Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

Pervasive chromosomal instability and karyotype order in tumour evolution.

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.

Real-world use of first-generation antiandrogens: impact on patient outcomes and subsequent therapies in metastatic castration-resistant prostate cancer.

OBJECTIVES: To investigate the recent real-world use of first-generation antiandrogens (FGAs) in metastatic castration-resistant prostate cancer (mCRPC) using a retrospective multicentre cohort study. PATIENTS AND METHODS: The electronic CRPC Australian Database (ePAD) was interrogated to identify patients with mCRPC. Clinicopathological features, treatment and outcome data, stratified by FGA use, were retrieved and reported through descriptive statistics. Survival analyses were calculated using the Kaplan-Meier method and groups compared using log-rank tests. Factors influencing overall survival (OS) were analysed using Cox proportional hazards regression model. RESULTS: We identified 634 patients with mCRPC, enrolled in ePAD between January 2016 and March 2019, including 322 (51%) who received FGAs. The median follow-up was 21.9 months. Patients treated with FGAs were more likely to have lower International Society of Urological Pathologists (ISUP) grade group (P = 0.04), longer median time to CRPC (25.6 vs 16.0 months, P < 0.001), and were less likely to have visceral metastases (5.0% vs 11.2%, P = 0.005) or to have received upfront docetaxel (P < 0.001). A ≥50% reduction from pre-treatment prostate-specific antigen (PSA) level (PSA50 response) during FGA treatment occurred in 119 (37%) patients and was independently associated with improved OS (hazard ratio 0.233, P < 0.001). Prior FGA treatment did not significantly influence the selection of subsequent life-prolonging treatments for mCRPC or their PSA50 response rates. CONCLUSION: In our present cohort, FGAs were commonly used in lower-risk mCRPC and their use did not significantly influence the choice or duration of subsequent systemic therapy. A PSA50 response to FGA therapy was an independent favourable prognostic marker associated with improved OS.

New survival standards for advanced melanoma.

The expectation for survival in patients with advanced melanoma now exceeds 50% at 5 years in patients treated with first-line combination ipilimumab and nivolumab, despite this regimen being associated with substantial toxicity. We discuss the latest updates from the Checkmate-067 study, framing the role of this combination in practice today.

Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series.

BACKGROUND: The efficacy and potential toxicity of rechallenge with combination ipilimumab and nivolumab has not been described. Retreatment of patients with immune checkpoint inhibitors in the setting of prior significant toxicity lacks evidence-based guidance. METHODS: We present the first three, consecutive patients who received re-treatment with combination ipilimumab and nivolumab for metastatic melanoma managed at our institution. RESULTS: Rechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable. CONCLUSIONS: Retreatment with ipi + nivo may be considered an option in carefully selected, well-informed patients. More research is required to delineate the benefits and risks with this approach.

Rare Immune-Related Adverse Events (irAEs): Approach to Diagnosis and Management.

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment landscape across many solid organ malignancies and form part of routine clinical practice in many tumours. As indications for monotherapy, doublet therapy and combination approaches with chemotherapy and targeted agents expand, clinicians must be aware of the wide range of possible immune-related adverse events (irAEs). Common toxicities, including rash, colitis, hepatitis and pneumonitis are well described in the literature, and have established diagnostic and management algorithms. Rarer toxicities, often with an incidence of less than 1%, are less defined. These syndromes can be poorly recognised, may take on a fulminant course and do not have established or evidence-based diagnostic and management strategies. As such, patients may experience increased morbidity, mortality and poorer outcomes, related both to these irAEs as well as how the treatment of these may affect the management of their underlying malignancy. In this review, we aim to explore the incidence, potential biomarkers, pathogenesis, diagnostic work-up and clinical sequelae of a selection of uncommon irAEs, with a focus on myocarditis, neurological and haematologic syndromes. Further prospective research is required to accurately define the incidence and pathogenesis of these conditions, with the aim of increasing clinician awareness of rare irAEs and to assist with a more personalised and mechanism-based approach to these syndromes.

Impact of Comorbidities and Drug Interactions in Patients With Metastatic Castration-Resistant Prostate Cancer Receiving Androgen Receptor Pathway Inhibitors.

PURPOSE: Androgen receptor pathway inhibitors (ARPIs) are widely prescribed in metastatic castration-resistant prostate cancer (mCRPC). Real-world frequencies and potential impacts of comorbidities and concomitant medication (conmed) interactions with ARPIs are not well described. METHODS: Patients receiving ARPIs for mCRPC were identified from the electronic Prostate Cancer Australian Database (ePAD). Demographics, clinicopathologic characteristics, and outcome data were extracted. Conmeds and comorbidities were collected from medical records. Potential interacting comorbidities were defined from trial and post-trial data. Clinically significant drug-drug interactions (DDIs) were identified using UpToDate Lexicomp and Stockley's databases. Patient characteristics, comorbidity interactions, DDIs, and outcomes were analyzed. RESULTS: Two hundred thirty-five patients received first- or second-line ARPIs for mCRPC from 2012 to 2021, with a median follow-up of 27 months. One hundred sixteen received abiraterone acetate (AAP) and 135 received enzalutamide (ENZ). The median age was 74 years, and the median number of conmeds was 4. Clinically significant DDIs occurred in 55 (47%) AAP patients and 90 (67%) ENZ patients. Only 5% of DDIs were predicted to affect ARPI pharmacokinetics (PK) or pharmacodynamics, whereas 95% were predicted to impact conmed PK or increase toxicity risk. In patients receiving ENZ, DDIs were associated with lower PSA50 (50% v 74%, P = .04) and poorer overall survival (28 v 45 months, P = .04), although statistical significance was not maintained on multivariate analysis. No significant survival differences were seen with DDIs in patients receiving AAP. Potential interactions between comorbidities and ARPI were present in 72% on AAP and 14% on ENZ with no significant associated survival differences. CONCLUSION: DDIs and drug-comorbidity interactions in real-world patients receiving ARPIs for mCRPC are common and may affect outcomes. Ongoing clinician education regarding DDIs is necessary to optimize patient outcomes.

Ultrasensitive plasma-based monitoring of tumor burden using machine-learning-guided signal enrichment.

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGESNV uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGECNV also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGESNV enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition.

Navigating the Current Landscape of Non-Clear Cell Renal Cell Carcinoma: A Review of the Literature.

Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology. A comprehensive review of the literature has been undertaken in order to describe molecular pathogenic mechanisms pertaining to each nccRCC subtype, and concisely summarise findings from therapeutic trials conducted in the nccRCC space.

Safety of Lutetium-177 prostate-specific membrane antigen-617 (PSMA-617) radioligand therapy in the setting of severe renal impairment: a case report and literature review.

Reported here is a case of rapidly progressive metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA-617 in the setting of severe renal impairment and impending ureteric obstruction. PSMA is expressed on renal tubular cells, raising the possibility of radiation-induced nephrotoxicity, and this level of renal impairment would typically exclude the patient from [177Lu]Lu-PSMA-617 therapy. Multidisciplinary input, individualized dosimetry, and patient-specific dose reduction were used to ensure the cumulative dose to the kidneys remained within acceptable limits. He was initially planned for treatment with six cycles of [177Lu]Lu-PSMA-617. However, he had an excellent response to therapy following four cycles of treatment and the last two cycles were omitted. He has been followed for 1-year posttherapy without evidence of disease recurrence. No acute or chronic nephrotoxicity was observed. This case report highlights the utility of [177Lu]Lu-PSMA-617 therapy in severe renal impairment and provides evidence of relative safety in patients who would otherwise not be considered candidates for therapy.

This report presents a case of a man with aggressive metastatic prostate cancer who received [¹⁷⁷Lu]Lu-PSMA-617 therapy, despite having severely reduced kidney function and worsening ureter obstruction. This treatment could have potential side effects on kidney function, but the medical team used a personalized approach to reduce patient risk. The man was initially planned to have six cycles of therapy, but his excellent response to treatment after four cycles meant the last two cycles were not given. The man has been followed for 1 year after treatment and has not experienced any worsening kidney function. This case shows the safe and effective use of [¹⁷⁷Lu]Lu-PSMA-617 therapy in a patient with severely reduced kidney function who would not normally qualify for this treatment.

Real-world clinical outcomes and cost estimates of metastatic castration-resistant prostate cancer treatment: does sequencing of taxanes and androgen receptor-targeted agents matter?

INTRODUCTION: Health economic outcomes of real-world treatment sequencing of androgen receptor-targeted agents (ARTA) and docetaxel (DOC) remain unclear. MATERIAL AND METHODS: Data from the electronic Castration-resistant Prostate cancer Australian Database (ePAD) were analyzed including median overall survival (mOS) and median time-to-treatment failure (mTTF). Mean total costs (mTC) and incremental cost-effectiveness ratios (ICER) of treatment sequences were estimated using the average sample method and Zhao and Tian estimator. RESULTS: Of 752 men, 441 received ARTA, 194 DOC, and 175 both sequentially. Of participants treated with both, first-line DOC followed by ARTA was the more common sequence (n = 125, 71%). mOS for first-line ARTA was 8.38 years (95% CI: 3.48, not-estimated) vs. 3.29 years (95% CI: 2.92, 4.02) for DOC. mTTF was 15.7 months (95% CI: 14.2, 23.7) for the ARTA-DOC sequence and 18.2 months (95% CI: 16.2, 23.2) for DOC-ARTA. In first-line, ARTA cost an additional $13,244 per mTTF month compared to DOC. In second-line, ARTA cost $6726 per mTTF month. The DOC-ARTA sequence saved $2139 per mTTF compared to ARTA-DOC, though not statistically significant. CONCLUSION: ICERs show ARTA had improved clinical benefit compared to DOC but at higher cost. There were no significant cost differences between combined sequences.

Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis.

Introduction: Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. Methods: This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. Results: There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. Conclusion: Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways.

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.

The Genetic Evolution of Metastasis.

Cancer is an evolutionary process that is characterized by the emergence of multiple genetically distinct populations or clones within the primary tumor. Intratumor heterogeneity provides a substrate for the selection of adaptive clones, such as those that lead to metastasis. Comparative molecular studies of primary tumors and metastases have identified distinct genomic features associated with the development of metastases. In this review, we discuss how these insights could inform clinical decision-making and uncover rational antimetastasis treatment strategies.

Real-world first-line systemic therapy patterns in metastatic castration-resistant prostate cancer.

Introduction: Several systemic therapies have demonstrated a survival advantage in metastatic castration resistant prostate cancer (mCRPC). Access to these medications varies significantly worldwide. In Australia until recently, patients must have received docetaxel first, unless unsuitable for chemotherapy, despite no evidence suggesting superiority over androgen receptor signalling inhibitors (ARSIs). Our study investigated real-world systemic treatment patterns in Australian patients with mCRPC. Methods: The electronic CRPC Australian Database (ePAD) was interrogated to identify mCRPC patients. Clinicopathological features, treatment and outcome data, stratified by first-line systemic therapies, were extracted. Comparisons between groups utilised Kruskal-Wallis tests and Chi-Square analyses. Time-to-event data were calculated using Kaplan-Meier methods and groups compared using log-rank tests. Factors influencing overall survival (OS) and time to treatment failure (TTF) were analysed through Cox proportional hazards regression models. Results: We identified 578 patients who received first-line systemic therapy for mCRPC. Enzalutamide (ENZ) was most commonly prescribed (n = 240, 41%), followed by docetaxel (DOC, n = 164, 28%) and abiraterone (AA, n = 100, 17%). Patients receiving ENZ or AA were older (79, 78.5 years respectively) compared with DOC (71 years, p = 0.001) and less likely to have ECOG performance status 0 (45%, 44%, 59% in ENZ, AA and DOC groups respectively p < 0.0001). Median TTF was significantly higher in those receiving ENZ (12.4 months) and AA (11.9 months) compared to DOC (8.3 months, p < 0.001). PSA50 response rates and OS were not statistically different. Time to developing CRPC > 12 months was independently associated with longer TTF (HR 0.67, p < 0.001) and OS (HR 0.49, p = 0.002). Conclusion: In our real-world population, ENZ and AA were common first-line systemic therapy choices, particularly among older patients and those with poorer performance status. Patients receiving ENZ and AA demonstrated superior TTF compared to DOC, while OS was not statistically different. Our findings highlight the important role of ARSIs, given the variability of access worldwide.

Beyond cabazitaxel: Late line treatments in metastatic castration resistant prostate cancer: A retrospective multicentre analysis.

AIMS: Multiple life-prolonging therapies are available for metastatic castration-resistant prostate cancer (mCRPC). However, the optimal treatment strategy following progression through standard treatment with docetaxel, androgen receptor signaling inhibitor (ARSI) and cabazitaxel, remains unclear. We aimed to describe treatment patterns in men with mCRPC following progression on standard treatments and determine whether subsequent treatment choice impacts overall survival. METHODS: Clinicopathologic and treatment data were extracted from the electronic CRPC Australian Database (ePAD) for patients who had received docetaxel, ARSIs and cabazitaxel in any order. Data were analyzed to compare groups that did versus did not receive subsequent systemic therapy. Treatment sequences, median duration of treatment, and median overall survival (mOS) were reported for each treatment group. RESULTS: Ninety-eight eligible patients were identified, with 51 receiving subsequent systemic therapy. Those who received further treatment were younger (68 vs. 71 years, p < .01) but did not have any other differences in clinicopathologic features compared to those who received no further treatment. Patients who received upfront docetaxel were more likely to proceed to subsequent treatment (p = .02). Subsequent systemic therapies varied, the most common being carboplatin-based regimens (n = 13, 25.5%) and many patients were rechallenged with ARSI (n = 10, 19.6%) or docetaxel (n = 6, 11.8%). There was no difference in mOS according to subsequent systemic therapy (p = .09). CONCLUSION: This retrospective multicenter analysis demonstrates the variation in treatment sequences used for mCRPC in the real-world setting. In the absence of high quality, prospective evidence, our results suggest that subsequent treatment choice does not influence survival outcomes and the optimal choice is guided by individual patient and disease-related factors.