% [1/7] [ < 0.005]). Men with negative imaging results (MRI, F-FCH, or PSMA) had high (78%) SRT response rates. F-FCH and PSMA had high detection rates for extra-PF disease in men with negative/equivocal conventional imaging results and rising PSA levels after RP. These findings affected management and treatment responses, suggesting an important role for PET in triaging men being considered for curative SRT.
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http://dx.doi.org/10.2967/jnumed.118.220103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581227PMC
June 2019

Good clinical practice can and must include comparative effectiveness research.

BJU Int 2018 11 13;122 Suppl 5:7-8. Epub 2018 Nov 13.

University of Otago, Christchurch, New Zealand.

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http://dx.doi.org/10.1111/bju.14590DOI Listing
November 2018