Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial.

BACKGROUND: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. METHODS: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. FINDINGS: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). INTERPRETATION: These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. FUNDING: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

Hidden in plain sight - Survival consequences of baseline symptom burden in women with recurrent ovarian cancer.

OBJECTIVE: To describe the baseline symptom burden(SB) experienced by patients(pts) with recurrent ovarian cancer(ROC) prior and associations with progression free survival (PFS) and overall survival (OS). METHODS: We analysed baseline SB reported by pts. with platinum resistant/refractory ROC (PRR-ROC) or potentially­platinum sensitive ROC receiving their third or greater line of chemotherapy (PPS-ROC≥3) enrolled in the Gynecologic Cancer InterGroup - Symptom Benefit Study (GCIG-SBS) using the Measure of Ovarian Symptoms and Treatment concerns (MOST). The severity of baseline symptoms was correlated with PFS and OS. RESULTS: The 948 pts. reported substantial baseline SB. Almost 80% reported mild to severe pain, and 75% abdominal symptoms. Shortness of breath was reported by 60% and 90% reported fatigue. About 50% reported moderate to severe anxiety, and 35% moderate to severe depression. Most (89%) reported 1 or more symptoms as moderate or severe, 59% scored 6 or more symptoms moderate or severe, and 46% scored 9 or more symptoms as moderate or severe. Higher SB was associated with significantly shortened PFS and OS; five symptoms had OS hazard ratios larger than 2 for both moderate and severe symptom cut-offs (trouble eating, vomiting, indigestion, loss of appetite, and nausea; p < 0.001). CONCLUSION: Pts with ROC reported high SB prior to starting palliative chemotherapy, similar among PRR-ROC and PPS-ROC≥3. High SB was strongly associated with early progression and death. SB should be actively managed and used to stratify patients in clinical trials. Clinical trials should measure and report symptom burden and the impact of treatment on symptom control.

Timing of prognostic discussions in people with advanced cancer: a systematic review.

PURPOSE: Many people with cancer (patients) want to know their prognosis (a quantitative estimate of their life expectancy) but this is often not discussed or poorly communicated. The optimal timing of prognostic discussions with people with advanced cancer is highly personalised and complex. We aimed to find, organise, and summarise research regarding the timing of discussions of prognosis with people with advanced cancer. METHODS: We conducted a systematic review of publications from databases, clinical practice guidelines, and grey literature from inception to 2023. We also searched the reference lists of systematic reviews, editorials, and clinical trial registries. Eligibility criteria included publications regarding adults with advanced cancer that reported a timepoint when a discussion of prognosis occurred or should occur. RESULTS: We included 63 of 798 identified references; most of which were cross-sectional cohort studies with a range of 4-9105 participants. Doctors and patients agreed on several timepoints including at diagnosis of advanced cancer, when the patient asked, upon disease progression, when there were no further anti-cancer treatments, and when recommending palliative care. Most of these timepoints aligned with published guidelines and expert recommendations. Other recommended timepoints depended on the doctor's clinical judgement, such as when the patient 'needed to know' or when the patient 'seemed ready'. CONCLUSIONS: Prognostic discussions with people with advanced cancer need to be individualised, and there are several key timepoints when doctors should attempt to initiate these conversations. These recommended timepoints can inform clinical trial design and communication training for doctors to help improve prognostic understanding.

Patients' perception of the benefits of palliative systemic therapy for advanced cancer.

BACKGROUND: Patients with advanced cancer who misunderstand their prognosis and chance of cure tend to overestimate the likely benefits of palliative systemic therapy. AIM: To determine patient perceptions of palliative systemic therapy benefits in advanced cancer. METHODS: We surveyed 104 outpatients with advanced cancer receiving systemic anticancer therapy and their treating oncologists. Patients recorded their understanding of treatment impact on chance of cure and symptoms. Life expectancy was estimated by patients and oncologists. A visual analogue scale (0-10) was used to record how patients and oncologists valued quality of life (QOL) and length of life (LOL) (<4 QOL most important; 4-7 QOL and LOL equal; >7 LOL most important). Patient-oncologist discordance was defined as a ≥4-point difference. RESULTS: The main reasons patients selected for receiving treatment were to live longer (54%) and cure their cancer (36%). Most patients reported treatment was very/somewhat likely to prolong life (84%) and improve symptoms (76%), whereas 20% reported treatment was very/somewhat likely to cure their cancer. 42% of patients selected a timeframe for life expectancy (choice of four timeframes between <1 year and ≥5 years); of these, 62% selected a longer timeframe than their oncologist. When making treatment decisions, 71% of patients (52% of oncologists) valued QOL and LOL equally. Patient-oncologist discordance was 21%, mostly because of oncologists valuing QOL more than their patients (70%). CONCLUSION: At least 20% of patients receiving systemic therapy for advanced cancer reported an expectation of cure. Most patients and oncologists value QOL and LOL equally when making treatment decisions.

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

BACKGROUND: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. METHODS: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. FINDINGS: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. INTERPRETATION: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. FUNDING: Astellas Pharma.

Prognostic value of patient reported outcomes in advanced gastro-oesophageal cancer: a systematic review.

To summarise the prognostic value of patient-reported outcomes (PROs) in advanced gastro-oesophageal (GO) cancer. We systematically searched multiple databases using search terms related to advanced GO cancer, PRO and prognosis. Studies examining the relationship between baseline PROs and prognosis were included. Two reviewers independently screened articles and extracted data on study design, survival and associations between PROs and survival, in both univariable and multivariable analyses. QUIPS was used for quality assessment. From 3004 studies screened, seven studies were eligible, comprising PRO data from 2761 of 3408 (81%) participants. Median survival times ranged from 4.5 to 9.5 months. Among participants with oesophageal squamous cell carcinoma (SCC), physical functioning, social functioning and fatigue (QLQ-C30) were associated with overall survival (OS) in one univariable analysis. Among three studies of participants with adenocarcinoma, univariable analyses revealed associations between OS and global quality of life (QOL), physical functioning, role functioning and social functioning; two studies showed association with pain. There was an association between emotional functioning, fatigue, lack of mobility, lack of self-care, appetite loss/anorexia and OS in one study. One multivariable analysis among participants with oesophageal SCC showed physical and social functioning was associated with OS. Among participants with adenocarcinoma, multivariable analyses showed associations between OS and physical functioning/lack of mobility, appetite loss/anorexia (three studies), global QOL, role functioning/lack of self-care, pain (two studies) and social functioning (one study). Physical functioning, role functioning, social functioning, pain, anorexia and global QOL were associated with OS in advanced GO cancer.

PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial.

BACKGROUND: Previously, results from the TheraP trial showed that treatment with lutetium-177 [177Lu]Lu-PSMA-617 improved frequency of prostate-specific antigen (PSA) response rate and progression-free survival compared with cabazitaxel in men with metastatic castration-resistant prostate cancer. In this study, we aimed to analyse gallium-68 [68Ga]Ga-PSMA-11 PET (PSMA-PET) and 2-[18F]fluoro-2-deoxy-D-glucose PET (FDG-PET) imaging parameters as predictive and prognostic biomarkers in this patient population. METHODS: TheraP was a multicentre, open-label, randomised phase 2 trial that recruited men with metastatic castration-resistant prostate cancer after treatment with docetaxel who were suitable for cabazitaxel from 11 hospitals in Australia. Participants were required to be 18 years old or older; have adequate haematological, renal, and liver function; and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned (1:1) using a centralised system using minimisation with a random component and that stratified patients by disease burden, previous treatment with enzalutamide or abiraterone, and study site. Patients were either given cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles) or [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles). The primary study endpoint, analysed previously, was PSA response rate. The prespecified tertiary study endpoint was association between total tumour quantitative parameters on PSMA-PET, FDG-PET, and baseline characteristics with clinical outcomes. A SUVmean of 10 or higher on PSMA-PET was evaluated as a predictive biomarker for response to [177Lu]Lu-PSMA-617 versus cabazitaxel. A metabolic tumour volume (MTV) of 200 mL or higher on FDG-PET was tested as a prognostic biomarker. Both cutoff points were prespecified. The analysis was intention-to-treat, using logistic regression. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: 200 patients were randomly assigned between Feb 6, 2018, and Sept 3, 2019. 101 men were assigned to the cabazitaxel group and 99 were assigned to the [177Lu]Lu-PSMA-617 group. The median follow-up at data cutoff of July 20, 2020, was 18·4 months (IQR 12·8-21·8). 35 (35%) of 99 men who were assigned [177Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel had high PSMA uptake (SUVmean of ≥10). Odds of PSA response to [177Lu]Lu-PSMA-617 versus cabazitaxel were significantly higher for men with SUVmean of 10 or higher compared with those with SUVmean of less than 10 (odds ratio [OR] 12·19 [95% CI 3·42-58·76] vs 2·22 [1·11-4·51]; padj=0·039 for treatment-by-SUVmean interaction). PSA response rate for [177Lu]Lu-PSMA-617 compared with cabazitaxel was 32 (91% [95% CI 76-98]) of 35 men versus 14 (47% [29-65]) of 30 men in patients with SUVmean of 10 or higher, and 33 (52% [39-64]) of 64 men versus 23 (32% [22-45]) of 71 men in those with SUVmean of less than 10. High-volume disease on FDG-PET (MTV ≥200 mL) was seen in 30 (30%) of 99 men who were assigned [177Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel. PSA response rate for both treatment groups combined for FDG-PET MTV of 200 mL or higher versus FDG-PET MTV of less than 200 mL was 23 (38% [95% CI 26-52]) of 60 men versus 79 (56% [48-65]) of 140 men (OR 0·44, 95% CI 0·23-0·84; padj=0·035). INTERPRETATION: In men with metastatic castration-resistant prostate cancer, PSMA-PET SUVmean was predictive of higher likelihood of favourable response to [177Lu]Lu-PSMA-617 than cabazitaxel, which provides guidance for optimal [177Lu]Lu-PSMA-617 use. High FDG-PET MTV was associated with lower responses regardless of randomly assigned treatment, warranting further research for treatment intensification. A strength of this analysis is the validation of pre-specified cutpoints within a multicentre, randomised, controlled trial. Quantitative PET parameters used, however, require specialised software and are not yet routinely available in most clinics. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organisation, Movember Foundation, It's a Bloke Thing, CAN4CANCER, The Distinguished Gentleman's Ride.

[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

BACKGROUND: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers ß 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 [177Lu]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 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]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 [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 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 [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]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 [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. INTERPRETATION: [177Lu]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. [177Lu]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.

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

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.).

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer.

BACKGROUND: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. METHODS: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. CONCLUSIONS: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.

Measure of Ovarian Symptoms and Treatment concerns (MOST) indexes and their associations with health-related quality of life in recurrent ovarian cancer.

PURPOSE: The Measure of Ovarian Symptoms and Treatment (MOST) concerns is a validated patient-reported symptom assessment tool for assessing symptom benefit and adverse effects of palliative chemotherapy in women with recurrent ovarian cancer (ROC). We aimed to examine (i) how symptoms within MOST symptom indexes track together (i.e. co-occur) and (ii) the association between MOST symptom indexes and key aspects of health-related quality of life (HRQL). METHOD: A prospective cohort of women with ROC completed the MOST-T35, EORTC QLQ-C30 and EORTC QLQ-OV28 at baseline and before each cycle of chemotherapy. Analyses were conducted on baseline and end-of-treatment data. Exploratory factor analysis and hierarchical cluster analysis identified groups of co-occurring symptoms. Path models examined associations between MOST symptom indexes and HRQL. RESULTS: Data from 762 women at baseline and 681 at treatment-end who completed all 22 symptom-specific MOST items and at least one HRQL measure were analysed. Four symptom clusters emerged at baseline and treatment-end: abdominal symptoms, symptoms associated with peripheral neuropathy, nausea and vomiting, and psychological symptoms. Psychological symptoms (MOST-Psych) and symptoms due to disease (ovarian cancer) or treatment (MOST-DorT) were associated with poorer scores on QLQ-C30 and OV28 functioning domains and worse overall health at both time points. CONCLUSION: Four MOST symptom clusters were consistent across statistical methods and time points. These findings suggest that routine standardized assessment of psychological and physical symptoms in clinical practice with MOST plus appropriate symptom management referral pathways is an intervention for improving HRQL that warrants further research.

'Pain-free TRUS B': a phase 3 double-blind placebo-controlled randomized trial of methoxyflurane with periprostatic local anaesthesia to reduce the discomfort of transrectal ultrasonography-guided prostate biopsy (ANZUP 1501).

OBJECTIVE: To determine whether the addition of inhaled methoxyflurane to periprostatic infiltration of local anaesthetic (PILA) during transrectal ultrasonography-guided prostate biopsies (TRUSBs) improved pain and other aspects of the experience. PATIENTS AND METHODS: We conducted a multicentre, placebo-controlled, double-blind, randomized phase 3 trial, involving 420 men undergoing their first TRUSB. The intervention was PILA plus a patient-controlled device containing either 3 mL methoxyflurane, or 3 mL 0.9% saline plus one drop of methoxyflurane to preserve blinding. The primary outcome was the pain score (0-10) reported by the participant after 15 min. Secondary outcomes included ratings of other aspects of the biopsy experience, willingness to undergo future biopsies, urologists' ratings, biopsy completion, and adverse events. RESULTS: The mean (SE) pain scores 15 min after TRUSB were 2.51 (0.22) in those assigned methoxyflurane vs 2.82 (0.22) for placebo (difference 0.31, 95% confidence interval [CI] -0.75 to 0.14; P = 0.18). Methoxyflurane was associated with better scores for discomfort (difference -0.48, 95% CI -0.92 to -0.03; P = 0.035, adjusted [adj.] P = 0.076), whole experience (difference -0.50, 95% CI -0.92 to -0.08; P = 0.021, adj. P = 0.053), and willingness to undergo repeat biopsies (odds ratio 1.67, 95% CI 1.12-2.49; P = 0.01) than placebo. Methoxyflurane resulted in higher scores for drowsiness (difference +1.64, 95% CI 1.21-2.07; P < 0.001, adj. P < 0.001) and dizziness (difference +1.78, 95% CI 1.31-2.24; P < 0.001, adj. P < 0.001) than placebo. There was no significant difference in the number of ≥ grade 3 adverse events. CONCLUSIONS: We found no evidence that methoxyflurane improved pain scores at 15 min, however, improvements were seen in patient-reported discomfort, overall experience, and willingness to undergo repeat biopsies.

Using three scenarios to explain life expectancy in advanced cancer: attitudes of patients, family members, and other healthcare professionals.

AIM: To evaluate a web-based tool for estimating and explaining three scenarios for expected survival time to people with advanced cancer (patients), their family members (FMs), and other healthcare professionals (HCPs). METHODS: Thirty-three oncologists estimated the "median survival of a group of similar patients" for patients seeking quantitative prognostic information. The web-based tool generated worst-case, most likely, and best-case scenarios for survival based on the oncologist's estimate. Oncologists presented the scenarios to each patient and provided a printed summary to patients, FMs, and HCPs. Attitudes to the information were assessed by questionnaires. Observed survival for each patient was compared with the oncologist's estimated survival and the three scenarios. RESULTS: Prognosis was discussed with 222 patients: median age 67 years; 61% male; most common primary sites pancreas 15%, non-small-cell lung 15%, and colorectal 12%. The median (range) for observed survival times was 9 months (0.5-43) and for oncologist's estimated survival times was 12 months (2-96). Ninety-one percent of patients, 91% of FMs, and 84% of HCPs agreed that it was helpful having life expectancy explained as three scenarios. The majority (77%) of patients judged the information presented about their life expectancy to be the same or better than they had expected before the consultation. The survival estimates met a priori criteria for calibration, precision, and accuracy. CONCLUSIONS: Patients, FMs, and HCPs found it helpful to receive personalized prognostic information formatted as three scenarios for survival. It was feasible, acceptable, and safe to use a web-based resource to do this.

Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer: the Gynecologic Cancer InterGroup-Symptom Benefit Study.

OBJECTIVE: The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3). METHODS: Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0-100). RESULTS: Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. CONCLUSION: Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants.

Palliative care facilitates the preparedness of caregivers for thoracic cancer patients.

OBJECTIVE: Palliative care improves outcomes for patients with thoracic cancer; however, limited evidence exists for the benefits of this approach for caregivers. This study aimed to advance understanding of the experiences of palliative care described by bereaved caregivers. METHODS: Fifteen adult caregivers completed semi-structured interviews following prior participation in a randomised controlled trial of early referral to palliative care versus discretionary referral to palliative care. Interviews explored caregiver experiences of palliative care delivery. Interview transcripts were thematically analysed. RESULTS: Four related themes about the experiences of palliative care were identified, each of which required sufficient time between palliative care first contact and death: 'relationship building'; 'clear communication and information'; 'access to practical support'; and 'access to psychosocial support'. The core category underpinning these themes was palliative care facilitates caregiver preparedness. Caregivers noted that palliative care played a critical role in preparing them for the future and described a sense of practical and emotional 'relief' associated with the support services made available to them. CONCLUSION: Our findings emphasise that palliative care can have a positive impact on caregivers' preparedness for providing the care needed by thoracic cancer patients and that this can improve the experiences of both caregivers and patients.

The International Collaboration for Research methods Development in Oncology (CReDO) workshops: shaping the future of global oncology research.

Low-income and middle-income countries (LMICs) have a disproportionately high burden of cancer and cancer mortality. The unique barriers to optimum cancer care in these regions necessitate context-specific research. The conduct of research in LMICs has several challenges, not least of which is a paucity of formal training in research methods. Building capacity by training early career researchers is essential to improve research output and cancer outcomes in LMICs. The International Collaboration for Research methods Development in Oncology (CReDO) workshop is an initiative by the Tata Memorial Centre and the National Cancer Grid of India to address gaps in research training and increase capacity in oncology research. Since 2015, there have been five CReDO workshops, which have trained more than 250 oncologists from India and other countries in clinical research methods and protocol development. Participants from all oncology and allied fields were represented at these workshops. Protocols developed included clinical trials, comparative effectiveness studies, health services research, and observational studies, and many of these protocols were particularly relevant to cancer management in LMICs. A follow-up of these participants in 2020 elicited an 88% response rate and showed that 42% of participants had made progress with their CReDO protocols, and 73% had initiated other research protocols and published papers. In this Policy Review, we describe the challenges to research in LMICs, as well as the evolution, structure, and impact of CReDO and other similar workshops on global oncology research.

Physician-patient communication of costs and financial burden of cancer and its treatment: a systematic review of clinical guidelines.

BACKGROUND: Optimising the care of individuals with cancer without imposing significant financial burden related to their anticancer treatment is becoming increasingly difficult. The American Society of Clinical Oncology (ASCO) has recommended clinicians discuss costs of cancer care with patients to enhance shared decision-making. We sought information to guide oncologists' discussions with patients about these costs. METHODS: We searched Medline, EMBASE and clinical practice guideline databases from January 2009 to 1 June 2019 for recommendations about discussing the costs of care and financial burden. Guideline quality was assessed with the AGREE-II instrument. RESULTS: Twenty-seven guidelines met our eligibility criteria, including 16 from ASCO (59%). 21 of 27 (78%) guidelines included recommendations about discussion or consideration of treatment costs when prescribing, with information about actual costs in four (15%). Recognition of the risk of financial burden or financial toxicity was described in 81% (22/27) of guidelines. However, only nine guidelines (33%) included information about managing the financial burden. CONCLUSIONS: Current clinical practice guidelines have little information to guide physician-patient discussions about costs of anticancer treatment and management of financial burden. This limits patients' ability to control costs of treatment, and for the healthcare team to reduce the incidence and severity of financial burden. Current guidelines recommend clinician awareness of price variability and high costs of treatment. Clinicians are recommended to explore cost concerns and address financial worries, especially in high risk groups. Future guidelines should include advice on facilitating cost transparency discussions, with provision of cost information and resources.