Objective
To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with 177Lu‐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 177Lu‐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 68Ga‐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/m2) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive 177Lu‐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 68Ga‐PSMA‐11 and Fluorine‐18 (18F)‐FDG‐PET/CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018.
Results and Conclusions
177Lu‐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 177Lu‐PSMA‐617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.
Lutetium-177 177LuLu-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 177LuLu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer.
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 68GaGa-PSMA-11 and 2-flourine-1818Ffluoro-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 177LuLu-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.
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 177LuLu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the 177LuLu-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 177LuLu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to 177LuLu-PSMA-617.
177LuLu-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. 177LuLu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel.
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, 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.
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.
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.
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.).
Previously, results from the TheraP trial showed that treatment with lutetium-177 177LuLu-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 68GaGa-PSMA-11 PET (PSMA-PET) and 2-18Ffluoro-2-deoxy-D-glucose PET (FDG-PET) imaging parameters as predictive and prognostic biomarkers in this patient population.
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 177LuLu-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 177LuLu-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.
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 177LuLu-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 177LuLu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel had high PSMA uptake (SUVmean of ≥10). Odds of PSA response to 177LuLu-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 177LuLu-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 177LuLu-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).
In men with metastatic castration-resistant prostate cancer, PSMA-PET SUVmean was predictive of higher likelihood of favourable response to 177LuLu-PSMA-617 than cabazitaxel, which provides guidance for optimal 177LuLu-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.
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.
Prostate cancer cells exhibit altered cellular metabolism but, notably, not the hallmarks of Warburg metabolism. Prostate cancer cells exhibit increased
synthesis of fatty acids (FA); however, little ...is known about how extracellular FAs, such as those in the circulation, may support prostate cancer progression. Here, we show that increasing FA availability increased intracellular triacylglycerol content in cultured patient-derived tumor explants, LNCaP and C4-2B spheroids, a range of prostate cancer cells (LNCaP, C4-2B, 22Rv1, PC-3), and prostate epithelial cells (PNT1). Extracellular FAs are the major source (∼83%) of carbons to the total lipid pool in all cell lines, compared with glucose (∼13%) and glutamine (∼4%), and FA oxidation rates are greater in prostate cancer cells compared with PNT1 cells, which preferentially partitioned extracellular FAs into triacylglycerols. Because of the higher rates of FA oxidation in C4-2B cells, cells remained viable when challenged by the addition of palmitate to culture media and inhibition of mitochondrial FA oxidation sensitized C4-2B cells to palmitate-induced apoptosis. Whereas in PC-3 cells, palmitate induced apoptosis, which was prevented by pretreatment of PC-3 cells with FAs, and this protective effect required DGAT-1-mediated triacylglycerol synthesis. These outcomes highlight for the first-time heterogeneity of lipid metabolism in prostate cancer cells and the potential influence that obesity-associated dyslipidemia or host circulating has on prostate cancer progression. IMPLICATIONS: Extracellular-derived FAs are primary building blocks for complex lipids and heterogeneity in FA metabolism exists in prostate cancer that can influence tumor cell behavior.
Objectives
To determine the activity and safety of lutetium‐177 (177Lu)‐prostate‐specific membrane antigen (PSMA)‐617 in men with metastatic castration‐resistant prostate cancer (mCRPC) commencing ...enzalutamide, who are at high risk of early progression, and to identify potential prognostic and predictive biomarkers from imaging, blood and tissue.
Participants and Methods
ENZA‐p (ANZUP 1901) is an open‐label, randomized, two‐arm, multicentre, phase 2 trial. Participants are randomly assigned (1:1) to treatment with enzalutamide 160 mg daily alone or enzalutamide plus 177Lu‐PSMA‐617 7.5 GBq on Days 15 and 57. Two additional 177Lu‐PSMA‐617 doses are allowed, informed by Day‐92 Gallium‐68 (68Ga)‐PSMA positron emission tomography (PET; up to four doses in total). The primary endpoint is prostate‐specific antigen (PSA) progression‐free survival (PFS). Other major endpoints include radiological PFS, PSA response rate, overall survival, health‐related quality of life, adverse events and cost‐effectiveness. Key eligibility criteria include: biochemical and/or clinical progression; 68Ga‐PSMA PET‐avid disease; no prior androgen signalling inhibitor, excepting abiraterone; no prior chemotherapy for mCRPC; and ≥2 high‐risk features for early enzalutamide failure. Assessments are 4 weekly during study treatment, then 6 weekly until radiographic progression. Response Evaluation Criteria in Solid Tumours (RECIST) are used to assess imaging conducted every 12 weeks, 68Ga‐PSMA PET at baseline, Days 15 and 92, and at progression, and 18F‐fluorine deoxyglucose (18F‐FDG) PET at baseline and progression. Translational samples include blood (and optional biopsies) at baseline, Day 92, and first progression. Correlative studies include identification of prognostic and predictive biomarkers from 68Ga‐PSMA and 18F‐FDG PET/CT, circulating tumour cells and circulating tumour DNA. The trial will enrol 160 participants, providing 80% power with a two‐sided type‐1 error rate of 5% to detect a hazard ratio of 0.625 assuming a median PSA‐PFS of 5 months with enzalutamide alone.
Results and Conclusion
The combination of 177Lu‐PSMA‐617 and enzalutamide may be synergistic. ENZA‐p will determine the safety and efficacy of the combination in addition to developing predictive and prognostic biomarkers to better guide treatment decisions.
Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of ...disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as “M0” at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval CI: 0.29–1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16–0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men.
Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting.
Patients with metachronous metastatic hormone-sensitive prostate cancer, including those with low-volume disease, have an overall survival benefit with the addition of potent androgen receptor inhibition to testosterone suppression and should be offered this therapy if there are no contraindications.
We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of ...health-related quality of life (HRQL).
HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible).
HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9;
< .001), cognitive function (4.0, 95% CI, 2.5 to 5.5;
< .001), and physical function (2.6, 95% CI, 1.3 to 3.9;
< .001), but not OHQL (1.2, 95% CI, -0.2 to 2.7;
= .1). Deterioration-free survival rates at 3 years, and log-rank
values comparing the whole distributions, favored enzalutamide over control for OHQL (31%
17%;
< .0001), cognitive function (31%
20%;
= .001), and physical function (31%
22%;
< .001), but not fatigue (24%
18%;
= .16). The effects of enzalutamide on HRQL were independent of baseline characteristics.
Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.
A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring ...validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re‐analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow‐up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow‐up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6–32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2–25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.
What's new?
In prostate cancer survivors, rising PSA levels can presage a return of the tumor. Much research has gone into identifying biomarkers associated with biochemical relapse, but often these biomarkers aren't individually useful for predicting survival. In this study, the authors surveyed a variety of available biomarkers, to test how well they predicted metastatic relapse. While they found seven markers to be associated with biochemical relapse, only two functioned as key predictors of metastasis. The authors propose that biochemical relapse is not a good surrogate for metastasis.
PDF
![[177Lu]Lu-PSMA-617 versus c...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0140-6736/small "[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial")
