bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1/2a study of PRL-02, a long-acting intramuscular (IM) depot injection of abiraterone decanoate in patients (pts) with advanced prostate cancer.
Authors: Avitia Jose W. , Tutrone Ronald F. , Shore Neal D. , Bailen James L. , Nordquist Luke T. , Richardson William , Peer Cody J. , Figg William Douglas , Walling Jacqueline M. , Eisner Joel Robert , Sharp Matthew , Schotzinger Robert , Moore William R.
Published: March 2023

141

Background: PRL-02 (abiraterone decanoate) is a novel, long-acting IM depot prodrug of abiraterone. In non-clinical models, PRL-02 provided high and durable concentrations of prodrug and abiraterone to target tissues including adrenal glands, lymph nodes and bone. Single doses of PRL-02 suppressed testosterone (T) through 14 weeks in a castrate monkey model to concentrations comparable to oral abiraterone acetate (AA) with lower and less variable plasma abiraterone exposures. Clinically, PRL-02 blocks androgens with minimal increases in mineralocorticoids or depletion of glucocorticoids via inhibition of CYP17 lyase and minimal inhibition of CYP17 hydroxylase. PRL-02 has the potential for a superior therapeutic index and safety profile compared to oral AA. Methods: Phase 1 is a standard 3+3 design intended to identify a recommended phase 2 dose (RP2D). Pts with metastatic castrate resistant or sensitive prostate cancer (mCRPC/mCSPC) and a screening T of 2 - 50 ng/dL were administered IM PRL-02 every 12 weeks with daily oral dexamethasone. Results: As of 8Sep22, 17 pts (6 mCRPC, 11 mCSPC) were treated across 5 dose cohorts (180, 360, 720, 1260, 1800mg). Generally, there was a dose-proportional increase in abiraterone concentrations following a single dose of PRL-02 with a Tmax of 14 - 28 days and a plasma half-life of 18.3 days. The median baseline T level was 7.45ng/dL. Among pts dosed at 720mg and above, 9 of 11 had a 90% reduction in T or values ≤ 1ng/dL at day 28, including 2 pts with T≤LLOQ of 0.1 ng/dL, and PSA50 responses were observed in 8 of 10 with post-baseline results. There were no treatment related serious adverse events (AEs) or dose limiting toxicities. G3 AEs related to PRL-02 included hip and shoulder pain. G2 related AEs included fatigue, decreased appetite, insomnia and hot flush; symptoms of mineralocorticoid excess were not reported. Minimal and transient changes in ‘up-stream’ steroids (e.g., progesterone (P) and corticosterone (C)) were observed through the 1800mg dose. Although serial radiology was not prospectively required, there was radiographic improvement in 6 pts with data available. Conclusions: PRL-02 was well tolerated. Dose-dependent T suppression was associated with clinical benefit including PSA responses and radiographic improvement. Based on a historical comparison, the levels of P and C are significantly lower than seen with AA + prednisone which appear to be due to greater CYP17 lyase selectivity. The 1260mg or 1800mg dose will be the RP2D. Clinical trial information: NCT04729114 . [Table: see text]
Preliminary results from a phase 1/2 study of co-stimulatory bispecific PSMAxCD28 antibody REGN5678 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Stein Mark N. , Zhang Jingsong , Kelly William Kevin , Wise David R , Tsao Kai , Carneiro Benedito A. , Falchook Gerald Steven , Sun Furong , Govindraj Shilpa , Sims Jennifer S , Zhu Min , Seebach Frank A. , Lowy Israel , Thanigaimani Pradeep , Sandigursky Sabina , Miller Elizabeth
Published: March 2023

154

Background: Pts with mCRPC have a poor prognosis with limited treatment options, including minimal response to immunotherapies. REGN5678 is a first-in-class, full-length anti-PSMAxCD28 bispecific costimulatory antibody designed to target prostate cancer cells and enhance T-cell activation. We report preliminary results from the dose escalation part of a first-in-human, open-label, Phase 1/2 study (NCT03972657) examining REGN5678 in combination with cemiplimab, a PD-1 blocking antibody. Methods: Pts with mCRPC had received ≥2 lines of systemic therapy in the metastatic and/or castration-resistant setting, including ≥1 second-generation anti-androgen. Pts received REGN5678 weekly at dose levels [DL] 0.1–300 mg, initially as monotherapy for 3 weeks, followed by combination with cemiplimab (350 mg Q3W) until progression or toxicity. Primary objectives are safety, tolerability, and pharmacokinetics. Preliminary efficacy measurements include decline in prostate-specific antigen (PSA) from the start of combination treatment and radiographic response from baseline. Results: At the data cutoff (DCO; July 27 2022), 35 pts had been treated. Treatment-emergent adverse events (TEAEs) ≥Grade (G)3 occurred in 54% (19/35) of pts. Cytokine release syndrome occurred in 6 pts (all G1) and there were 2 dose-limiting toxicities (both G3): pain (at 1 mg) and Guillain-Barré syndrome (at 300 mg). 4 pts (11%) experienced a ≥G3 immune-mediated adverse event (imAE; at DLs 30–300 mg). REGN5678 exposure was non-linear over the tested DLs (more than dose proportional). There were minimal signs of efficacy at lower DLs (REGN5678 0.1–10 mg), with only 1/16 pts showing a PSA decline (of 21%). More PSA declines occurred at higher DLs: 1/4 pts at 30 mg (a PSA decline of 100%), 3/8 at 100 mg (>99%, 44%, 22%), and 3/4 at 300 mg (>99%, 99%, 82%). Notably, all ≥G3 imAEs occurred in pts with PSA declines. Among pts with measurable disease and ≥1 on-treatment scan, radiographic response per RECIST 1.1 occurred in 1/3 pts at 30 mg (complete response), 1/4 at 100 mg (unconfirmed partial response [PR]), and 1/1 at 300 mg (PR confirmed after DCO). Conclusions: Preliminary data on REGN5678 plus cemiplimab in pts with mCRPC provide first evidence of clinical activity of a CD28 co-stimulatory bispecific antibody in solid tumors. Clinical activity was observed at DLs 30–300 mg. ≥G3 imAEs occurred in pts with PSA declines, suggesting a possible association. The study is ongoing to determine the maximum tolerated and recommended Phase 2 doses. Clinical trial information: NCT03972657 . [Table: see text]
Phase II trial evaluating olaparib maintenance in patients with metastatic castration resistant prostate cancer (mCRPC) after docetaxel treatment, reaching partial or stable response: SOGUG-IMANOL study.
Authors: Juan FITA Maria Jose , Anido Herranz Urbano , Mendez Vidal Maria Jose , Gironés Regina , Mellado-Gonzalez Begoña , Sepulveda Sánchez José Manuel , Alvarez-Fernandez Carlos , Climent Miguel Ángel , Heras Lucia
Published: March 2023

168

Background: Prostate cancer is the second most common cancer in men. A number of important systemic therapies have been developed to treat mCRPC and now comprise the current therapeutic landscape. Docetaxel became the first systemic therapy to improve survival in these men in a randomized study demonstrating superiority versus mitoxantrone (18.9 months versus 16.5, p=0,004). But, inexorably, after stopping, disease progresses. Methods: A prospective phase II trial was designed to test Olaparib maintenance efficacy, in terms of progression free survival (PFS), in patients with mCRPC with DNA-repair defects that have achieved partial or complete response after being treated with systemic therapy (at least six cycles of docetaxel). Results: 134 mCRPC patients were included since Feb-2018 to Nov-2020 and were tested for DDR alterations. 19.4% of patients had somatic mutations (30.8% BRCA2, 3.8% BRCA1, 19.2% ATM, 7.7% CHEK2, 7.7% PALB2). 53,8% received Olaparib maintenance treatment, with a median follow-up of 23.3 months. Median age was 73 years. Median basal PSA was 17 ng/dL. 100% were metastatic (14.3% de novo and 85.7% relapsed after primary treatment), 78.6% had bone metastasis, 35.7% visceral and 35.7% adenopathies. 42.9% had previous treatment with abiraterone and 35.7% with enzalutamide. 46.2% received at least 8 cycles of docetaxel. 7.1% achieved a partial response and 92.9% a disease stabilization. Response to Olaparib treatment was 14.3% partial response, 71.4% stabilization and 7.1% disease progression.14.3% had a PSA50 decrease. Median duration of response was 8.27 months. Median PFS was 10.1 months. Median PSA-PFS was 3.5 months. G3/4 adverse events were 21.4% asthenia,14.3% anemia and 7.1% neutropenia. Conclusions: Olaparib maintenance after at least six cycles of docetaxel shows promising activity in mCRPC with DDR alterations, with an acceptable toxicity profile. Our pathogenic mutations percentage (19,4%) is in line with previous publications. Clinical trial information: NCT03434158 .
Phase Ib trial of enzalutamide (Enza) with venetoclax (Ven) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Perimbeti Stuthi , Jamroze Anmbreen , Attwood Kristopher , Farmer Bailey , Beumer Jan Hendrik , Bies Robert , Levine Ellis Glenn , Kirk Jason , Tang Dean , Chatta Gurkamal S. , Gopalakrishnan Dharmesh
Published: March 2023

182

Background: Androgen receptor (AR) signaling is critical to prostate cancer (PCa) cell survival and proliferation. Androgen ablation leads to expansion of both AR−/lo and AR+/hi resistant clones in CRPC xenografts. Most current therapies for mCRPC are directed towards AR+/hi cells. BCL-2 is highly up-regulated in CRPC xenografts and human tumors post-Enza. Ven, a selective BCL-2 inhibitor, inhibits Enza resistance in AR−/lo and CRPC models. We hypothesize that co-targeting AR−/lo and AR+/hi clones with Ven and Enza may inhibit Enza resistance in human mCRPC. Methods: This is a phase 1b single center, single arm trial of fixed dose Enza (160mg/d) with escalating doses of Ven in patients with mCRPC that has progressed on multiple lines of prior therapies including antiandrogens to evaluate pharmacokinetics, safety and recommended phase 2 dose. A total of 10 patients were enrolled in the study. Three dose levels of Ven (400mg (DL1), 600mg (DL2), and 800mg (DL3)/d q28d) were evaluated using a 3+3 study design. Kaplan Meier method was used to estimate median overall survival (OS) and time to next systemic therapy (TNST). Results: Median age was 71.3 years and mean duration on treatment was 28.7 weeks (range: 8-140 weeks). On an average, each patient received 3 lines of treatment prior to enrollment(range:1-8). The most frequent treatment related adverse events (TRAEs) (>10%) were mostly grade 1-2 as listed. Grade 3 TRAEs included hypertension (20%), fatigue (10%), and thrombocytopenia (10%). Grade 3 fatigue as DLT was reported in one patient in DL3. Only 1/10 (10%) attained PSA50 response; 4/10 (40%) patients had stable disease and 6/10 (60%) had disease progression as their best radiographic response. Median OS for the study population was 18.8 months (95% CI 5.3-28.2 months) and median TNST was 5.4 months (95% CI 0.9-34.6 months). Conclusions: This phase 1b trial demonstrates an acceptable toxicity profile for the combination of Enza and Ven in refractory mCRPC. PK evaluations and correlative biomarker studies are currently ongoing. Clinical trial information: NCT03751436 . [Table: see text]
Therapeutic potential of plant-derived nanovesicles for neuroendocrine prostate cancer.
Authors: Saini Sharanjot , Sreekumar Amritha , Lee Tae Jin , Sharma Ashok , Simmons Matthew
Published: March 2023

186

Background: Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of prostate cancer (PCa) that often emerges after androgen receptor (AR)-targeted therapies such as enzalutamide and abiraterone. NEPC arises via trans-differentiation of prostate adenocarcinomas to neuronal lineage, a process referred to as ‘neuroendocrine trans-differentiation’ (NED), wherein prostate cancer cells show an altered expression of lineage markers such as decreased expression of AR and increased expression of neuronal markers. Currently, there is a lack of effective targeted therapies for NEPC. Current treatment options are limited to highly toxic platinum-based drugs. Hence, there is an urgent need to develop novel treatment strategies to treat NEPC. The focused objective of this study is to develop novel, non-toxic therapeutic intervention against NEPC. Towards this, we exploited the potential of plant-derived nanovesicles/extracellular vesicles as a novel therapeutic. Extracellular vesicles (EVs) are lipid-bilayer-delimited particles that are released from almost all types of cells, including plant cells, typically between 30-150 nm in size. Methods: EVs/nanovesicles were isolated from plant-derived sources by ultracentrifugation. Isolated nanovesicles were characterized by Nanoparticle Tracking Analyses and electron microscopy. After characterization, the effects of nanovesicles were tested in NEPC cell lines in vitro. Effects on cell viability and apoptosis were assessed by MTS assay and flow cytometry, respectively. To understand the mechanistic basis of EV induced alterations, next generation RNA sequencing was performed in control vs EV treated NCI-H660 cells on Illumina HiSeq platform. Significant targets were further validated by real time PCR and Western blot analyses. Results: Plant-derived nanovesicles reduced viability and induced apoptosis in NEPC cell lines. Genes involved in ECM-receptor interaction, focal adhesion, proteoglycans in cancer and small cell lung cancer genes were significantly impacted by these vesicles in NEPC cell line. Remarkably, nanovesicles led to significantly attenuated levels of key proneural transcription factors including ASCL1, BRN2 and SOX2. In addition, neuronal markers ENO2 and NCAM1 were downregulated suggesting that treatment with nanovesicles reverse the ‘cardinal’ genetic alterations that drive NEPC. Conclusions: Plant-derived nanovesicles can be employed as a novel treatment modality in neuroendocrine prostate cancer.
Transdermal square-wave testosterone therapy: A pilot trial in metastatic castration-resistant prostate cancer.
Authors: Candelario Nellowe , Nicklawsky Andrew , Graham Laura , Lam Elaine T. , Callihan Eryn , Wacker Michael , Flaig Thomas W. , Kessler Elizabeth R
Published: March 2023

188

Background: Metastatic castration-resistant prostate cancer (mCRPC) becomes resistant to anti-androgen therapies due to a variety of adaptive mechanisms. Intramuscular bipolar androgen therapy (BAT) which alternates between high and low testosterone (T) levels is therapeutically active in mCRPC and confers sensitivity to second-generation androgen receptor antagonists such as enzalutamide (ENZA). We hypothesized that transdermal T with sustained supraphysiologic T levels would lead to high response rates to ENZA in mCRPC. We also hypothesized Square-wave transdermal T therapy would be a safe alternative to BAT due to the ability to quickly withdraw therapy in the setting of symptoms. Methods: This was an open-label, single-site, phase 2 feasibility trial in men with asymptomatic mCRPC who had not previously received ENZA. Transdermal T was administered at a dose of 100 mg/day for a minimum of 12 weeks and until disease progression. Therapy was then switched to ENZA 160 mg/day until next disease progression. Patients who initially responded to T could receive a second course of transdermal T followed by ENZA, remaining on study until progression on both T and ENZA, or for the 12-month study duration, whichever was sooner. ADT was continued throughout. The primary endpoint of the study was feasibility. T dose was adjusted to achieve T levels between 900-1500 ng/dL. Secondary end points included PSA50 response rate (50% decline in PSA) and safety. Results: Fifteen patients were enrolled. Ten (66.7%) had Gleason >8 disease. Thirteen (86.7%) patients had bone metastases. Median baseline PSA was 11.73 ng/mL. Primary endpoint of feasibility based on patient recruitment and retention was met. The median testosterone level on T was 901.3 ng/dL (Range: 645.2 to 1171.1). Median time on therapy was 15.9 weeks on T and 25.9 weeks on ENZA. PSA50 was 13.3% on initial T therapy and 66.7% after switching to ENZA. Three (20%) patients did not initiate ENZA after T progression. Two desired to avoid androgen-related side effects and 1 initiated chemotherapy. No Grade 3 or higher adverse events (AEs) occurred on T and the most common AEs were weight gain, rash, and nipple sensitivity. Conclusions: Square-wave transdermal T alternating with ENZA is feasible and achieves adequate T levels in the treatment of asymptomatic mCRPC. Given the acceptable safety profile and quick reversibility, transdermal T warrants further exploration, and we have expanded enrollment to include higher risk patient populations. Clinical trial information: NCT03734653 .
Outcomes of systemic treatment in patients with metastatic pheochromocytoma and paraganglioma: A single center retrospective analysis.
Authors: Park Young Gyu , Yoon Shinkyo , Park Inkeun , Lee Jae-Lyun
Published: March 2023

2

Background: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. Although 15-17% of patients develop metastatic disease, there are very limited systemic treatment options. In this study, we aimed to evaluate the treatment landscape and outcome in PPGL patients retrospectively. Methods: Between December 2004 and December 2021, 33 patients were diagnosed with metastatic PPGLs and received systemic treatment at the Department of Oncology, Asan Medical Center, Seoul, South Korea. Metastatic PPGLs included a locally advanced unresectable disease, initially metastatic disease, and recurrent disease. Systemic treatment involves cytotoxic chemotherapy and targeted agents, and efficacy analysis included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: The median age at diagnosis was 49 years (range, 15–74), 17 patients were male (52%), and 22 patients were pheochromocytomas (67%). Disease status was recurrent (73%), initially metastatic (21%), and locally advanced (6%). Of 23 patients who underwent germline tests, 14 (61%) were identified with germline mutations, and the most frequent mutation was SDHB germline mutation (n=8, 57%). Of the 33 patients, 18 received chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD). The ORR was 22% (4/18; all PR), and the disease control rate (DCR) was 67% (n=12). The median PFS was 7.9 months [95% confidence interval (CI), 1.6-not available (NA)], and the median OS was 36.2 months (95% CI, 5.7-NA). Six patients were treated with sunitinib, and the ORR was 33% (2/6; all PR), and the DCR was 83% (n=5). The median PFS was 14.6 months (95% CI, 3.6-NA), and the median OS was 14.6 months (95% CI, 3.6-NA). In CVD treatment, patients with SDHB/SDHD mutation (either germline or somatic) were significantly associated with superior OS & PFS compared with the non-SDHB/SDHD mutation group, with a median OS of 94.0 months vs. 5.7 months (P = 0.01) and a median PFS of 20.1 months vs. 1.6 months (P = 0.03), respectively. In the SDHB/SDHD mutation group, the ORR was 50% (3/6, all PR), and the DCR was 100% (n=6), but in a non-SDHB/SDHD mutation group, the ORR was 11% (1/9, PR) and the DCR was 44% (n=4). Conclusions: Systemic treatment with CVD and sunitinib provided meaningful disease control, and outcomes were comparable with previous data. Especially, CVD treatment was effective in patients with SDHB/SDHD mutation, and further validation is needed in future studies.
Effects of docetaxel on circulating immune cell subsets and association with outcomes in metastatic castration-sensitive prostate cancer.
Authors: Chandran Elias , Goswami Meghali , Donahue Renee Nicole , Atiq Mohammad O. , Karzai Fatima , Bilusic Marijo , Marte Jennifer L. , Arlen Philip M. , Cordes Lisa M. , Owens Helen , Hausler Megan , Hankin Amy , Williams Monique , Dahut William L. , Figg William Douglas , Schlom Jeffrey , Gulley James L. , Madan Ravi Amrit
Published: March 2023

207

Background: Docetaxel with androgen deprivation therapy (ADT) has been shown to improve survival in metastatic castration-sensitive prostate cancer (mCSPC). There is limited data on the immunologic effects of docetaxel in mCSPC. Greater knowledge of the immune impact of docetaxel could inform future trials in prostate cancer. Methods: A clinical trial in mCSPC evaluated sequencing docetaxel and ADT with Prostvac, a poxviral vaccine targeting prostate-specific antigen (PSA). Eligibility criteria included mCSPC within 4 months of ADT and ECOG performance status 0-2. Patients given 6 cycles of docetaxel 75mg/m2 with ADT alone for mCSPC were included in this analysis. Peripheral blood mononuclear cells (PBMCs) were sampled at baseline and at 3 weeks after commencing docetaxel. Immune cell subsets analyzed included CD4+ and CD8+ T-cells, T regulatory cells (Tregs), natural killer (NK) cells, dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs). Analyses were performed to determine if the baseline immune status or immune changes induced by therapy associate with PSA at 2 years. Results: Fifteen patients were evaluated for peripheral immune responses in this study. Median age was 63 years (range 50-73). Fourteen were white and 1 was black. ECOG performance status was 0 in 11 patients, 1 in 4 patients. Disease volume was high in 7 and low in 8 patients. Among 158 immune cell subsets assessed, only changes in Tregs and activated NK cells with a lytic and cytokine producing phenotype (CD16+ CD56br) were noted after initiation of docetaxel in addition to ADT. Patients with PSA ≤0.2 at 2 years had higher baseline frequencies of total CD4+ T cells, several activated CD4+ T-cell subsets, plasmacytoid DCs, and CD49d- Tregs. They also had lower baseline frequencies of total CD8+ T cells, naïve CD8+ T cells, and CD73+CD8+ T-cells. Patients with PSA ≤0.2 at 2 years also had greater percent increases in CD8+ effector memory (EM) PD-1+ T-cells after treatment. Conclusions: This is the first study to demonstrate increases in activated NK cells with lytic and cytokine producing potential after treatment with docetaxel. Given that NK cells are associated with clinical outcomes in prostate cancer (Zhao SG, JNCI, 2019) and that increased NK cells were seen after treatment with enzalutamide as well (Madan, JITC, 2021), developing immunotherapy combinations to capitalize on NK cell activity may be a path forward for developing immunotherapy in prostate cancer. Clinical trial information: NCT02649855 . [Table: see text]
Evaluating p53 nuclear expression and prostate cancer progression in a predominantly African American cohort.
Authors: Gesztes William , Lap Coen , Dalivand Maryam , Hamilton Colleen , Martha Antonio , Byrne Morgan , Diao Guoqing , Jain Maneesh Rajiv , Nava Victor
Published: March 2023

217

Background: Increased utilization of next-generation sequencing has revealed evidence of early TP53 alterations in localized prostate cancer (PCa), suggesting a growing clinical potential for p53 immunohistochemistry (IHC). Prior research by Harmon and Gesztes et al. (Radiology, 2021 & Scientific Reports, 2022) support the clinical utility of detecting p53 overexpression in core biopsies and radical prostatectomies (RP) to predict underlying TP53 alterations, biochemical recurrence (BCR), and metastasis. However, to date, no established consensus exists evaluating p53 “overexpression” in PCa. This study aimed to compare two fundamental approaches to assess p53 expression across various specimens with regard to PCa progression. A secondary study aim explored whether ethnic differences in p53 expression exist. Methods: This retrospective cohort study comprised 84 randomly selected PCa patients (46 metastatic; 38 non-metastatic) enrolled between 1996 – 2021 at the DC VA Medical Center. Representative sections of core biopsies (60%), RP (17%), prostate chips (7%), and metastatic deposits (16%) were examined, where (%) equals a share of the total cohort. IHC was performed on selected sections with a p53 monoclonal antibody (Biocare Medical; p53 Tumor Suppressor Protein; clone DO-7). p53 nuclear expression was manually scored according to the highest intensity (0 absent, 1+ weak, 2+ moderate, or 3+ marked) and percentage (0%, <1%, 1-5%, and >5%) of tumor cell nuclei observed in one index block per patient. All slides were reviewed by two pathologists who were blinded to clinical data. Fisher’s exact test was used to test the association between p53 positivity and categorical variables. Results: Of 84 men included, 63 (75%) self-identified as African American (AA). The median follow-up time was 6.2 years. Thirty-four patients (40%) exhibited p53 nuclear expression, of which 18 patients (21%) showed marked (3+) nuclear intensity. Notably, 11 of 18 (61%) 3+ patients displayed <5% p53 expression. All patients with >5% p53 positivity showed marked (3+) p53 staining. The presence of marked p53 staining, regardless of percentage, was found to be significantly associated with a higher Gleason score ( p=0.0002), higher PSA at the time of biopsy ( p<0.0001), BCR ( p=0.0007) and metastasis ( p<0.0001). Importantly, marked p53 staining was identified only in patients who developed metastatic disease. No significant differences were observed in marked p53 expression between AA and Caucasian men. Conclusions: In prostate cancer, marked (3+) p53 nuclear intensity (regardless of the percentage) is associated with disease progression with no observable ethnic predilection. Therefore, careful assessment of intensity is essential to avoid under-detection (when percent criteria are applied) and maximize the number of patients who may benefit from enhanced clinical interventions.
Clinical and genomic factors associated with tumor mutational burden (TMB) in prostate cancer.
Authors: Hougen Helen Y , Graf Ryon , C. F. Quintanilha Julia C. F. , Li Gerald , Punnen Sanoj , Mahal Brandon A
Published: March 2023

240

Background: TMB is an emerging biomarker to predict clinical benefit from immune checkpoint inhibitors (ICI). Although high TMB in prostate cancer is rare, and we sought to evaluate independent associations of TMB by clinical factors, prior treatment, and genomics. Methods: This study used the US-based nationwide de-identified Flatiron Health-Foundation Medicine prostate cancer clinico-genomic database. The de-identified data originated from approximately 280 US cancer clinics (~800 sites) between January 2011-March 2022. Multivariable linear regression model was used to assess independent prediction of TMB levels, which were log2+1 transformed to better normalize distribution. Data are expressed as (estimate, [95% CI], p-value). Results: The study included 2,748 tissue specimens: 51.7% were from the prostate, 10.3% from bone, and 14.6% from lymph nodes. Specimens from white patients comprised 61.2% of samples, with another 7.5% from Black, 1.1% from Asian, and 30% from other or unknown race patients. Of our cohort, 58.5%, 15.5%, and 26.0% were from patients who received 0, 1-24 months, and >24 months of androgen deprivation therapy (ADT), respectively. Also 19.7%, 1.8%, 11.4%, and 0.4% had any exposure to novel hormonal therapies (NHT), Radium-223, taxanes, and ICI, respectively. Higher TMB was independently associated with ADT use >24 months (0.16, [0.05-0.27], p=0.005) and Asian race (0.36, [0.03-0.69], p=0.034). Prior treatment with NHT, taxanes, or radium was not associated with higher TMB. Compared to prostate, bladder (0.22, [0.03-0.41], p=0.023), liver (0.27, [0.13-0.42], p<0.001), and other (0.29, [0.15-0.43], p<0.001) biopsy sites were associated with high TMB, but lymph node biopsy was not. MSI-high (2.30, [1.96-2.64], p<0.001), MSI-intermediate (0.51, [0.14-0.88], p=0.007), and MSI-unknown (0.84, [0.60-1.09], p<0.001) were associated with increased TMB. Individually altered genes associated with increased TMB included MLH1 (0.77, [0.31-1.24], p=0.001), MSH2 (1.09, [0.74-1.45], p<0.001), MSH3 (0.64, [0.018-1.11], p=0.006), MSH6 (0.94, [0.61-1.26], p<0.001), BRCA2 (0.56, [0.43-0.69], p<0.001), CDK12 (0.38, [0.24-0.53], p<0.001), FANCA (0.42, [0.07-0.77], p=0.02), MRE11 (0.87, [0.11-1.62], p=0.025), and PALB2 (0.83, [0.48-1.18], p<0.001). No individual gene was independently associated with lower TMB. Conclusions: TMB associates with MSI status and MMR genes. However, aside from associating with long term ADT use, TMB does not have strong association with prior systemic treatment. Certain biopsy specimen sites including bladder and liver have increased TMB but overall, the association is relatively weak in comparison to MMR genes and MSI status. This study allows better understanding of how prior treatments, clinical and genomic factors affect TMB status, which may add value to MSI status in predicting treatment response in advanced prostate cancer.
Biology and usefulness of [-2]proPSA as a prognostic marker in CRPC patients.
Authors: Miyazawa Yoshiyuki , Tsuji Yusuke , Arai Seiji , Sekine Yoshitaka , Suzuki Kazuhiro
Published: March 2023

242

Background: Prostate health index (phi) using -2proPSA (p2PSA), which is a precursor of PSA, has been reported to be useful as a marker for predicting the presence of cancer in the gray zone with a PSA value of 4-10 ng/ml. There is no detailed report on the biology of p2PSA in castration resistant prostate cancer (CRPC) patients and it is unknown. We retrospectively investigated the biology of p2PSA and its usefulness as a marker using CRPC patient's samples. Methods: The study was performed using samples from a prospective study of CRPC patients treated with enzalutamide. We examined 98 pre-enzalutamide treatment serum samples that can measure p2PSA. The samples were collectively measured by Beckman Coulter (Tokyo, Japan). We also examined the correlation between the measurement results of p2PSA and the prognosis of phi and CRPC patients calculated accordingly. This study was approved by the IRB of Gunma University Hospital (IRB 2021-092, 1983). Results: The study population of 98 patients had a median age of 73 years. The median PSA before administration of enzalutamide was 23.8 ng/ml, the median p2PSA was 208.8 pg/ml, and the median phi was 188.0. The median values of each parameter were divided into two groups, and the PSA progression free survival (PSA-PFS) and overall survival (OS) rate were compared by the Kaplan-Meier method. In the study of PSA-PFS, PSA, p2PSA, and phi could not be significant markers. In the OS study, the median OS of the PSA low group was NYR (not yet reached), the high group was 26.8 months, the p2PSA low group was NYR, the high group was 26.8 months, the phi low group was NYR, and the high group was 26.8 months. The OS was significantly better in the low- value group for each parameter (p-values 0.024, 0.034, 0.018, respectively). Conclusions: The biology of p2PSA in CRPC patients has been clarified. Although we couldn't find a clear advantage over PSA, we would like to add a study based on the data of this study.
Genomic alterations in patients with prostate cancer with liver metastases.
Authors: Casado Crystal , Caputo Sydney , Jaeger Ellen B. , Jang Albert , Sweeney Patrick L , Lanka Sree M , Gupta Kanika , Pocha Olivia , Hawkins Maddie , Huang Minqi , Lieberman Alexandra , Schwartz Jennifer , Miller Patrick , Barata Pedro C. , Layton Jodi Lyn , Lewis Brian E. , Ledet Elisa M. , Sartor A. Oliver
Published: March 2023

248

Background: mCRPC patients with liver metastases have a poor prognosis and often progress rapidly on a variety of treatments. Previously, preliminary ctDNA analyses of mCRPC patients with liver metastases showed a range of commonly altered genes in patients with liver metastases (Ranasinghe et al; 2019). In this follow-up, we evaluated ctDNA alterations in an expanded cohort of mCRPC patients with liver metastases. Methods: From Tulane Cancer Center, retrospective review of mCRPC patients was used to identify patients with confirmed liver metastasis. All liver metastases were confirmed based on imaging data. All patients included had ctDNA evaluated with a multi-gene cancer panel via Guardant 360 assay (Guardant Health, Inc). Additional clinical annotation including family history, germline testing, staging, imaging, and laboratory values. Statistical analyses were performed with Fisher’s Exact and Wilcoxon Rank Sum tests. Results: 158 mCRPC patients with appropriate diagnostic imaging as well as ctDNA testing. From this group, 8% (n= 12) had confirmed liver metastases. Among the patients with liver metastasis, the most common alterations detected were in AR (50%; 6/12) and PIK3CA (25%; 3/12). Patients with liver metastasis were more likely to have amplifications in FGFR1 detected in their ctDNA (OR= 14.40; 95% C.I. (1.83, 113.22); p= 0.03). In addition to ctDNA, germline data was assessed, and it was found that patients with liver metastasis were more likely to have a pathogenic germline mutation (OR= 7.61; 95% C.I. (2.85, 20.31); p<.0001). The most common germline mutations detected in patients with liver metastasis were in BRCA2 (n= 3) and TP53 (n= 2). Conclusions: Though liver metastasis are less common in prostate cancer, it often occurs following extensive treatment and results in a poor prognosis for patients. In patients with liver metastasis, FGFR1 amplification was more often detected in ctDNA. Importantly, patients with liver metastasis were significantly more likely to have a pathogenic germline alteration.
Survival patterns based on site-specific visceral metastasis in patients with metastatic prostate cancer: Are outcomes of visceral metastases the same?
Authors: Ahmed Mohamed E. , Andrews Jack R. , Mahmoud Ahmed , Lee Matthew , Childs Daniel S , Kendi Ayse T. , Johnson Geoffrey , Tollefson Matthew K. , Boorjian Stephen A. , Karnes R. Jeffrey , Kwon Eugene D.
Published: March 2023

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Background: Metastatic visceral involvement in prostate cancer patients conveys a poor prognosis. Survival patterns of site-specific visceral metastasis are poorly understood. Here, we sought to investigate survival patterns in prostate cancer patients according to their first detected site of visceral metastasis. Methods: Retrospectively, we identified 200 patients with visceral metastatic prostate cancer. Patients were divided into three groups according to first site detected with visceral metastases; first-site lung metastases, first-site brain metastases, and first-site liver metastases. Visceral metastases were detected on either conventional imaging (CT/MRI), metabolic imaging (C-11 choline), or PSMA PET-CT scan. Follow up duration of our study was 80 months. Results: Clinicopathological variables are shown. The K-M curve of overall survival of the entire cohort suggests better survival patterns in patients with first-site lung metastases compared to patients with first-site brain or liver metastases (p<0.0001). In subset analysis of patients with CRPC, the K-M curve of overall survival, which demonstrates better survival outcomes in patients with first-site lung metastases in comparison with patients with first-site brain or liver metastases (p<0.0001). Conclusions: Our data suggests that prostate cancer patients with visceral metastatic disease have different survival patterns according to the first site detected with visceral metastasis. In our cohort, patients with first-site lung metastasis demonstrated better survival outcomes than patients with first-site brain or liver metastasis. Further studies are warranted. [Table: see text]
The profile study: Prostate cancer screening in men of Black African and African Caribbean ancestry—Early results.
Authors: Kinsella Netty , McHugh Jana Kathlyn , McGrowder Eva , James Denzil , Saunders Ed , Bancroft Elizabeth , Kote-Jarai Zsofia , Eeles Ros A.
Published: March 2023

306

Background: Heritable risk factors account for a significant proportion of prostate cancer (PrCa) risk, of which only a minority are high risk Mendelian traits. Men of Black African and African Caribbean ancestry are at higher risk of developing PrCa in their lifetime (1 in 4) compared with the general population in the United Kingdom (1 in 8). PROFILE is a multi-cohort study of targeted screening for groups of men at higher risk of developing PrCa: 1) men of European ancestry with family history of PrCa, 2) men of black African and African Caribbean ancestry regardless of family history and 3) men with known rarer higher risk gene mutations for PrCa. This abstract concentrates on group 2. The aim is to investigate the role of targeted PrCa screening in men at higher genetic risk and its association with specific genetic profiles and biomarkers. Methods: Healthy men aged 40-69 are invited to participate. Inclusion Criteria: Both parents and all four grandparents must be of either black African or African Caribbean ancestry. Arm 1: PSA only – once PSA is below an age-related threshold (aged 40-49 and PSA ≥0ng/ml, aged 50-69 PSA >/= 2ng/ml) they continue on the study with annual PSA, only triggering a prostate MRI and Biopsy if the PSA is above the threshold. Arm 2: Regardless of PSA men opt for prostate mpMRI and biopsy. Polygenic risk score (PRS) calculated based on 230 SNPs including latest AA specific variants. Results: Arm 1: 121 enrolled PSA only (this has triggered 8 biopsies with 3 cancers). Arm 2: 58 enrolled MRI and biopsy, 58 MRIs and 36 biopsies carried out, PrCa detected in 15 men (42%). 22% are Gleason score ≥7. Association between PRS and MRI/Biopsy results will be presented. Conclusions: We will continue to perform MRI and biopsies on men, we will also carry out polygenic risk scores on these men to verify whether a genetic PRS can help guide enhanced screening for certain men in the population. Although data are early, a significant proportion of biopsies are positive for PrCa that needs radical treatment. Clinical trial information: NCT02543905 .
Geometry of hydrogel rectal spacer placement and risk of MRI-identified rectal wall infiltration.
Authors: Lischalk Jonathan W. , Haas Jonathan A. , Santos Vianca F. , Mendez Christopher , Sanchez Astrid , Doshi Ankur , Akerman Meredith , Kaminetsky Jed , Carpenter Todd , Sadowsky David , Katz Aaron , Lepor Herbert , Tong Angela
Published: March 2023

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Background: The use of rectal spacers in the management of localized prostate cancer treated with definitive radiotherapy has become ubiquitous in recent years. However, pre-treatment MRIs often identify varying degrees of hydrogel involvement within the rectal wall. In the present study, we evaluate the geometry of spacer placement and its association with radiological rectal wall infiltration. Methods: We identified all patients who underwent hydrogel rectal spacer placement in preparation for 5-fraction prostate SBRT from 1/2020 to 9/2021. Two specialty trained body radiologists evaluated all MRIs independently. Scans were evaluated for the following spacer parameters: spacer thickness, prostate-rectal distance, symmetry, and degree of rectal wall infiltration. Prostate-rectal distance was measured at the level of the prostatic apex, midgland, and base. Symmetry of the rectal spacer was measured using right or left lateralization from midgland. Degree of rectal wall invasion was categorized as follows: none, muscularis, submucosal, and intraluminal. Results: A total of 336 patients underwent MRI following hydrogel rectal spacer placement from 1/2020 to 9/2021. Patients were excluded from MRI if they had AICD/pacemaker, foreign body, or patient refusal. In those patients with any rectal wall invasion, gel thickness as measured at the base (11 vs. 10 mm, p = 0.02), midgland (14 vs. 10 mm, p < 0.001), and apex (12 vs. 8 mm, P < 0.001) was significantly larger than those patients without invasion. This translated into significantly larger distances between the posterior aspect of the prostate and anterior aspect of the rectum at the level of the apex (12 vs. 8 mm, p < 0.001) and midgland (13 vs. 11, p < 0.001), but not at the base (14 vs. 14 mm, p = 0.5). There was no association seen with asymmetrical spacer placement and rectal wall invasion (p = 0.7). Subgroup analysis of patients with more extensive invasion into the muscularis or submucosa confirmed significantly larger gel thickness at all prostate levels, as well as a larger prostate-rectal distance at the level of the apex and midgland. Significant associations remained consistent with both independent radiological evaluations. Conclusions: Hydrogel spacer rectal wall infiltration was associated with increased axial gel thickness, specifically at the level of the prostatic midgland and apex. Rectal wall infiltration was not associated with lateralization of gel. Rectal infiltration may be a result of surplus hydrogel placed particularly in the region where the potential space between the prostate and the rectum is limited.
Patient experiences with tissue-based genomic testing during active surveillance for prostate cancer.
Authors: Leapman Michael , Sutherland Ryan Andrew , Gross Cary Philip , Ma Xiaomei , Jeong Farah , Seibert Tyler M , Cooperberg Matthew R. , Catalona William , Loeb Stacy , Schulman-Green Dena
Published: March 2023

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Background: Tissue-based gene expression (genomic) tests improve estimates of prostate cancer aggressiveness and are increasingly used for patients considering or engaged in active surveillance; however, little is known about patient experiences with genomic testing and its role in decision-making for active surveillance. Methods: We performed a qualitative descriptive study consisting of in-depth, semi-structured interviews of patients with low- or favorable-intermediate-risk prostate cancer managed with active surveillance. The interview guide focused on experiences with biopsy-based genomic testing during their decision-making for prostate cancer management. We used purposive sampling to include patients who received genomic testing as part of routine clinical care and we over-sampled Black and Latino men. We continued interviews until thematic saturation was reached, iteratively created a code key and used conventional content data analysis. Results: The mean age was 68 years (range 51-79; n=20). At initial biopsy, 17 (85%) had a Gleason grade group 1, and 3 (15%) had a grade group 2 tumor. Fourteen (70%) participants identified their race/ethnicity as White, 5 (25%) as Black, and 2 (10%) as Latino. The decision to undergo genomic testing was driven by both participants and physicians’ recommendations; however, some participants were unaware that testing had occurred. Overall, participants understood the role of genomic testing in estimating their prostate cancer risk, and the test results increased their confidence in the decision for active surveillance. However, participants did not understand the difference between tissue-based gene expression tests and germline genetic tests, and commonly believed that tissue-based tests measured hereditary cancer risk. While some participants expressed satisfaction with the explanations provided by their physicians, others felt that communication was inaccessible and lacked sufficient detail. Conclusions: Patients interact with and are influenced by the results of biopsy-based genomic testing during active surveillance for prostate cancer, however testing may increase informational needs. Our findings indicate areas for improvement in patient counseling that can be used to increase patient knowledge and comfort with genomic testing.
Trends in the use of local intervention and its impact on oncological outcomes for metastatic castration-sensitive prostate cancer: A multicenter retrospective study.
Authors: Hatakeyama Shingo , Narita Shintaro , Tanaka Toshikazu , Sakurai Toshihiko , Ito Akihiro , Tsuchiya Norihiko , Habuchi Tomonori , Ohyama Chikara
Published: March 2023

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Background: The role of local intervention in addition to the standard of care for metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Therefore, this study evaluated the trends of local intervention and their impact on oncological outcomes in patients with mCSPC in real-world practice. Methods: This multicenter retrospective study included 760 patients treated with either androgen deprivation therapy (ADT) without local treatment (no castration-resistant prostate cancer [CRPC] progression within 12 months, control group) or ADT plus local intervention (intervention group) between January 2005 and March 2022. The primary outcome was trends in the use of local intervention in patients with mCSPC. The secondary outcomes included evaluations of factors associated with CRPC-free survival in the intervention group. Results: The use of local intervention gradually increased in combination with upfront treatment for the duration of our study. The number of patients with local intervention combined with upfront treatment was significantly higher in patients with high tumor burden disease than in those with low tumor burden disease. Of the 108 patients who received local intervention comprising radiation therapy targeted to the prostate, a duration of >7 months of initial therapy before local intervention and a level of prostate-specific antigen <0.20 ng/mL at the time of local intervention were significantly associated with prolonged CRPC-free survival. Conclusions: Regardless of the tumor burden, the use of local intervention in combination with upfront therapy to treat mCSPC increased for the duration of our study. Local intervention in addition to the standard of care for mCSPC may be a feasible treatment option for selected patients, taking into consideration the duration of and response to initial treatment.
Length and Gleason pattern at positive surgical margin after radical prostatectomy to assess risk of postoperative recurrence in localized prostate cancer.
Authors: Kato Masashi , Tsuzuki Toyonori
Published: March 2023

359

Background: The prostatic apex is most popular location of positive surgical margin (PSM) at radical prostatectomy (RP) and the frequency of apex is reported to be about 20-40% of all positive cases. Prostatic apex is also reported to lack a well-defined capsule. Some recommendation suggest that reporting require location of a PSM, as well as length of PSM, though there are also reports that these classifications is inadequate in some patients. In addition, there is a lack of tumor grade at PSM in these recommendations. This study aims to investigate the impact of location, number, length, and tumor grade at PSM on biochemical recurrence (BCR) after RP. Methods: We retrospectively evaluated 1013 patients with prostate cancer who underwent radical prostatectomy without neoadjuvant or adjuvant therapy at the hospitals that the authors were affiliated with between 2005 and 2013. All prostatectomy specimen slides were reviewed by a single genitourinary pathologist according to ISUP 2019 criteria. PSM were subcategorized according to the length of PSM (≤ 5mm or > 5mm), Gleason pattern (GP3 vs. GP4 or 5) at PSM, the number (single or multiple), and the location (apex-only or others). Results: The median patient age was 67 (range, 45–80) years. The median initial PSA was 6.8 ng/ml (0.4–82 ng/ml). The median follow-up period was 69 (0.7–135) months. Pathological T stage was in 73% of pT2 (n=733), 22% of pT3a (n=229), and 4% of pT3b (n=41). PSM was found in 377 cases. Length of margin is total and 5mm in median. PSM was found at apex-only in 187 cases (50%), and others showed other single location or multiple PSM. Single PSM is found in 293 cases (78%). GP3 at PSM was found in 130 cases, GP4 in 214, and GP5 in 33. GP3 at PSM tended to be more common in apex-only PSM. GP5, extra prostatic extension (EPE), seminal vesicle invasion, IDC-P, and PSM were significant in all the patients to predict BCR. Among the patients with PSM, multivariate analysis showed that length and GP at PSM were significantly strong factors and were stronger than location and number of PSM. The prognosis in pT2 patients with PSM were significantly subcategorized into 3 groups according to the length and GP at PSM (P<0.001). Conclusions: We proposed the recurrence risk classification based on the length and the GP at PSM to predict BCR after radical prostatectomy. It is useful for prognosis prediction and high-risk group should be considered for adjuvant radiation and/or hormonal therapy in postoperative care.