Sweeney, Christopher J.

5013 Background: There is no established role for the use of docetaxel with ADT and RT for HRLPC, with mixed results seen in prior RCTs. Prior work from ICECaP (Ravi et al, Eur Urol 2024) has shown that patients (pts) with very high-risk disease (i.e. 2 or 3 risk factors [RFs]: Gleason ≥8, PSA >20, ≥cT3 and/or cN1) have the poorest outcomes with RT+ADT for HRLPC, with 5-year metastasis-free survival (MFS) of ≤80%. We aimed to perform an IPD meta-analysis of the role of docetaxel with ADT+RT for HRLPC and specifically evaluate whether patients with very high-risk disease benefit from the addition of docetaxel. Methods: IPD from RCTs involving pts with HRLPC treated with RT+ADT +/- docetaxel collated by ICECaP were analyzed. “High-risk” disease was defined as presence of 1 RF and “very high-risk” disease as 2-3 RFs and/or cN1 disease. The primary outcomes of interest were MFS and overall survival (OS). Hazard ratios (HR) for MFS and OS were estimated using Cox regression, stratified by year of randomization and adjusted for age at randomization and ECOG performance status. 5-year MFS and OS rates were estimated using the Kaplan-Meier method. Subgroup analyses were performed according to the severity of disease (high- and very high-risk), and p-values for interaction were tested using the likelihood ratio test. Results: 1690 pts treated on 4 RCTs (GETUG-12, DFCI 05-043, STAMPEDE, RTOG-0521) between 2002-2015 were eligible. Median age was 65, median PSA was 23 (IQR 10-48); 154 (9%) pts had cN1 disease and 1444 (85%) received long-term ADT with RT. Median follow-up was 10 years (range: <1-15). Overall, the addition of docetaxel to RT+ADT was not associated with a significant benefit in MFS (HR=0.89 [0.76-1.05], p=0.160) or OS (HR=0.88 [0.74-1.05], p=0.167). Though there was some evidence for favoring docetaxel in pts with very high-risk disease (n=1054; MFS HR=0.86 [0.71-1.05]; OS HR=0.85 [0.68-1.07]) compared to high-risk disease (n=636; MFS HR=0.97 [0.74-1.27]; OS HR=0.95 [0.71-1.28]), there was no evidence of a significant difference in treatment effect by risk group (p-interaction >0.1). 5- and 10-yr MFS and OS in pts with high- and very high-risk disease, stratified by receipt of docetaxel, are shown in the Table. Conclusions: Some HRLPC pts with very high-risk disease may benefit from the addition of docetaxel to RT+ADT. Biomarker evaluation within this group may identify those who are candidates for treatment intensification with docetaxel with RT+ADT (+/- androgen receptor pathway inhibitors) in HRLPC. % (95% CI) High risk Very high-risk RT+ADT RT+ADT+docetaxel RT+ADT RT+ADT+docetaxel 5yr MFS 87 (82-90) 90 (86-93) 74 (71-78) 80 (76-83) 5yr OS 90 (86-93) 93 (90-96) 84 (80-86) 89 (86-92) 10yr MFS 67 (61-72) 71 (65-76) 51 (46-55) 55 (49-60) 10yr OS 74 (69-79) 77 (72-82) 62 (57-67) 67 (62-72)

171 Background: Treatment effects vary by volume of disease and timing of metastatic presentation in patients with mCSPC. Therefore, we updated the existing body of evidence to assess the comparative efficacy of systemic therapy in mCSPC by prognostic subgroups to inform clinical practice guidelines. Methods: This living systematic review was conducted using the living interactive evidence (LIvE) synthesis framework. Phase III clinical trials assessing contemporary systemic therapy in mCSPC and reporting overall survival (OS) by four prognostic subgroups were included. Prognostic subgroups included synchronous high volume (SHV), synchronous low volume (SLV), metachronous high volume (MHV), and metachronous low volume (MLV) disease. Mixed treatment comparisons were made using a network-meta-analytic approach in each subgroup. P-scores were used to assess relative treatment rankings in congruency with pairwise estimates. Higher scores indicated better efficacy. Results: This study included a total of nine trials with eight unique treatment options. In patients with SHV disease, darolutamide+docetaxel+ADT (DARO+D+ADT) significantly improved OS when compared to D+ADT (HR: 0.69; 0.57-0.85), enzalutamide (E)+ADT (HR: 0.67; 95% CI: 0.46-0.99), and apalutamide (APA)+ADT (HR: 0.65; 95% CI: 0.43-0.96). In patients with SLV disease, E+ADT (HR: 0.62; 95% CI: 0.42-0.91) and AAP+ADT (HR: 0.66; 95% CI: 0.49-0.89) significantly improved OS when compared to ADT. Although E+D+ADT trended toward improvement compared to other treatments, the results were not statistically significant. In patients withMHV disease, no statistically significant differences were observed among mixed treatment comparisons. However, OS with DARO+D+ADT trended toward improvement when compared to D+ADT (HR: 0.69; 95% CI: 0.39-1.23), APA+ADT (HR: 0.72; 95% CI: 0.23-2.33), E+ADT (HR: 0.67; 95% CI: 0.24-1.86), and E+D+ADT (HR: 0.59; 95% CI: 0.26-1.34). In patients with MLV disease, E+ADT significantly improved OS compared to ADT (HR: 0.51; 95% CI: 0.32-0.79), and D+ADT (HR: 0.48; 95% CI: 0.27-0.85). APA+ADT significant improved OS compared to ADT (HR: 0.22; 95% CI: 0.09-0.54), and D+ADT (HR: 0.21; 95% CI: 0.08-0.55). No other statistically significant differences were observed among mixed treatment comparisons. Conclusions: Current evidence suggests that triplet systemic therapy may be preferred in SHV, E systemic triplet and E hormonal doublet in SLV, DARO systemic triplet and APA hormonal doublet in MHV, and APA or E hormonal doublets in MLV mCSPC. [Table: see text]

5094 Background: In prior studies, basal vs. luminal differentiation portends differential response to a) androgen suppression (AS) duration for high-risk prostate cancer (PCa) (NRG-GU-TS006) and b) docetaxel chemotherapy (CT) and AS for metastatic hormone-sensitive disease (CHAARTED). In NRG-GU-TS006, basal tumors appeared to benefit the most from longer duration of AS while those with luminal subtype did not whereas, in CHAARTED, luminal subtype had greater benefit from addition of CT. Herein, we examined basal-luminal subtyping to predict differential response to the addition of CT in the setting of high-risk PCa treated with AS and definitive radiotherapy (AS + RT) in NRG/RTOG 0521. Methods: Per pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available NRG biobank biopsy specimens from patients enrolled on the NRG/RTOG 0521 phase III trial, which randomized patients to AS + RT +/- CT. The highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA). Basal-luminal subtypes were generated using a 215-gene PCa subtyping classifier (PSC), a second generation PAM50 basal-luminal model. Treatment effects in Luminal Proliferating (LP) and non-LP subtypes were examined with Cox (for overall survival, OS, and metastasis-free survival, MFS) and Fine & Gray (for distant metastasis, DM) multivariable (MVA) models adjusted for age and trial risk stratification, as well as with restricted mean survival times (RMST). Results: Of 183 samples available for analysis (91 from control and 92 from the CT arm), 52 (28%) were classified as LP subtype. Median follow-up for OS was 9.9 years. No significant differences in clinical or pathological variables were observed between LP and non-LP subtypes. In MVA, we did not detect any significant LP subtype-by-CT treatment interaction but observed evidence of non-proportional hazards (Grambsch-Therneau test, p<0.05). In unselected patients, 5- and 10-year RMST difference between the arms was 0.9 (95% CI [-1.5, 3.4], p=0.46) and 5.7 (95% CI [-2.5, 13.9], p=0.17) months of OS. Stratifying by tumor subtype, at 5 years the RMST difference in months was 3.8 (95% CI [0.3, 7.2], p=0.03) for LP and -0.2 ([-3.4, 2.9], p=0.89) for non-LP. The RMST difference in months at 10-years was 13.7 (95% CI [-0.2, 27.5], p=0.053) for LP and 2.5 ([-7.6, 12.5], p=0.63) for non-LP. Conclusions: In pre-treatment biopsy samples from a Phase 3 trial cohort of localized high-risk men, luminal-basal subtyping of tumors demonstrated differential response to docetaxel CT. Similar to results from the CHAARTED trial of metastatic disease, LP tumors may derive greater benefit from addition of CT. Validation of these findings may enable effective earlier use of CT in men with PCa.

AbstractBackgroundProstate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression‐based subtyping model based on prostate‐specific biological processes was sought.MethodsUnsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts.ResultsClustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01–0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09–0.51).ConclusionsWith the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features.Plain language summary Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors—the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.

241 Background: We previously reported on the use of gene expression profiling to characterize four primary subtypes in an analysis of over 100,000 prostate cancer primary tumors. Here we examine these subtypes and response to radiation (RT) after prostatectomy or chemotherapy in addition to androgen deprivation therapy (ADT) in hormone-sensitive metastatic prostate cancer (mHSPC). Methods: We examined a 215-gene prostate subtyping classifier (PSC) which groups luminal and basal gene expression profiles into one of four subtypes; luminal differentiated (LD), luminal proliferating (LP), basal immune (BI) and basal neuroendocrine-like (BN). The log-rank method was used to compare (i) metastasis-free survival between patients who did and did not receive salvage RT in the META855 cohort of localized disease patients treated with radical prostatectomy (n=855) and the (ii) overall survival of patients on the Phase III mHSPC EA3805 CHAARTED trial of ADT or ADT + docetaxel chemotherapy (n=160). Results: After radical prostatectomy, patients with BI tumors derived benefit from RT in terms of metastasis-free survival ( P=9.23e-4) while those with other subtype tumors did not (Each Log-rank P≥0.5). Patients with metastatic disease and LP tumors derived benefit from docetaxel (Log-rank P=0.002) while those with other subtypes tumors did not (Log-rank P=0.2). Conclusions: Basal-luminal subtyping segments tumors by relevant biological processes with potential implications for identifying patients who benefit from salvage radiation post prostatectomy and addition of docetaxel to ADT in mHSPC.

Importance The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Objective To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups. Data Sources For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database’s inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a “living” auto search was created with weekly updates to identify new evidence as it became available. Study Selection Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC. Data Extraction and Synthesis Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022. Main Outcomes and Measures Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. Results This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT. Conclusions and Relevance The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Purpose of review To summarize the role of chemotherapy and offer some guidance regarding the selection of chemotherapy in mPC. Recent findings Patients with mHSPC have varied prognoses with testosterone suppression alone (androgen deprivation therapy, ADT) and differential responses to docetaxel with ADT. Patients with de novo and metachronous high-volume disease have a robust survival benefit with the addition of docetaxel to hormonal therapies. Patients with synchronous low-volume disease have a more modest survival benefit from docetaxel and there is no evidence of survival benefit with docetaxel in patients with metachronous low-volume disease. Integration of biomarkers may refine treatment selection regardless of volume of disease. Docetaxel and cabazitaxel also impart an OS benefit in patients with metastatic castration-resistant prostate cancer (mCRPC). The choice of chemotherapy in mCRPC depends on treatment received in mHSPC setting. Docetaxel remains the first line chemotherapy in castration-resistant patients who have not received it in mHSPC followed by cabazitaxel, otherwise cabazitaxel can be deployed without docetaxel retreatment. Summary Chemotherapy is a key class of therapy for selected patients with mHSPC and mCRPC.

AbstractBackgroundE3805 (CHAARTED) is a phase 3 trial demonstrating improved survival for men with metastatic hormone‐sensitive prostate cancer (mHSPC) randomized to treatment with docetaxel (D) and androgen‐deprivation therapy (ADT) versus ADT alone. We assessed the association of baseline body mass index (BMI) and metformin exposure with quality of life (QOL) and prostate cancer outcomes including survival in patients enrolled in the CHAARTED study.MethodsWe performed a posthoc exploratory analysis of the CHAARTED trial of men with mHSPC randomized to treatment with ADT with or without D between 2006 and 2012. Cox proportional hazards models and Kruskal–Wallis test were used to evaluate the association between BMI with QOL and prostate cancer outcomes and between metformin exposure and survival.ResultsIn 788 of 790 enrolled patients with prospectively recorded baseline BMI and metformin exposure status, lower BMI was not associated with survival, but was associated with high volume disease (p < 0.0001) and poorer baseline QOL on functional assessment of cancer therapy–prostate (p = 0.008). Only 68 patients had prevalent metformin exposure at baseline in the CHAARTED trial. Four groups were identified: ADT + D + metformin (n = 39); ADT + D (n = 357); ADT + metformin (n = 29); and ADT alone (n = 363). Baseline clinicopathologic characteristics were similar between groups. In this small exploratory multivariable analysis, metformin exposure was not associated with survival (hazard ratio: 1.15; 95% confidence interval: 0.81–1.63, p = 0.44).ConclusionsThere was no link between baseline BMI and survival, but lower baseline BMI was associated with features of greater cancer burden and poorer QOL.

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.