Addition of androgen-receptor pathway inhibitors to standard of care in metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis.

Current Value Frameworks—What's New?

20 Background: Clinical features of people with mHSPC may affect their outcomes from the addition of ARPIs to androgen deprivation therapy (ADT). The STOPCAP Collaboration is seeking IPD to reliably investigate potential ARPI effect modifiers and determine who benefits more from an ARPI vs docetaxel plus ADT doublet. Methods: Full methods are in registered protocols (CRD42023431331; CRD4202540066). We sought IPD for completed trials examining effects of ARPIs for mHSPC. Initially, we examined ARPI effects using intention-to-treat, two-stage, common-effect meta-analysis of hazard ratios (HRs), adjusted for a core set of covariates and use of concomitant docetaxel. Main effects were based on overall survival (OS). Interaction effects were based on progression-free survival (PFS) to maximise power, then OS whenever PFS interactions were found (P<0.10). Within clinically-relevant subgroups, ARPI and docetaxel doublet effects were compared using two-stage, contrast-based, random-effects network meta-analysis (NMA). Results: By October 2024, we had updated IPD from five trial comparisons: LATITUDE, STAMPEDE A vs G, SWOG-1216, ENZAMET, and STAMPEDE A vs J. Based on these (2882 events/5472 pts), adding an ARPI to ADT improved OS (HR=0.69, 95% CI=0.64-0.74). Four trial comparisons (excluding SWOG-1216) provided PFS data (2781 events/4161 pts) and showed improved PFS (HR=0.49, 95% CI=0.45-0.53). The relative benefit of ARPIs on PFS increased with younger age (interaction p=0.034), higher BMI (interaction p=0.048), and lower burden of metastases (interaction p=0.096). These effects were similar for OS (age interaction p=0.035; BMI interaction p=0.031; volume interaction p=0.25). The age effect was most pronounced in the abiraterone trials. Combining IPD from the ARPI + ADT and docetaxel + ADT trials (GETUG-AFU-15, CHAARTED, STAMPEDE A vs C) in NMA suggested that overall, an ARPI doublet may improve OS more than a docetaxel doublet (HR=0.85, 95% CI=0.70-1.03). However, when the NMA was confined to participants with high-volume, synchronous disease, where docetaxel is most efficacious (but excluding SWOG-1216, for which these data were not available), effects on OS were: HR=0.89, 95% CI=0.74-1.06. Conclusions: Our preliminary results suggest that people with mHSPC who are younger, have a higher BMI, or have low volume disease, may benefit more from ARPIs. ARPI and docetaxel doublets seem similarly effective in high-volume, synchronous disease. We will present updated analyses, incorporating recently received PEACE 1 IPD, for a clearer picture of ARPI effects, including subgroup-specific effects. Ongoing collection of IPD from other key trials will allow robust comparison of ARPI doublet with triplet therapy (including docetaxel), guiding more personalised treatment.

Progression-free survival with darolutamide and docetaxel vs. androgen receptor pathway inhibitors vs. docetaxel in metastatic hormone-sensitive prostate cancer: A real-world multicenter retrospective study.

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

Assessment of Value Using the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) Frameworks for Novel Therapies for the Hematologic Malignancies

Combination therapy for metastatic hormone-sensitive prostate cancer (mHSPC) has been widely adopted, yet clinical use and outcomes are unknown. Furthermore, optimal therapy is uncertain due to lack of direct comparison of androgen receptor pathway inhibitors (ARPIs) and docetaxel in high-volume disease. To evaluate the use of combination therapy and its association with overall survival among patients with mHSPC and to compare ARPIs vs docetaxel doublet therapy by volume of disease. This retrospective cross-sectional study was conducted in the US Veterans Health Administration among 6216 US veterans with de novo mHSPC from January 1, 2013, to December 31, 2022, treated with androgen deprivation therapy (ADT) within 3 months of diagnosis. Treatments for mHSPC were collected within 4 months of ADT. Volume of disease was assessed from radiology report review. Data were analyzed from July 2023 to October 2024. Overall survival (OS) and clinical progression-free survival (PFS), indicated by time to castration resistance or death. Among 6216 male veterans with mHSPC (mean [SD] age, 73.9 [9.7] years), use of combination therapy increased from 344 of 637 veterans (54.0%) in 2020 to 465 of 737 veterans (63.1%) in 2022. Among 4106 veterans treated from 2017 to 2022, combination therapy was associated with longer OS (40.3 [95% CI, 38.0-42.1] months vs 33.0 [95% CI, 31.2-35.1] months; hazard ratio [HR], 0.80 [95% CI, 0.74-0.87]) and was used more frequently among younger veterans with fewer comorbidities. Among 1174 veterans with high-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (32.3 [95% CI, 29.5-35.3] months vs 34.7 [95% CI, 31.7-37.1] months; HR, 1.06 [95% CI, 0.91-1.23]); however, ARPIs were associated with longer PFS (18.7 [95% CI, 17.1-20.9] months vs 16.0 [95% CI, 14.0-17.7] months; HR, 0.80 [95% CI, 0.70-0.91]; P = .001). In a multivariable model of high-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (adjusted HR, 0.89 [95% CI, 0.76-1.05]). Among 366 veterans with low-volume mHSPC, there was no difference in OS between ARPIs and docetaxel (68.4 [95% CI, 52.6 months to not reached] months vs 55.3 [95% CI, 41.7-78.9] months; HR, 0.81 [95% CI, 0.58-1.13]), but ARPIs were associated with longer PFS (39.7 [95% CI, 34.3-52.9] months vs 24.0 [95% CI, 20.3-32.9] months; HR, 0.57 [95% CI, 0.43-0.76]). In this cross-sectional study of veterans with de novo mHSPC, use of combination therapies increased over time and were associated with longer survival compared with ADT monotherapy. In both high- and low-volume mHSPC, no differences in OS were observed between ARPI and docetaxel combinations; however, ARPIs had longer PFS. Future research into the role of docetaxel is needed to elucidate the benefit of chemotherapy in mHSPC.

Immune checkpoint inhibitors (ICIs) have yielded conflicting results in hepatocellular carcinoma (HCC). The overall effect of ICIs compared with standard therapies in unresectable HCC requires more research. To estimate the efficacy and safety associated with ICIs compared with standard therapies in patients with unresectable HCC. PubMed, Cochrane Library, Web of Science, Latin American and Caribbean Health Sciences Literature, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings were systematically searched. Reference lists from studies selected by electronic searching were manually searched to identify additional relevant studies. The search included literature published or presented from February 2010 to February 2020. From December 2019 to February 2020, independent reviewers evaluated each database, scanning the title, abstract, and keywords of every record retrieved. Full articles were further assessed if the information given suggested that the study was a randomized clinical trial (RCT) comparing ICIs vs standard therapies in the treatment of unresectable HCC. The full text of the resulting studies and extracted data were reviewed independently according to PRISMA guidelines. Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated by a random-effects model. The likelihood of ICIs being associated with overall response rate (ORR) and treatment-related adverse events (TRAEs) was expressed by odds ratios (ORs) using a random-effects model. The main outcomes were OS, PFS, ORR, and TRAEs. Of 1836 studies yielded by the search, 3 were retained, totaling 1657 patients (985 treated with ICIs vs 672 receiving standard treatment). Two studies evaluated ICIs as monotherapy, and 1 study investigated the combination of ICIs with bevacizumab. Compared with standard therapies (sorafenib in first-line therapy or placebo in second-line therapy), ICIs were associated with significantly improved OS (HR, 0.75; 95% CI, 0.62-0.92; P = .006), PFS (HR, 0.74; 95% CI, 0.56-0.97; P = .03), and ORR (OR, 2.82; 95% CI 2.02-3.93; P < .001). The probability of grade 3 or 4 TRAEs was lower with ICIs than with sorafenib (OR, 0.44; 95% CI, 0.20-0.96; P = .04). This meta-analysis found superior efficacy and safety associated with ICIs compared with standard therapies and highlights the survival benefit associated with the combination of antiangiogenic therapy with ICIs in first-line systemic therapy of unresectable HCC.

PurposeNo currently available phase III trial compared docetaxel vs. androgen receptor pathway inhibitors (ARPI) regarding cancer-control outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Moreover, few is known about the effect of sequential therapies in mHSPC and subsequent metastatic castration resistant prostate cancer (mCRPC).MethodsWe relied on the FRAMCAP database and compared docetaxel vs. ARPI in mHSPC patients regarding time to mCRPC (ttCRPC) and overall survival (OS). Sensitivity analyses addressed high volume mHSPC patients. Finally, sequential therapies were compared regarding progression-free survival (PFS) and OS in first-line mCRPC.ResultsOf 419 included mHSPC patients, 25% received docetaxel vs. 75% ARPI. ARPI patients were significantly older (71 vs. 66 years), and harbored lower baseline PSA (38 vs. 183 ng/ml, both p ≤ 0.002). Median ttCRPC was significantly longer for ARPI than for docetaxel-treated patients (30 vs. 17 months, hazard ratio [HR]: 0.49, p < 0.001). In OS analyses, ARPI patients also exhibited significantly longer OS, relative to docetaxel patients (96 vs. 50 months, HR: 0.67, p = 0.03). After multivariable adjustment in Cox regression models, no difference between both treatments remained in both analyses (all p > 0.05). In sensitivity analyses of high volume mHSPC patients only, also no ttCRPC or OS differences were observed for ARPI vs. docetaxel (all p > 0.05). Regarding sequential therapies, no PFS and OS differences were observed for all and specifically high volume mHSPC patients, when ARPI-ARPI vs. ARPI-docetaxel vs. docetaxel-ARPI treatments were compared (all p > 0.05).ConclusionIn real-world setting, ARPI treatment performs comparable to docetaxel chemotherapy in mHSPC. Therefore, docetaxel should only be used in triplet therapy. Moreover, no differences for sequential therapies of ARPI/docetaxel combinations in first-line mCRPC were observed.

169 Background: Combination therapies, such as androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI) +/- docetaxel, were shown to improve overall survival (OS) in pts with mHSPC. However, some pts are still characterized by EP. EMETPRO study analyzed these pts and their response to treatments administered at progression. Methods: EMETPRO is a multicenter, retrospective registry of pts with EP mHSPC defined as pts who have progression ≤ 6 months (m) under combination therapies (ADT + docetaxel or ADT + ARPI) or ≤ 9 m from ADT alone start. The primary endpoint is progression-free survival (PFS) calculated from the start of first-line (1°L) treatment for mCRPC in the entire population and in the different treatments sub-cohorts based on the treatment received in mHSPC. Secondary endpoints included OS calculated from the start of treatment for mHSPC and from the start of 1°L treatment for mCRPC. Results: From May 2005 to May 2023 431 pts were enrolled in the study. Median age was 69 years. Molecular analyses were available in 195 (45.2%) pts (Table). 206 (47.8%) pts received ADT alone for mHSPC while 123 (28.6%) and 77 (17.8%) pts received ADT + docetaxel and ADT + ARPI, respectively. 80 (38.8%) and 66 (32.0%) pts treated with ADT alone in mHSPC received ARPI or docetaxel as 1°L mCRPC treatment, respectively. 77 (62.6%) and 13 (10.6%) pts treated with ADT+ docetaxel in mHSPC received ARPI or cabazitaxel in mCRPC, respectively. 46 (59.7%) and 7 (9.1%) pts treated with ADT+ ARPI in mHSPC received docetaxel or a second ARPI in mCRPC, respectively. 14 pts (3.2%) received olaparib or radioligand treatments as 1°L mCRPC therapy. The median PFS from the start of 1°L treatment for mCRPC was 6.5, 4.9, and 5.4 m for pts that received ADT, ADT + docetaxel and ADT + ARPI, respectively. The median OS from mHSPC was 27.0, 20.0, and 19.5 m, in the same groups while the median OS from 1°L treatment for mCRPC was 18.5, 12 and 14.6 m, respectively. The 1°L therapy received in the mCRPC setting and the molecular profile did not correlate with PFS or OS. Conclusions: Pts with EP mHSPC are characterized by poor outcomes regardless of treatment received at progression. The best 1°L mCRPC therapy to use in these pts remains a crucial unmet clinical need. Future studies evaluating novel mechanisms (e.g. olaparib or lutetium PSMA) or intensification strategies (e.g. cabazitaxel and/or carboplatin) in this setting are urgently needed. Baseline characteristics. Number (N°) of pts 431 GS≥8 at mHSPC, N° (%) 278 (64.5) High-volume disease (CHAARTEED), N° (%) 302 (70.1) N° of pts with germline testing results 63 Alterations detected, N° (%) 24 (38.1) BRCA alterations detected, N° (%) 13 (20.6) N° of pts with somatic testing results 181 DNA damage response and repair gene alterations, No. (%) 47 (26.0) At least one TP53/PTEN/RB1 gene mutation detected, No. (%) 84 (46.4)

Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis

17 Background: The advent of checkpoint inhibitor therapy (CIT) has dramatically changed the oncology landscape, but is associated with significant costs. A positive randomized clinical trial (RCT) may not translate to meaningful outcomes for patients. The American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) have developed frameworks to quantify the value of cancer treatment. We applied these frameworks to RCTs involving CIT in order to explore the relationship between trial outcomes and magnitude of clinical benefit. Methods: A literature search was conducted to identify CIT RCTs. Data extracted included study characteristics, pre-specified estimated hazard ratios (eHR) and observed HR (oHR). ASCO Value Framework version 2016 and ESMO Magnitude of Clinical Benefit (MCB) scale v1.1 were applied to each publication by 2 authors independently. Results: 30 RCTs (3 adjuvant, and 27 advanced setting) using CIT were identified between January 2010- October 2018. The majority of trials were in lung cancer (37%) and melanoma (36%). The eHR was 0.71±0.06 (range: 0.55-0.78), and oHR was 0.76±0.15 (range: 0.49 – 1.11). 54% RCTs did not achieve eHR, with a difference of 0.16±0.12 (range: 0.01 – 0.41). ASCO framework scores ranged -24.0 to 71.3, far below the maximum potential score of 180. 18 RCTs formed the basis for FDA approvals. The mean ASCO framework score was 45.6 ± 16.6 (range: 14.4 - 71.3) for FDA approved indications, and 14.0 ± 18.4 (range: -24 – 49) for non-FDA approvals (p &lt; 0.001). All FDA approvals scored grade 4 or 5 on the ESMO MCB scale, indicating a meaningful clinical benefit. Many non-FDA approved RCTs did not receive an MCB grade as they were negative trials. There was no difference in the ASCO framework scores between MCB grade 4 and 5 RCTs. 3 adjuvant RCTs had an ASCO framework score ranging from 20.5 to 38.7 despite an MCB Grade A. Conclusions: Many trials did not meet the pre-specified eHR. FDA approval had statistically significantly higher NHB scores than non-FDA approvals, and they were deemed to have a meaningful clinical benefit according to the ESMO MCB scale. ASCO framework scores may require re-calibration since the highest score achieved in CIT RCTs was only 40% of the maximum score.

Metastatic Burden in Hormone-Naive Prostate Cancer: A Tale of Two Subgroups

244 Background: The addition of androgen receptor pathway inhibitors (ARPI) to androgen deprivation therapy (ADT) has improved survival in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC), both as doublets and as triplets with docetaxel. The prognostic role of genomic alterations (GA) is of growing interest in this setting. We evaluated the GA profiling of a population treated with ARPI-based therapy in a single-center institution. Methods: Our retrospective analysis included patients with mHSPC treated at IRCCS San Raffaele Hospital between 2020 (when ARPI were authorized for mHSPC in Italy) and 2023 (when triplets of ARPI + ADT + docetaxel were authorized). Included patients had a diagnosis of mHSPC, tissue biopsy available for genomic profiling, and were treated with ARPI plus ADT (plus or minus docetaxel) within 120 days of initial diagnosis. Comprehensive genomic profiling (CGP) using a commercial hybrid capture-based system (Foundation Medicine) was performed on all pts to evaluate all classes of GA, homologous recombination score (HRDsig), genomic ancestry, and signature. The log-rank test and Cox proportional hazards models compared GA between responders (Rs: defined as non-progressive pts) and not-responders (NRs: pts developing a progressive disease). Kaplan Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS). Results: 28 patients were included in our analysis. Among them, 25 pts received ARPI + ADT, 3 ARPI + ADT + docetaxel. The median age was 71.8 years (range 53.1-83.9). After a median follow-up of 55.1 months, there were no differences in median PFS (mPFS) between patients treated with triplets and doublets (55.42 vs. 78.0 mos - HR = 1.12; 95%CI, 0.13-9.87; p = 0.92). The median OS (mOS) was not reached in both subgroups, without significant differences in survival rates (HR = 0.32; 95%CI, 0.01-7.33; p = 0.48). The overall response rate was 71.4%, and the disease-control rate was 85.7%. Comparing the CGP profiling between responders and progressive-pts, SPOP mutations were more frequent among Rs than NRs to ARPI (25% vs 0%; p = 0.183). TMPRSS2 - ERG fusions, which tend to be less frequent in SPOP mutated cases, were less frequent in Rs (12.5%) than NRs (20.0% - p = 0.648). There was a similar incidence of other GAs between the two groups of pts, such as PTEN , BRCA1/2 , ATM , and CDK12 (all 12.5% vs. 10.0%; all p &gt; 0.05). Conclusions: In a real-world setting, response to ARPI-based therapy may be associated with characteristic genomic features, such as SPOP mutations, or TMPRSS2 / ERG fusions, both in doublets and in triplet regimens. These findings underscore the importance of larger cohorts to further validate this hypothesis and inspire future research in the treatment selection for mHSPC pts.

ESMO/ASCO recommendations for a Global Curriculum (GC) in medical oncology—edition 2016

For patients with advanced prostate cancer (PC) treated with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI), the decline in prostate-specific antigen (PSA) is a potential biomarker for treatment response. We synthesised data regarding the association of the PSA response with overall survival (OS). The MEDLINE, Embase, Web of Science, and Google Scholar databases were searched up to November 2024 to identify studies evaluating the association between the PSA response and OS among patients treated with ADT+ARPI. Hazard ratios (HRs) were pooled in random-effects meta-analyses. We identified 14 studies comprising a total of 8883 patients. Among four studies in metastatic hormone-sensitive PC (n=2197), achievement of an undetectable PSA level was associated with better OS (HR 0.33, 95% confidence interval [CI] 0.23-0.49). In two studies in nonmetastatic castration-resistant PC (n=1507), a PSA decline to <0.2ng/ml (HR 0.28, 95% CI 0.21-0.36), a PSA reduction of ≥90% (HR 0.39, 95% CI 0.28-0.52), and a PSA reduction of ≥50% (HR 0.34, 95% CI 0.16-0.69) were associated with better OS. Among four studies in metastatic castration-resistant PC (n=3728), PSA reductions of ≥90% (HR 0.22, 95% CI 0.14-0.34) and ≥50% (HR 0.29, 95% CI 0.20-0.41) were associated with better OS. The main limitations include heterogeneity in study designs and use of ADT before baseline PSA measurement in mHSPC studies. The PSA response following ADT+ARPI therapy is significantly associated with OS across all metastatic and castration-resistant PC states and could serve as a clinically useful early signal of efficacy. It remains to be proven whether the PSA response is a surrogate for OS or should guide changes in clinical care.