8 PSMA PET does not alter ongoing systemic therapy in this patient cohort and is not advocated by many experts. The goal standard of systemic therapy is an improvement of overall survival, but other factors should be considered especially in the nmCRPC group of patients who remain asymptomatic from disease. Drug-drug interactions, side effects of therapy and quality of life are important issues that one should consider when selecting appropriate therapy in nmCRPC. Darolutamide was found to delay the onset of metastatic disease from 18 months to 40 months. In addition, there were fewer neurological side effects, treatment discontinuations or severe adverse events (ARAMIS NEJM 2019). Management of High-risk disease Local therapies include external beam radiotherapy (EBRT), EBRT and brachytherapy or surgery (radical prostatectomy and radical lymph node dissection). Patient and disease related factors are important in selecting appropriate treatment. The inclusion of the regional nodes in radiotherapy elds has always been contentious. The POP-RT study has conrmed that nodal EBRT was superior in terms of disease-free survival but not overall survival (Murthy, JCO 2021). Clinical trials with SBRT boost to the prostate and prophylactic hypofractionated RT (5Gy x 5 fractions) to pelvic nodes are currently under way and will provide a resource friendly alternative for busy radiotherapy centres. The Canadian PCS IV has conrmed that there is no benet with extended adjuvant ADT in high-risk prostate cancer (18 months vs 36 months). There have been no gains with the inclusion of systemic therapy (neoadjuvant or adjuvant) to surgery for highrisk disease. Two years of adjuvant abiraterone +- enzalutamide conferred a metastases free survival benet in patients with high-risk disease. However, 15% of patients did not receive radiotherapy, a signicant number did not receive pelvic nodal RT and grade 3 toxicity was increased. This option may be suitable for patients with PSMA signicant disease, but this remains investigational. There are several ongoing studies looking at the addition of adjuvant ARPI in high-risk prostate cancer including DASL-HiCAP where darolutamide will be added to ADT following RT for denitive or salvage RT in high-risk disease. Biochemical recurrence (BCR) Both the PRESTO and EMBARK (J Urol 2023) demonstrated a benet in metastases free survival with the use of ARPI in high risk BCR patients. Radium 223 The use of Radium 223 (Ra-233) has declined despite overall survival data dating back to 2013. It should be introduced early on during the disease and, in the setting of bone only metastases. It should not inuence the use of Lutetium-177 (LU-177) therapy during later lines of therapy. This is evident from the LARU study presented at ESMO in 2022. Bone marrow toxicity and response rates were not altered by prior Ra-223 use even when docetaxel was sequenced between these two strategies. Treatment sequencing Treatment selection is guided by: 1. The timing of metastatic disease: de novo or metachronous metastatic disease 2. Prior therapies in the case of metachronous disease 3. Patient risk prole and preference 4. Access to care 5. Volume of disease (CHAARTED) or high-risk disease (LATITUDE). This is always a matter for discussion. Patients often defer to ARPI therapies in view of the convenience of oral therapies and acceptable side effect prole. The use of ARPI following prior ARPI therapy is not clinically meaningful with enzalutamide followed by abiraterone (and vice versa) offering a modest 3month PFS. The results of the CARD study demonstrated that cabazitaxel produces clinically meaningful benet when offered after prior ARPI or docetaxel therapy as compared to a switch in ARPI therapies. This included benets in PFS and OS. Ra-223 is appropriate for bone only disease while LU177 is active in both bone and soft tissue disease provided the disease is PSMA avid. The mean SUV may be predictive of LU-177 response, but this remains investigational. Most experts concurred that PSMA PET was only utilised if LU-177 was being considered for treatment. Most experts utilise conventional imaging (CT scan and bone scan) to monitor disease progression. Conclusion The future of metastatic prostate cancer is promising. As one expert indicated, it is a chess game anticipating the tumour behaviour, initiating an appropriate therapy for the clinical scenario, and consistently staying ahead to optimise sequencing and to gain durable responses. Nonetheless, tumour biology is a predeterminant of treatment outcomes and much of the future research lies in this area. CHAARTED ≥4 bone metastases including >=1 outside the vertebral column or pelvis +/or visceral metastases LATITUDE ≥2 high risk features of ≥3 bone metastases Visceral metastases ≥ISUP Grade 4 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
RkJQdWJsaXNoZXIy NTIyOTQ=