bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment patterns and survival in men with metastatic castration-resistant prostate cancer (mCRPC): A systematic literature review of 35 real-world observational studies.
Authors: Raval Amit D , Queen V Viji , Korn Matthew J. , Quintero Vanessa , Freedland Stephen J.
Published: February 2025

101

Background:
Treatment landscapes have changed dramatically in prostate cancer in the past decade. Therapies like androgen receptor pathways inhibitors (ARPIs), which were initially approved for mCRPC are now approved in the earlier disease spectrum, including biochemical recurrence (BCR), non-metastatic castration-resistant prostate cancer (nmCRPC), and hormone-sensitive metastatic prostate cancer (mHSPC). Further, several other life-prolonging therapies, including radiopharmaceuticals, immunotherapies, and poly-ADP ribose polymerase inhibitors (PARPi), have been approved for mCRPC in the last decade. Given these changes, this systematic literature review (SLR) aimed to summarize treatment patterns and survival in patients with mCRPC.
Methods:
Electronic databases (PubMed, Embase) and key conferences (2022-2024) were searched systemically for real-world (RW) observational studies published between Jan 2015 and March 2024 that examined treatment patterns and survival in patients with mCRPC. A GenAI-powered literature review platform assisted in study selection alongside human validation, and independent reviewers extracted and assessed the data for narrative synthesis of key findings.
Results:
From 4,565 retrieved citations, 35 studies with a total of 86,131 patients with mCRPC met inclusion criteria. In most studies, patient median age ranged from 65 to 75. Studies predominantly utilized electronic medical records (EMR)/chart review (n=24), followed by a registry/-linked claims (n=10). Most studies were from North America (n=21; 18 United States; 3 Canada), followed by Europe (n=6), Asia (n=3), Oceania (n=3), and others (n=2). Bone and visceral metastases were present in ≥ 70% of mCRPC and ≤30% in most studies, respectively. ARPI was the most frequently utilized first line of therapy(1L) for mCRPC in all studies (≥50% in most studies), followed by chemotherapy, albeit with varying magnitude by geographic regions. Chemotherapy for 1L mCRPC was more common in Europe and Oceania than in the US. The use of radiopharmaceuticals, PARPIs, and immunotherapy was low in most studies (<10%) as 1L mCRPC. Most studies found ARPI to ARPI was the most common 1L to 2L mCRPC sequence, though in few studies, ARPI-chemotherapy was the common 1L to 2L mCRPC sequence. In most studies, median real-world overall survival ranged from 18 to 27 months and varied by genetic mutation status.
Conclusions:
Findings highlight that ARPI remained the most utilized 1L/2L in men with mCRPC, and back-to-back ARPI was also a common practice even after the availability of the other life-prolonging therapies. This SLR highlights the need to optimize treatment beyond systemic hormone therapy.
Receipt of poly(ADP) ribose polymerase inhibitors (PARPi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring
BRCA1/2
alterations.
Authors: Ostrowski Micah , Jo Yeonjung , Hage Chehade Chadi , Ozay Zeynep Irem , Gebrael Georges , Sayegh Nicolas , Lin Edwin , Srivastava Ayana , Ji Richard , Li Haoran , Mathew Thomas Vinay , Gupta Sumati , Riaz Irbaz Bin , Maughan Benjamin L. , Roy Soumyajit , Swami Umang , Agarwal Neeraj
Published: February 2025

108

Background:
PARPi are approved for the treatment of pts with mCRPC either as single agents or as a combination with an androgen receptor pathway inhibitor (ARPI) [PMID: 37442702]. In a US Food and Drug Administration (FDA) pooled analysis, the benefit from PARPi appeared greatest for pts harboring
BRCA1/2
alterations [PMID: 38484203]. However, real-world uptake of PARPi in pts with mCRPC with
BRCA1/2
alterations is unknown. Herein, our objective was to assess the usage of PARPi in real-world pts with mCRPC harboring
BRCA1/2
alterations.
Methods:
A de-identified nationwide Flatiron Health electronic health record (EHR)-derived database was used to extract pt-level data. Eligibility criteria: pts with mCRPC harboring alterations in
BRCA1
or
BRCA2
or both and alive after 8/15/2020 (i.e., 3 months following the approval of the first PARPi, rucaparib, in mCRPC) with available treatment information. The data cutoff date was 5/31/2024. Pts were categorized into two cohorts based on the receipt of any PARPi or not. Baseline characteristics at the time of mCRPC diagnosis, including age, race-ethnicity, and insurance plan, were collected in both cohorts.
Results:
Of the overall cohort of 24,105 pts with metastatic prostate cancer, 443 pts had mCRPC with
BRCA1/2
alterations and were eligible and included in this analysis. 227 (51.2%) received a PARPi, while 216 did not (48.8%). Among the 227 pts who received a PARPi, 166 received it as a single agent (73.1%), 40 received it in combination with an ARPI (17.6%), and 21 received it in combination with other agents (9.3%). The median age was 72 in both cohorts (IQR 65 – 79 in patients receiving a PARPi and 66 – 78 in patients who did not). Other baseline characteristics in both groups are shown (Table).
Conclusions:
Despite PARPi demonstrating survival improvement in pts with mCRPC with
BRCA1/2
alterations, a significant proportion of pts do not receive them. Our findings highlight the need to improve education among clinicians of level 1 evidence and improve access to life-prolonging therapies in pts with mCRPC.

Baseline characteristics of pts with mCRPC who received vs. did not receive a PARPi.

Characteristic
Subgroup
Pts who received a PARPiN = 227
Pts who did not receive a PARPiN = 216

Race-ethnicity, n (%)
Asian
9 (4)
1 (0.5)

Black
22 (9.7)
30 (13.9)

Hispanic-Latino
10 (4.4)
10 (4.6)

White
149 (65.6)
124 (57.4)

Other and unknown
37 (16.3)
51 (23.6)

Insurance, n (%)
Commercial health plan
192 (84.5)
182 (84.3)

Medicare-other government programs
31 (13.7)
18 (8.3)

Medicaid
1 (0.4)
3 (1.4)

Others and unknown
3 (1.3)
13 (6)
Real-world outcomes in metastatic prostate cancer patients with ctDNA-detected
SPOP
mutations.
Authors: Dean-Colomb Windy , Saha Jayati , Lewis Courtney , Bucheit Leslie A , Yates Clayton Clopton
Published: February 2025

110

Background:
Comprehensive genomic profiling (CGP) is recommended for patients (pts) with metastatic prostate cancer (mPC) to inform therapy. ctDNA analysis provides rapid results with high concordance to tissue-based CGP avoiding the need for invasive biopsy.
SPOP
mutations (
SPOP+
) define a novel group of mPC enriched in black pts. Tissue-based data suggests a subset of pts with
SPOP+
mPC have improved outcomes with hormonal therapy and may not require intensified treatments. This study examined outcomes for mPC pts following ctDNA-detected
SPOP
mutations by race.
Methods:
Real-world (rw) data was sourced from GuardantINFORM from 2014 to September 2024. GuardantINFORM is comprised of aggregated commercial payer health claims and de-identified records from pts with clinical ctDNA testing via Guardant360 (G360). Index date was defined as the first metastatic claim post-mPC diagnosis and baseline period as the six months prior to the index date. Adult mPC pts with >2 mPC claims in the baseline period were analyzed. Demographics and rw first-line outcomes (rw time to next treatment (rwTTNT) and rw overall survival (rwOS), months) in both unmatched and propensity score matched and weighted
SPOP
+ vs.
SPOP-
were assessed. A subgroup analysis was also conducted by stratifying by the two main racial groups, white and black.
Results:
SPOP
mutations were observed in 2.6% of pts meeting inclusion criteria (346/13283). 346
SPOP+
mPC pts were included as cases, of which 205 (59%) were White, 90 (26%) Black, and 51 (15%) other/unknown race; 43% had prior ADT use (n=151) and the median age was 72 years (range: 45-84). A larger proportion of black pts were in the
SPOP
+ cohort compared to
SPOP
- (21.8% vs. 14.9%) with other demographics similar between cohorts (age, non-Black race, line of therapy, prior ADT use). In unmatched analyses,
SPOP+
had numerically similar median rwTTNT and shortened median rwOS compared to
SPOP
-, although not significant [rwTTNT:
SPOP
+ 12.7 (10.1-14.3) vs.
SPOP
- 12.4 (11.8-13.0); p=0.86; rwOS:
SPOP
+ 18.3 (15.2-25.8) vs.
SPOP
- 21.9 (20.7-22.7); p=0.33]. Upon stratifying by race in matched and weighted cohorts,
SPOP
+ black pts had numerically improved median rwTTNT and median rwOS compared to
SPOP
+ white pts, yet not significant [rwTTNT: Black-
SPOP
+ 13.7 (9.2-NR) vs. White-
SPOP
+ 12.4 (8.3-14.5); p=0.66; rwOS: Black-
SPOP
+ 18.9 (14.7-NR) vs. White-
SPOP
+ 17.1 (13.1-29.1); p=0.38].
Conclusions:
This data supports ctDNA use for detecting S
POP
mutation status in mPC.
SPOP
+ may impact rwTTNT and rwOS among black pts. Further modeling of real-world matched cohorts and additional studies in clinical cohorts are needed to continue to assess the impact of
SPOP
+ on patient outcomes.
Assessment of cardiovascular (CV) toxicity by providers in advanced prostate cancer (PCa) patients (pts) on novel hormonal therapy (NHT).
Authors: Kaakour Dalia , Cho Eunah , Ozaki Aya , Raad Ali , Macaraeg Amanda , Go Jeanah , Seyedin Steven Neema , Naqvi Ali , Mar Nataliya
Published: February 2025

125

Background:
Addition of NHT, including Abiraterone, Enzalutamide, Apalutamide, and Darolutamide, to androgen deprivation therapy in patients with advanced PCa demonstrated improved survival in large randomized controlled trials. However, NHTs are associated with development of metabolic syndrome and CV toxicity. Treatment related adverse events (TRAEs) may include hypertension (HTN), hyperglycemia, atrial fibrillation, myocardial infarction (MI), congestive heart failure (CHF), and stroke. As such, monitoring for these toxicities by treating providers is essential. Cardio-oncology is an emerging field that addresses CV needs of cancer pts and fosters collaboration between oncologists and cardiologists.
Methods:
This is a retrospective analysis of 92 pts with advanced PCa, who initiated an NHT in 2022 at the University of California Irvine. Medical records were analyzed for various metrics relating to CV risk assessment performed by treating providers.
Results:
Pts of 11 different providers, including medical and urologic oncology, were examined. Characteristics of the study population at NHT start are described (Table). Within specific study population subgroups outlined, corresponding provider interventions within 3 months of NHT start are also listed.
Conclusions:
In this dataset of pts with pre-existing features of metabolic syndrome and CV risk factors at NHT start, only a minority had screening for hyperglycemia, hyperlipidemia, and cardiac dysfunction as well as had counseling about appropriate nutrition or referred to cardiology. Provider education about NHT-related TRAEs and emphasis on early screening for CV toxicity is key.

Characteristics of the study population and corresponding provider interventions.

Pt characteristic at NHT start
% of pts
Had lipid panel checked (%)
Had hemoglobin A1C checked (%)
Seen by cardiology before NHT start (%)
Referred to cardiology post NHT start (%)
Had documented counseling about nutrition (%)
Had echocardiogram (%)

Body mass index (BMI) 25.0 - 29.9
50.0
26.1
32.6
23.9
6.5
10.9
23.9

BMI ≥30
21.7
40.0
40.0
35.0
0.0
10.0
30.0

Former or active smoker
41.3
42.1
42.1
23.7
5.3
5.3
34.2

Hx of HTN
69.6
29.7
42.2
29.7
3.1
7.8
23.4

On ≥2 blood pressure (BP) agents
29.3
48.1
55.6
40.7
3.7
3.7
40.7

Hx of hyperlipidemia
64.1
30.5
35.6
28.8
1.7
8.5
25.4

On a statin
51.1
31.9
34.0
29.8
2.1
8.5
27.7

Hx of MI
20.7
36.8
36.8
52.6
0.0
5.3
31.6

Hx of CHF
9.8
44.4
77.8
55.6
11.1
0.0
55.6

Hx of arrhythmia
20.7
42.1
57.9
57.9
0.0
0.0
31.6

Hx of stroke
8.7
25.0
62.5
37.5
0.0
0.0
25.0

Hx of diabetes mellitus (DM)
34.8
34.4
50.0
37.5
3.1
9.4
31.3

On a non-insulin DM agent
38.0
28.6
37.1
28.6
2.9
14.3
25.7

On insulin for DM
14.1
23.1
61.5
23.1
0.0
7.7
15.4
Survival in advanced prostate cancer (PCa) patients with visceral metastasis: A population-based SEER study.
Authors: Jajja Salman Ayub , Naqvi Syed Arsalan Ahmed , Khan Muhammad Ali , Afzal Muhammad Umar , Anjum Muhammad Umair , Raina Ammad , Jain Prateek , Swati Fnu , Riaz Zaryab Bin , Childs Daniel S , Cobran Ewan Kemar , Bryce Alan Haruo , Zakharia Yousef , Singh Parminder , Riaz Irbaz Bin
Published: February 2025

134

Background:
Prostate cancer patients with visceral metastases at diagnosis are often treated using one-size-fits-all approach. For example, CHAARTED criteria treats any visceral metastasis as high volume. Therefore, we aimed to assess overall survival (OS) by site of visceral involvement in patients with metastatic PCa.
Methods:
Surveillance, Epidemiology, and End Results (SEER) database (2010-2021) was queried to obtain case listing data on metastatic PCa patients from 17 registries. The patients were categorized into three groups based on visceral metastasis at diagnosis: lung metastasis, liver metastasis, and others. Kaplan-Meier survival analysis was performed to estimate median OS with 95% confidence interval (CI). Log-rank test was conducted to assess if survival was significantly different among the groups. Cox proportional hazard regression analysis was performed to assess the magnitude of difference among the groups. P-value <0.05 established statistical significance.
Results:
This analysis included 21,007 metastatic PCa patients (lung: n=319; liver: n=123; brain: 107; bone: 20538). Metastatic PCa population with lung metastasis exhibited a median OS of 60 months (95% CI: 48-72) compared to 24 months (95% CI: 12-36) in population with liver metastases and to 36 months (95% CI: 36-36) in population with other metastases. The difference in OS among the groups was statistically significant (p < 0.001). Compared to population with lung metastasis, those with liver (HR: 1.91; 95% CI: 1.41-2.57) but not those with other metastases (1.16; 0.97-1.39) had significantly worse OS adjusting for Gleason score, PSA and race (Table).
Conclusions:
In metastatic PCa, patients with lung-only metastasis have significantly better overall survival and should be considered differently in prognostication to liver metastases. Consideration of site of visceral metastasis is critical for treatment intensification decisions. Limitations of this analysis include lack of accounting for confounding relationships at individual patient level.

Variable
Hazard Ratio (95% CI)

Metastases (Lung)
REFERENCE

Metastases (Liver)
1.91 (1.41-2.57)

Metastases (Other)
1.16 (0.97-1.39)

Gleason score≥8
REFERENCE

Gleason score <8
0.68 (0.64 -0.72)

PSA - ng/dL
1.01 (1.00 – 1.01)

Race (White)
REFERENCE

Race (Black)
0.99 (0.94 – 1.05)

Race (Asian or Pacific Islander)
0.70 (0.64 – 0.76)
Updated results from a phase I/II study of CBP-1018, a bi-ligand–drug conjugate (Bi-XDC) as late line therapy for patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Li Kaiwen , Guo Jianming , Guo Hongqian , Zhang Qi , Huang Hang , Zhou Liyan , Dai Junyong , Chen Jimin , Yang Lu , Yao Xudong , Huang Robert , Xu Mo , Zhang Jing , Tang en-Tzu , Shi Yehui , Huang Hai
Published: February 2025

161

Background:
Patients (Pts) with mCRPC have a poor prognosis with limited treatment options, particularly those who have progressed after novel hormonal agents (NHA) and chemotherapy. CBP-1018 has demonstrated a well-tolerated safety profile based on 112 pts and preliminary efficacy in mCRPC at RP2D of 0.14mg/kg as shown in 2024ASCO and 2024ESMO. Here we report the updated safety data of 120 pts and efficacy at ≥0.14mg/kg including pts treated with prior 2
nd
generation androgen receptor pathway inhibitor (ARPI) and taxane from the Phase I/II study.
Methods:
In this study, pts with progressive mCRPC after standard of care regardless of the number of prior therapies were enrolled. Response evaluation was undertaken per PCWG3 and RECIST v1.1. Primary endpoints were ORR, rPFS and safety.
Results:
As of cutoff date of 31-Aug 2024, a total of 120 pts were enrolled. 8.3% (10/120) of pts experienced treatment related adverse event (TRAE) leading to dose reduction and 4.2% (5/120) had TRAE leading to discontinuation. The AEs were consistent with the known safety profile, with the most common ≥G3 TRAE primarily being hematologic, which were transient and easily manageable. Typical common AEs seen with ADC were rarely observed; only 1 pt experienced treatment related visual acuity reduction and 11.7% (14/120) of pts experienced peripheral neuropathy. All of these TRAEs were G1. 76 pts were enrolled at ≥0.14mg/kg dose level (0.14mg/kg N=69; 0.16mg/kg N=7). 68.4% (52/76) with ECOG 1. 17.1% (13/76) had liver metastases and 15.8% (12/76) had lung metastases. Additionally, 67.1% (51/76) had received at least one prior taxane and at least one 2
nd
generation ARPI, while 53.9% (41/76) had received ≥ 2 prior 2nd generation ARPIs. 21.1% (16/76) had received prior PARP inhibitors. Among 25 pts with target lesion (≥0.14mg/kg), ORR was 20% and DCR was 88.0%. Target lesion reduction was observed in 60% of pts. In the subset of 15 pts with prior taxane and 2
nd
generation ARPI treated pts with target lesion (0.14mg/kg), ORR was 20% and DCR was 80%. Among 69 pts (0.14mg/kg), median radiographic progression-free survival (rPFS) has not yet been reached; 7-month rPFS rate was approximately 70%, and 12-month rPFS rate was about 60%. Among the 48 pts with prior taxane and 2
nd
generation ARPI treated (0.14mg/kg), 7-month rPFS rate was around 66%.
Conclusions:
CBP-1018 shows potential as a viable therapeutic option for heavily treated mCRPC pts based on the superior rPFS and anti-tumor activity, warranting further evaluation in later phase III trials. Clinical trial information:
NCT04928612
.
Targeting TROP2 in aggressive variant and neuroendocrine prostate cancer.
Authors: Von Amsberg Gunhild , Kaune Moritz , Bergmann Lina , Busenbender Tobias , Strewinsky Nadja , Paulsen Finn-Ole , Dum David , Tilki Derya , Graefen Markus , Bokemeyer Carsten , Werner Stefan , Dyshlovoy Sergey
Published: February 2025

171

Background:
Aggressive variant prostate cancer (AVPC) including neuroendocrine prostate cancer (NEPC) is characterized by rapid, androgen-independent tumor growth. Standard therapies often show limited efficacy. Alternative treatment strategies are therefore urgently required. Here, we present preclinical and first clinical results on the potential impact of TROP2 targeting in AVPC/NEPC.
Methods:
TROP2 expression was assessed in AVPC/NEPC cell lines, circulating tumor cells (CTCs) and metastatic biopsies. Efficacy of the TROP2 targeted antibody drug conjugate (ADC) Sacituzumab Govitecan (SG) was evaluated in prostate cancer (PC) cell lines with high and low/- TROP2 expression. TROP2+ AVPC/NEPC patients with exhausted standard therapy options are currently undergoing treatment with SG in an individual approach.
Results:
TROP2 expression was detected at varying levels in PC cell lines, with increased expression in docetaxel-resistant cells. CTCs of AVPC and NEPC patients were TROP2+ in 74.0% (37/50) and 48.6% (17/35), respectively, while the vast majority of biopsies from both cohorts expressed TROP2. SG was highly effective in TROP2+ cells
in vitro
, regardless of their degree of resistance to standard therapies while reduced activity was seen in TROP2 low/- cells after short-term exposure. Remarkably, SG exhibited a pronounced antiproliferative effect and/or apoptosis induction in TROP2-low LNCaP and PC3 cells, when co-cultured with TROP2+ DU145-DR or PC3-DR cells, indicating a bystander effect. The antiproliferative activity of SG was attributed to an increased G2/M cell cycle arrest. Proteomic analyses suggested suppression of cell cycle related processes and proliferation as well as signaling pathways involved in neuronal dedifferentiation and cell stemness. First clinical results of heavily pretreated TROP2+ AVPC/NEPC patients (n=9) revealed partial remission (PR) or stable disease in 44% and 33% at radiological follow-up, with a disease control rate of 78% and 44% at 3 and 6 months, respectively. Of note, in a NEPC patient with sudden, rapid progression following initial PR, loss of TROP2 expression on CTCs was detected. In addition, preclinical data suggested AKT activation and upregulation of p-glycoprotein as further possible resistance mechanisms.
Conclusions:
TROP2-directed therapy with SG demonstrates promising preclinical and clinical activity in AVPC and NEPC. A clinical trial evaluating a TROP2-directed ADC in AVPC is in preparation.
Extreme bipolar androgen therapy: Alternating darolutamide and testosterone cypionate in patients with metastatic castration-resistant prostate cancer (mCRPC; ExBAT trial/LACOG 0620).
Authors: Isaacsson Pedro , Soares Andrey , Fontes Jardim Denis Leonardo , Maluf Fernando Cotait , Morbeck Igor Alexandre Protzner , Girardi Daniel da Motta , Dias Mariane Fontes , Souza Vinicius Carrera , Silva Adriano Goncalves E , de Jesus Rafaela Gomes , Werutsky Gustavo , Rebelatto Taiane , Bastos Diogo Assed
Published: February 2025

178

Background:
Sequencing androgen-receptor signaling inhibitors (ARSi) has limited activity in metastatic castration-resistant prostate cancer (mCRPC). Bipolar Androgen Therapy (BAT), consisting of supraphysiological doses of exogenous testosterone, followed by a decline to castrate levels, has shown benefit in a subset of patients (pts) with mCRPC, by the downregulation of AR levels, a therapeutic vulnerability which led to resensitization to ARSi in trials. We hypothesize that BAT could significantly enhance the efficacy of subsequent ARSi darolutamide in pts who had progressed to abiraterone.
Methods:
The ExBAT/LACOG 0620 (
NCT04558866
) study is a phase II, single-arm, multi-center trial investigating a pre-planned regimen of alternating BAT and darolutamide in mCRPC pts after progression on abiraterone. Prior docetaxel for hormone-sensitive disease was allowed. Pts received intramuscular testosterone cypionate 400 mg on day 1, followed by oral darolutamide 1200 mg/day from day 29 to day 56, followed by a washout period of 7 days, in 63-day cycles. The primary endpoint was radiographic progression-free survival (rPFS) at 12 months. Secondary endpoints include median rPFS, PSA50 response, overall survival (OS), quality of life (QoL) and safety.
Results:
From Jun2021 to Mar2023, 51 pts were enrolled in 9 centers and 48 pts were eligible for efficacy analysis. Median age was 69y (range, 48-92), 23.5% had received abiraterone on castration-sensitive setting and 76.5% on mCRPC. The rPFS rate at 12 months was 40.9% (95% CI, 26.3 – 55.0) and median rPFS was 9.0 months (95% CI, 3.9 – 12.9). PSA50 response was 16.7% (95% CI, 7.4–30.2) and median OS was 23.0 months (95% CI, 17.7 – not reached). At cut-off date (22Mar24), 10 pts remained on treatment. QoL was maintained during the treatment. Treatment-related adverse events (TRAEs) rates of any grade and grade 3-4 were 64.7% and 9.8% respectively, and no grade 5 TRAE was reported. The most common AEs were bone and breast pain.
Conclusions:
ExBAT study demonstrated durable (12 months or more) antintumor activity of alternating BAT and darolutamide in around 40% of pts, with manageble safety profile. Further studies evaluating ExBAT are needed to identify biomarkers of response and the impact of ARSi sequencing in subsequent lines of therapy. Clinical trial information:
NCT04558866
.
Evaluating the impact of single vs. combination therapy on survival outcomes in mHSPC patients stratified by BMI.
Authors: Rohde Luke , Agarwal Rohan , Schoen Martin W.
Published: February 2025

187

Background:
Metastatic hormone sensitive prostate cancer (mHSPC) is a heterogenous disease with a variety of treatment options. De novo mHSPC can be treated with androgen deprivation therapy (ADT) monotherapy or combinations including docetaxel or androgen receptor pathway inhibitors. Body mass index (BMI) is known to be associated with survival, but there is little data to show the effectiveness of treatment intensity (single or combination therapy) based on BMI.
Methods:
Patients treated for mHSPC within the Veterans Health Affairs from 2017-2023 were included. BMI was assessed using height and weight at diagnosis and treatment intensity was determined by treatments within 4 months of start of ADT. Additional baseline characteristics for each group included age, prostate specific antigen (PSA), and Charlson Comorbidity Index (CCI). Survival was estimated using the Kaplan-Meier method and Cox proportion hazard modeling was used to account for known covariates.
Results:
There were 4184 veterans identified with 33.5% BMI <25, 35% BMI 25-30, and 31.5% with BMI >30. The BMI 25-30 group had longer survival compared to BMI of <25 (37.3 vs. 30.7 months, HR 0.78 95% CI 0.71-0.86) and the BMI >30 had longer survival compared to BMI 25-30 (42.5 vs. 37.3 months, HR 0.87 95% CI 0.79-0.96). In patients with BMI of <25 combination therapy was associated with longer survival (HR 0.73 (0.63-0.83)) and in patients with BMI of 25-30, combination therapy was also associated with longer survival 0.76 (0.67-0.88). However, in patients with BMI >30, there was no difference in overall survival based on combination or monotherapy (HR 0.97 (0.83-1.13)). In a multivariable model including age, PSA, CCI, and treatment intensity, BMI >30 and BMI 25-30 was associated with decreased risk of death compared to BMI <25, aHR 0.80 (95% CI 0.72-0.89) and aHR 0.89 (95% CI 0.81-0.98) respectively.
Conclusions:
In patients with mHSPC, higher BMI is associated with longer survival compared to lower BMI. In all patients, combination therapy was associated with longer survival, however, there was no difference in survival with combination therapy compared to monotherapy in patients with BMI >30. Future studies could investigate the reason why combination therapy is only associated with benefit in patients with BMI <30.

BMI (kg/m
2
)

<25 n=1403

25-30 n=1465

>30 n=1316

P value (ANOVA)

Age (mean years)
76.2
74.4
71.8
p<0.001

PSA (median ng/mL)
177
91.6
61.25
p<0.001

Overall Survival (median months)
30.7
37.3
42.5
p<0.001

ADT monotherapy
26.9 (n=736)
33.1 (n=683)
42.5 (n=582)

Combination therapy
36.3 (n=667)
41.5 (n=782)
42.6 (n=734)

HR (95% CI)
0.73 (0.63-0.83)
0.76 (0.67-0.88)
0.97 (0.83-1.13)
Image-based artificial intelligence algorithms for molecular diagnostics in prostate pathology: How far are we? A systematic review.
Authors: van Hees Jacqueline E. , Vlaming Michiel , Stathonikos Nikolas , Suelmann Britt B.M. , Meijer Richard P. , Willemse Peter-Paul M. , van Diest Paul J.
Published: February 2025

193

Background:
Guidelines recommend molecular diagnostics for homologous and mismatch repair (MMR) defects in men with metastatic castration-resistant prostate cancer. However, in clinical practice, routine testing is hindered because it is costly, time-consuming and not available in all laboratories. Moreover, many patients need to be tested to identify the few with these genetic aberrations. To address these challenges, image-based artificial intelligence (AI) algorithms have been developed to predict molecular alterations from hematoxylin and eosin (HE) slides that are beyond the pathologist's visual detection. This review aims to assess the advancements of image-based AI algorithms in molecular diagnostics in prostate pathology and their potential in daily clinical practice.
Methods:
Through a search query, 3213 articles were identified and screened by two reviewers. In total, 12 articles were selected for this review and were assessed using the QUADAS-2 criteria.
Results:
Out of 12 articles, 5 focused exclusively on a specific set of preselected genes in prostate cancer, while the other articles examined broader ranges of genomic or transcriptomic changes, with some covering various cancer types. Training datasets consisted of up to 451 prostate cancer slides and most studies included only slides from radical prostatectomies. The majority made use of the cancer genome atlas program (TCGA). The best performance reported was 0.91 area under the curve (AUC) on internal and AUC of 0.89 on external validation. However, only 5 of the 12 studies performed external validation and none looked into the application of their algorithm in a clinical setting.
Conclusions:
Our review shows that in concept, AI is reasonably capable of detecting molecular changes based on HE slides of prostate pathology with reasonable predictive power. This has been shown in different specific genetic alterations, as well as in genome- or transcriptome-wide alterations. The predictive power of AI may however not be good enough to forgo molecular testing in patients predicted negative. Furthermore, these systems have only reached the developmental stage, leaving their potential performance in a clinical setting yet to be determined.
Transdermal oestradiol (tE2) patches as androgen deprivation therapy (ADT): Efficacy and safety of combining with androgen receptor pathway inhibitors (ARPIs) in metastatic (M1) prostate cancer—Randomised comparison from the STAMPEDE trial platform.
Authors: James Nicholas David , Rush Hannah , Nankivell Matthew Guy , Sehjal Jyoti , Mangar Stephen A , McPhail Neil , Brown Simon , Tanguay Jacob S , Gale Joanna , Mohamed Wael , Crabb Simon , Khan Omar , Russell John , Cross William , Murphy Claire , Deighan John , Clarke Noel W , Parmar Mahesh K. B. , Gilbert Duncan C. , Langley Ruth
Published: February 2025

21

Background:
Recent phase III data (n=1360) has shown that starting ADT with tE2 patches is non-inferior in terms of metastasis-free survival (with similar overall survival) to luteinising hormone releasing hormone analogues (LHRHa) for locally advanced (M0) prostate cancer. For both M0 and M1 patients, tE2 has advantages in terms of reported quality of life, bone mineral density, hot flushes and metabolic outcomes compared to LHRHa, with no excess of thromboembolic events. However, there is currently no data on the use of androgen receptor pathway inhibitors (ARPIs) (abiraterone, enzalutamide or apalutamide) with tE2.
Methods:
STAMPEDE [NCT00268476] is a multi-arm, multi-stage platform trial. This embedded phase 2 randomised study assessed efficacy and toxicity in participants (pts) randomly allocated (1:1) to tE2 patches (releasing 100mcg/24hrs, 3 patches changed twice weekly once testosterone ≤1.7ng/ml) or LHRHa (standard doses) and scheduled to receive ARPIs. Primary outcome measure was the proportion of pts reaching a PSA nadir of ≤0.2ng/ml during the first 6 months. Other PSA parameters, testosterone ≤1.7ng/ml at 12 weeks with tE2, and adverse events within the first 12 months (including hypertension, hot flushes and gynaecomastia) were assessed.
Results:
Between Oct-2020 and Mar-2023, 79 pts with histologically confirmed M1 prostate cancer (median (IQR) age 69 (65-75), median (IQR) baseline PSA 43.3 (11.5-296.2)) received either LHRHa+ARPI (n=41) or tE2+ARPI (n=38). Baseline characteristics were similar between the 2 groups. The proportion of pts achieving PSA ≤0.2ng/ml was LHRHa+ARPI 25/41 (61%) and tE2+ARPI 23/38 (61%). LHRHa v tE2: PSA90 (93% v 95%) and PSA50 (100% v 100%). 31/34 (91%) men treated with tE2 had testosterone ≤1.7ng/ml at 12 weeks. Hot flushes: LHRHa (grade 1: 32%, grade 2: 20%) v tE2 (grade 1: 24%, grade 2: 5%). Gynaecomastia: LHRHa (grade 1: 10%, grade 2: 0%) v tE2 (grade 1: 35%, grade 2: 8%) and any grade hypertension LHRHa v tE2 17% versus 5%.
Conclusions:
PSA responses were similar in pts treated with tE2+ARPI or LHRHa+ARPI further supporting the use of tE2 patches for ADT in prostate cancer management. tE2 patches provide patients with ADT choices about expected toxicity profiles, including reduced hot flushes (and subsequent impact on quality of life), and mode of administration. Clinical trial information:
NCT00268476
.
Radiographic progression without PSA progression in advanced prostate cancer patients.
Authors: Chaudhary Ruchi , Bhaumik Amitabha , Agarwal Neeraj , Shotts Kristin Michelle , Lopez-Gitlitz Angela , McCarthy Sharon , Mundle Suneel Dinkar , Chi Kim N. , Small Eric J.
Published: February 2025

213

Background:
Androgen Receptor Pathway Inhibitors (ARPIs) are frequently combined with Androgen Deprivation Therapy (ADT) to treat prostate cancer patients (pts) with castration sensitive (CSPC) or castration resistant (CRPC) disease. We sought to characterize pts who experienced radiographic progression without PSA progression (R-PD) while under treatment with ADT with or without an ARPI.
Methods:
We undertook a retrospective analysis of two phase 3 trials testing apalutamide (Apa) + ADT vs Placebo (Pbo) + ADT: TITAN (NCT02489318) in pts with metastatic CSPC (mCSPC) and SPARTAN (NCT01946204) in pts with non-metastatic CRPC (nmCRPC). We compared pts with R-PD with pts who experienced PSA progression before or concurrently with radiographic progression (PSA-PD). Kaplan-Meier and Cox proportional-hazard models were used to estimate time-to-event and hazard ratios.
Results:
The distribution of types of progression, and location of R-PD by study is shown in the table. Pts with R-PD had shorter overall survival (OS) compared with PSA-PD pts in both studies (median OS R-PD vs PSA-PD: 22.9 m vs 37.4 m in TITAN; 49.8 m vs 53.7 m in SPARTAN). Compared with Pbo, Apa delayed the time to R-PD in both studies (HR 0.51, 95% CI: 0.36 to 0.73 in TITAN; HR 0.17, 95% CI: 0.1 to 0.28 in SPARTAN). No pre-treatment variables predictive of R-PD vs PSA-PD were identified; transcriptional profile analysis is ongoing.
Conclusions:
Radiographic progression in the absence of PSA progression is not uncommon amongst patients with advanced prostate cancer, and carries a poor prognosis. The addition of Apa prolongs the median time to R-PD. Our findings underscore the importance of monitoring these pts with imaging, independent of PSA dynamics. The impaired survival of R-PD pts warrants evaluation of new therapeutic approaches for these pts.

OVERALL
TITAN (mCSPC; n=1052)
SPARTAN (nmCRPC; n=1207)

% pts with R-PD
12.4%
10.4%

% pts with PSA-PD
41.2%
45.4%

Sites of progression in R-PD pts (% of randomized pts)

Bone only
6.3%
1%

Non-bone
6%
8.8%

Both
0.1%
0%
Lewis Y antigen as a novel target for CAR (chimeric antigen receptor) T-cell therapy in patients with neuroendocrine prostate cancer.
Authors: Kulakowska Weronika , Taylor Renea , Ranasinghe Weranja , Darcy Phillip K. , Trapani Joseph , Risbridger Gail
Published: February 2025

217

Background:
Neuroendocrine prostate cancers (NEPC) currently have no effective therapies. While CAR (Chimeric Antigen Receptor) T cell therapies targeting PSMA and PSCA receptors are currently in phase 1/2 studies in metastatic castrate-resistant prostate cancer (mCRPC), antigen targets for NEPC remain limited. Lewis Y antigen (LeY) is an oncofetal antigen expressed only in adult tumour cells and is considered a target for CAR T cell therapy in haematological, lung, ovarian and colon cancer. We previously found that LeY is a promising target for CAR T cell therapy in prostate cancer and that preconditioning LeY-directed CAR T cells with carboplatin further enhances tumour responses in mCRPC. We investigated if LeY can be used as a novel CAR T cell target for NEPC.
Methods:
The expression of the Lewis Y antigen was assessed in our patient-derived prostate cancer xenograft collection using immunohistochemistry (IHC). To assess the efficacy of LeY-CAR T cells, we used specimens established from a patient (Patient 508) with NEPC who had incurable metastatic disease and failed standard treatments. We generated CAR T cells from his peripheral blood mononuclear cells (PBMCs) to test their specificity and efficacy
in vitro
against established cell lines.
Results:
In our MURAL PDX collection of 59 prostate tumours, 81% (9/11) NEPCs expressed LeY antigen on IHC. Next, we successfully produced anti-LeY CAR T cells from the patient’s PBMCs using retroviral transduction. Flow cytometry verified efficient transduction of the CAR constructs. Previous studies found that a 1:1 ratio of CD4
+
:CD8
+
T cells improved outcomes following CAR T cell therapy
5,6
, so we further phenotyped patient T cells by flow cytometry. The CD4
+
:CD8
+
T cell ratio was nearly 1:1 (51.7% and 41.4% of total T cells, respectively). Next, we used an immunobead assay to investigate CAR-T specificity in releasing proinflammatory cytokines. Significant cytokine production was observed after a 4-hour co-culture with LeY+ human ovarian cancer cell line, OVCAR3, vs co-culture with control LeY- MDA-MB435 cells (p=0.0004), demonstrating the specificity of the CAR T cells.Lastly, we showed that patient CAR T cells effectively killed LeY+ cells (OVCAR3), but not control LeY- cells (MDA-MB435; p<0.0001). Tumour cell death was measured by the amount of released chromium following 16-hour co-culture. CAR T cells killed LeY+ target cells more effectively than their non-transduced equivalents at a range of effector-to-target ratios, with up to 15-fold increase in cell death.
Conclusions:
Our preclinical studies show that most NEPC tumors express the LeY antigen and that patient-derived CAR T cells specifically kill those cells. These findings identified a potential CAR T treatment target for NEPC for a phase 1/2 study.
Whole-slide multiplexed tissue imaging of prostate adenocarcinoma to investigate immune niches in high- versus low-grade tumors.
Authors: Amiryousefi Ali , Wala Jeremiah , Labadie Brian William , Atmakuri Aishwarya , Chaudagar Kiranj , Toye Eamon , Gagné Andréanne , Lin Jia-Ren , Van Allen Eliezer Mendel , Patnaik Akash , Sorger Peter
Published: February 2025

224

Background:
The tumor-immune microenvironment (TME) is crucial in the progression of prostate cancer (PCa), yet little is known about its spatial organization and immune composition in treatment-naïve, localized PCa. While immunotherapy has had limited success in metastatic PCa, its efficacy in localized disease remains largely unknown. This study aims to dissect tumor-immune interactions in primary PCa and explore differences in immune landscape between low- and high-Gleason PCa, thus providing biologic insights for immunotherapy actionability.
Methods:
We performed spatial profiling of radical prostatectomy (RP) specimens from 28 treatment-naïve prostate cancer patients. These included 14 patients with low-grade disease (Gleason Grade Group 1–2) and 14 patients with high-grade disease (Gleason Grade Group 4–5). Using multiplex cyclic immunofluorescence (CyCIF) and a 27-marker panel, we obtained single-cell resolution across whole-slide images. Tumor and stromal compartments were manually annotated, and immune cell densities and neighborhood were analyzed and compared between low- and high-grade tumors. Spatial analysis focused on identifying immune clusters (IC -suggestive of tertiary lymphoid structures -TLS) and quantified the degree of immune infiltration along with characterization of T cell exhaustion markers such as CD8+PD1+TCF1+ cells.
Results:
High-grade tumors exhibited significantly higher infiltration of CD8+ T cells and CD20+ B cells compared to low-grade tumors. Spatial profiling revealed organized ICs, especially in high-grade tumors, which exhibited characteristics consistent with TLS. These ICs were enriched with precursor-exhausted CD8+PD1+TCF1+ T cells (TPEX), suggesting a state of immune exhaustion that may be therapeutically reactivatable. The presence of TLS and immune exhaustion markers in high-grade tumors highlights a more active immune microenvironment than previously appreciated in primary prostate cancer.
Conclusions:
Our findings reveal that a subset of high-grade prostate cancers harbor an organized, immune-infiltrated tumor microenvironment, including adaptive immune features such as TLS and CD8+ T cell exhaustion. These immune landscapes, marked by significant CD8+ and CD20+ cell infiltration and spatial clustering, suggest that high-grade prostate tumors may be amenable to immune-based therapies, despite the failure of immune checkpoint blockade in metastatic PCa. These results raise the hypothesis that immunotherapy might be effective in treatment-naïve high-grade prostate cancer. Future efforts should explore whether these immune profiles can be leveraged for risk stratification or as biomarkers for response to immunotherapy in advanced disease.
Biomarker testing patterns among patients newly diagnosed with prostate cancer in a community oncology network.
Authors: Dwyer Orr Lisa , Mahmud Siraje , Cline Vivian Jean M. , Mirsalehi Ayda , Lisi Monica , Ensley Laura , Brisbin Lorraine , Paulson Roy Steven
Published: February 2025

229

Background:
Prostate cancer guidelines recommend that clinicians order biomarker testing for patients with metastatic prostate cancer. In addition, testing is recommended to determine patients’ eligibility for clinical trials and to identify potential actionable mutations that can inform appropriate treatment strategies. The aim of this study was to evaluate biomarker testing patterns among patients newly diagnosed with prostate cancer who received care in a large community oncology provider network.
Methods:
A retrospective database analysis, using several sources that include iKnowMed (EMR), Ellkay CareEvolve (Genetic HL7 interface), and the Molecular Data Warehouse and covers approximately 1.7 million distinct patients, was conducted on patients newly diagnosed with prostate cancer between Jan 1, 2018, and Jun 30, 2022, and receiving care in a large oncology network in West South-Central United States. Baseline demographics and clinical characteristics were analyzed descriptively and the proportion of patients who received biomarker testing was determined.
Results:
Data on 18,743 patients with prostate cancer (mean age at diagnosis, 71 years; 46% White, 13% Hispanic, 7% Black, 1% Asian, 33% other/unknown) were abstracted. The proportion of patients who received biomarker testing was 14% overall and 23% among those with Stage IV disease. Of all biomarker tests performed, roughly 6% was single gene testing, 49% was broad panel testing, 25% was both single gene testing with broad panel testing, and approximately 20% of the tests were unknown. The average time from first biomarker testing to disease diagnosis was approximately 5 months. Less than 10% of the patients who tested positive with an actionable mutation received targeted therapy. Hormone therapy (32%) was the most common treatment received, followed by supportive care (7%).
Conclusions:
These findings provide insights into the frequency of biomarker testing among patients newly diagnosed with prostate cancer who receive care in a large community practice setting. Advancement in targeted therapies is predicated on improved testing rates, and this study suggests opportunities exist for interventions and increased education among healthcare providers based on observed time to testing and the rate of testing.

Biomarker testing patterns in patients with prostate cancer.

Parameter
Patients with prostate cancer(N=18,743)

Received biomarker testing

All patients, n (%)
2,585 (14)

Patients with metastatic Stage IV disease, n/n (%)
941/4,168 (23)

Received targeted therapy after positive biomarker testing indicating actionable mutation, n/n (%)
36/450 (8)

Mean (standard deviation) days from ordering biomarker test to:

Disease diagnosis
156 (545)

Receiving results
52 (213)

Treatment initiation
113 (525)
Characterizing immunogenicity of
MYC-
amplified, metastatic prostate cancer as reflected by the recovery rates of adaptive immune receptor recombinations from RNAseq files.
Authors: Kahlon Sunny , Barker Vayda , Varkhedi Mallika , Wang Alex , Huda Taha , Blanck George
Published: February 2025

241

Background:
In prostate cancer, identifying biomarkers to predict patients who are at higher risk for metastatic disease remains a key question. The interaction of oncogenes such as
MYC
with the adaptive immune system may be a potential marker for worse progression; for example,
MYC
-amplified neuroblastoma has been shown to be immunologically cold both in vitro and with respect to the amount of adaptive immune receptor (IR) recombinations recovered from genomics files. Thus, we performed a correlative study identifying the relationship between
MYC
amplification and detection of adaptive IR recombinations in genomics files in prostate cancer.
Methods:
We utilized datasets for this study: The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD, n = 475), Count Me In-Metastatic Prostate Cancer (CMI-MPC, n= 63) and West Coast Dream Team – Metastatic Castration Resistant Prostate Cancer (WCDT-MCRPC, n = 76). Copy number variation (CNV) assessments were done for the cases in these studies, identifying oncogene amplification as those with high ratios of exome, tumor to blood sequencing read counts for a given gene. We also mined productive IR recombination sequencing reads from RNAseq files, with associated V and J-IDs, as described in Chobrutskiy et al. 2020, which yielded reads for
TRA
,
TRB
,
TRD
,
TRG
,
IGH
,
IGK
, and
IGL
. Then, MYC-amplified cases and MYC-deficient cases were compared with a two-proportion test for progression-free survival and with a t-test for the counts of IR receptors.
Results:
We first determined that, for TCGA-PRAD dataset, cases representing the top 20
MYC
read tumor to blood count ratios, in comparison to all other cases, represented a poorer progression free survival (p = 0.01) at the 70-month timepoint. We also noted that average
MYC
CN in both metastatic prostate cancer datasets (CMI-MPC and WCDT-MCRPC) was higher than in the TCGA-PRAD dataset, which represented primary tumor samples (p < 0.001 for both analyses). Further, for the WCDT-MCRPC dataset, we found that
MYC
-amplified cases were associated with significantly reduced
IGH
,
IGK
, and
IGL
recombination reads in RNA-seq files (p = 0.005, 0.01, 0.004 respectively). For the WCDT-MCPRC dataset, we found that
MYC
-amplified cases were associated with reduced
TRA
and
TRB
recombination reads in WGS files (p = 0.008 and 0.017 respectively).
Conclusions:
This report further evidences the negative effects of MYC amplification with regard to immune evasion and being a key driver of prostate cancer metastasis. This report thus supports risk stratification by MYC-amplification, as well as noting that patients with MYC-amplification may benefit more from immune-boosting therapies. In particular, this report identifies immunoglobulins and by proxy, B-cells, as a major deficiency in those with MYC-amplified prostate cancer.