bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient-reported outcomes (PROs) among men receiving talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase 3 study (TALAPRO-2).
Authors: Agarwal Neeraj , Azad Arun , Matsubara Nobuaki , Saad Fred , De Giorgi Ugo , Joung Jae Young , Fong Peter C.C. , Jones Robert J. , Zschaebitz Stefanie , Oldenburg Jan , Shore Neal D. , Dunshee Curtis , Carles Joan , Fay Andre P. , Cislo Paul , Chang Jane , Healy Cynthia G. , Niyazov Alexander , Fizazi Karim
Published: June 2023

5013

Background: TALAPRO-2 (NCT03395197) showed statistically significant improvement in radiographic progression free survival with TALA + ENZA (n=402) vs PBO + ENZA (n=403) (HR=0.63 95% CI 0.51-0.78; P<0.001) in men receiving 1L treatment for mCRPC. Here we report PRO endpoints from TALAPRO-2. Methods: PROs were assessed at day 1 (baseline) and at scheduled visits until radiographic progression (every 4 weeks until week 53, and then every 8 weeks) using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. Prespecified PRO analyses included overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to definitive clinically meaningful (≥10-point change) deterioration (TTD). Between-arm comparisons of TTD were made using a stratified log-rank test and a Cox proportional hazards model. Results: Of the 805 men randomized and treated, 793 had a baseline score followed by at least 1 post-baseline score; TALA + ENZA (n=395), PBO + ENZA (n=398). Although the treatment effect on global health status (GHS)/quality of life (QoL) significantly favored PBO + ENZA, the predefined threshold of clinical meaningfulness was not met; moreover, no significant differences between the arms were observed in any functioning scales. A significantly longer TTD in GHS/QoL was observed for TALA + ENZA; HR=0.780 (95% CI: 0.62, 0.99), P=0.038; median: 30.8 months vs 25.0 months. A numerical greater delay in TTD in urinary symptoms was longer for TALA + ENZA; HR=0.759 (95% CI: 0.543, 1.061), P=0.105; median not reached vs 35.9 months. Additional PRO results will be presented. Conclusions: Compared with PBO + ENZA, in the TALA + ENZA arm there was 1) a modest deterioration disfavoring GHS/QoL (deterioration was not clinically meaningful based on the predefined threshold), and 2) a maintenance in all functioning scales. TTD in GHS/QoL was significantly longer with TALA + ENZA vs PBO + ENZA, reflecting improved disease control. These results complement the benefit-risk assessment of TALAPRO-2. Clinical trial information: NCT03395197 . [Table: see text]
Association of adaptive immunity/inflammatory genes with survival in prostate cancer.
Authors: Hopper Austin , Krause Harris Benjamin , Elliott Andrew , Farrell Alex Patrick , Sutton Leisa , Tamayo Pablo , Carter Hannah , Shabaik Ahmed , Sharabi Andrew , Kuhn Peter , Heath Elisabeth I. , Antonarakis Emmanuel S. , Nabhan Chadi , Ferrara Napoleone , Asimakopoulos Fotis , Deichaite Ida
Published: June 2023

5022

Background: Advances in immunotherapy have had little impact in prostate cancer (PCA). We have previously examined the immune microenvironment in both localized and metastatic PCA and found that primary PCA shows local inflammation/adaptive immunity whereas metastatic disease shows a shift towards immune suppression (Deichaite, 2022). Herein, we examine immune remodeling in PCA by evaluating changes in gene expression between localized and metastatic disease with heterogeneous treatment patterns in both primary and metastatic samples. Methods: Tumors from PCA (N = 5,419) were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). Samples collected from the prostate gland (N = 3,284) or metastatic sites (N = 2,135) were analyzed. The Mann-Whitney U test was applied as appropriate, with P-values adjusted for multiple comparisons ( q < .05). Real-world overall survival (OS) data was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined subpopulations. Survival for tumors with high (-H) and low (-L) expression of genes of interest, defined as top and bottom quartile of expression (transcripts per million, TPM) across all tumors, was investigated. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Results: Compared to metastatic PCA, primary samples had increased median expression of pro-inflammatory genes IL-6 (1.2-fold), SELE (1.9-fold), NRK (6.3-fold), CEBPD (1.2-fold), NFKB2 (1.4-fold) and FOXP3 (1.4-fold) (each q < .05). GSEA identified enrichment of E2F target genes in primary samples, while metastatic samples were enriched in inflammatory response, KRAS signaling and IL2/ STAT5 signaling pathways. The expression of inflammatory genes affected OS differently based on site. IL-6, NRK and SELE-H levels in primary samples were associated with increased OS. Within metastatic samples, CEBPD-H was associated with decreased OS and NFKB2-H was associated with an increased OS. FOSB-H was associated with increased OS in both primary and metastatic samples. Conclusions: We identify significant differences in the expression of inflammatory regulators and cytokines between localized and metastatic PCA tumors, which correlate with OS. These changes in the immune microenvironment can be leveraged for rational immunotherapy development and better targeted approaches. [Table: see text]
Prostate cancer public health system database from Brazil: Racial disparities and heterogeneity of treatment interventions to understand evidence-based practice patterns in a large real-world database.
Authors: Herchenhorn Daniel , McKay Rana R. , Sasse Andre Deeke , Monteiro Fernando Sabino Marques , Rose Brent Shane , Carvalhal Gustavo , Maluf Fernando Cotait , Morbeck Igor Alexandre Protzner , Souza Vinicius Carrera , Fernandes Elcio Firminiano , Valverde Douglas Andreas , James Nicholas D.
Published: June 2023

5025

Background: The Brazilian Public National Health System (SUS) provides an opportunity to understand epidemiologic information, treatments, discrepancies in care, and costs of men with prostate cancer (PCa) using a large real-world dataset. This analysis focuses on racial disparities and heterogeneity of specific interventions to understand evidence-based practice patterns in Brazil. Additionally, the dataset can serve as a model for other low-middle income countries (LMIC). Methods: Patients included in the database were those with a diagnosis of PCa receiving care in the SUS from 01/01/2008 to 08/31/2022. Data were analyzed using a proprietary Healthcare Data Science platform offered by TECHTRIALS and included information regarding stage, demographics, cancer-related information, treatment-related information, and resources utilized. Results: 657,609 PCa pts were diagnosed and treated at SUS during the 14.5-year study period of whom 382,263 (58%) were brown/black (non-white) and 262,820 (42%) white. Median age of the population was 72.6 years, and did not vary with race. 26.16% of the pts were diagnosed with stage IV and this was not impacted by race or localization, including state or type of city (capital or not). Rates of radical prostatectomy and radiation utilization were similar between race categories. Additionally, in patients with stage IV disease, rates of systemic therapy utilization including chemotherapy with docetaxel (7.7%), with a tendency to increase use in the last years, and androgen receptor signaling inhibitors (ARSI) with (0.6%) or enzalutamide (0.08%), were low and similar between race categories. Rates of first-generation anti-androgens and estrogens were higher (56%) The total costs of prostate cancer directed care was R$4.31 billions (US$820 millions) and race did not impact total cost of care and cost by procedure or therapy type options. Conclusions: This is one of the largest studies using public health-system databases for Prostate cancer with Real World Data ever published. Race had no impact in presenting stage, treatment received and even in the costs involved. Underutilization of chemotherapy (docetaxel) in a scenario of limiting resources and without the use of new hormonal therapies is a matter of concern, together with an overuse of agents without proven survival advantage. Our data highlights the need for increased access to life prolonging agents for patients with metastatic PCa in the SUS.
Building a predictive model for outcomes with [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer using VISION data: Preliminary results.
Authors: Herrmann Ken , Gafita Andrei , De Bono Johann S. , Sartor A. Oliver , Chi Kim N. , Krause Bernd J. , Rahbar Kambiz , Tagawa Scott T. , Czernin Johannes , El-Haddad Ghassan , Wong Connie , Zhang Zhaojie , Wilke Celine , Mirante Osvaldo , Morris Michael J. , Fizazi Karim
Published: June 2023

5028

Background: 177Lu-PSMA-617 is approved in adults with PSMA+ metastatic castration-resistant prostate cancer (mCRPC). This analysis of VISION data sought to build predictive models for clinical outcomes after 177Lu-PSMA-617. Methods: In VISION, adults with PSMA+ mCRPC received 177Lu-PSMA-617 (7.4 GBq every 6 weeks, ≤6 cycles) plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, 29 baseline parameters were assessed for prognostic and predictive value on overall survival (OS), radiographic progression-free survival (rPFS) and PSA response (≥50% reduction; PSA50). Parameters associated with outcome regardless of treatment were prognostic, and those associated with outcome after treatment with 177Lu-PSMA-617+SoC vs SoC were predictive. Cox proportional hazards (OS and rPFS) or logistic regression (PSA50) models were used in univariate analyses for parameter selection and to build statistical models. Here, univariate analyses are presented. Multiplicity was corrected by use of q values (ɑ = 0.05). Results: Data from 831 adults were analyzed. In initial univariate analyses, 76%, 69% and 38% of parameters assessed were prognostic for OS, rPFS and PSA50, respectively; fewer were predictive of better outcomes after 177Lu-PSMA-617+SoC vs SoC (subset shown). Conclusions: Baseline prognostic and predictive parameters were identified for OS, as well as for rPFS and PSA50, in adults with mCRPC in VISION receiving 177Lu-PSMA-617+SoC or SoC alone. For clinical application, select parameters will be reassessed categorically, and multivariate predictive models will be developed using identified parameters and parameter shrinkage.[Table: see text]
Effects of ovarian ablation or suppression on breast cancer recurrence and survival: Patient-level meta-analysis of 14,993 pre-menopausal women in 25 randomized trials.
Authors: Gray Richard G. , Bradley Rosie , Braybrooke Jeremy , Clarke Mike , Hills Robert Kerrin , Peto Richard , Bergh Jonas C. S. , Swain Sandra M. , Davidson Nancy E. , Francis Prudence A. , Regan Meredith M. ,   Early Breast Cancer Trialists' Collaborative Group
Published: June 2023

503

Background: Suppressing ovarian function of women with breast cancer may improve outcome by preventing estrogenic stimulation of any residual cancer, particularly for pre-menopausal women with estrogen receptor (ER)-positive tumors. We report a collaborative meta-analysis of individual participant data from randomized trials of ovarian ablation or suppression. Methods: Data were sought from randomized trials that compared ovarian ablation or suppression versus not. Primary analyses included only premenopausal women age < 55 with ER-positive or unknown tumors, stratified into those who received no chemotherapy, or remained premenopausal following chemotherapy, and those whose menopausal status following chemotherapy was not ascertained. Standard log-rank methods estimated ER-weighted annual event rate ratios (RR). Results: Individual patient data were provided for 25 of 27 relevant trials, comprising 14,993 (98.7%) of 15,195 women randomized. Overall, fewer breast cancer recurrences were seen with ovarian ablation/suppression than control (RR = 0·82, 95%CI 0·77–0·88; p < 0·0001). Recurrence reductions were significantly (p = 0.0003) larger among women (n = 7,213) known to be premenopausal prior to ovarian suppression (RR = 0·70, 0·63–0·78; p = 0·0003) than among those (n = 7,786) whose menopausal status was uncertain after chemotherapy (RR = 0·91, 0·83–0·99; p = 0·03). For known premenopausal women, 15-year risk of recurrence was improved by 12·1% (28·9% vs 41·0%; p < 0·0001. 15-year breast cancer and all-cause mortality were improved by 8·0% (20·9% vs 28·9%; RR 0·69, 0·60–0·80; p < 0·0001) and 7.2% (26·0% vs 33·1%; RR = 0·73, 0·64–0·82; p < 0·0001), respectively, with no increase in deaths without recurrence (RR = 0·88, 0·67–1·14; p = 0·33). Recurrence reductions were significantly (p = 0·003) larger among premenopausal women aged under 45 (RR = 0·63, 0·55–0·72; p < 0·0001) than among those aged 45-54 (RR = 0·84, 0·70–1.00; p = 0·045), but did not differ significantly by other recorded patient or tumor characteristics. Conclusions: For pre-menopausal women aged under 45, ovarian ablation or suppression substantially reduces the 15-year risk of recurrence and death from breast cancer without increasing mortality from other causes.
The impact of household income on prostate cancer diagnosis, treatment, and outcomes.
Authors: Panzone John , Wu Maximillian S , Chandrasekar Thenappan , Basnet Alina , Bratslavsky Gennady , Goldberg Hanan
Published: June 2023

5038

Background: Financial difficulties can lead to cancer patients delaying or deferring necessary care, resulting in later presentation with more advanced disease and worse clinical outcomes. Methods: A cross-sectional study was conducted assessing 488,853 prostate cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program between the years of 2010 and 2018. The association between annual household income (HHI) and diagnosis and outcomes of prostate cancer were examined using ANOVA and Chi-square analyses comparing clinical measures based on categorical HHI groupings. Results: Sociodemographic data and univariate analyses are displayed. The average age across all HHI classifications was 66.63 years. ANOVA analysis demonstrated that patients with a lower HHI had higher PSA levels upon diagnosis (12.10 vs. 10.90, 10.61, and 10.37 for <=35k, 35-55k, 55-75k, and >=75k, respectively, p<0.001). Patients with lower HHI also demonstrated lower rates of undergoing surgical treatment (31.9%, 36.9%, 37.6%, and 35.1% for <=35K, 35-55k, 55-75k, and >=75k, respectively, p<0.001) and the highest rate of disease metastasis to bone upon diagnosis (6.3%, 5.6%, 5.7%, and 5.8% for <=35k, 35-55k, 55-75k, and >=75k, respectively, p<0.001). Lastly, patients with lower HHI demonstrated progressively higher rates of cancer-specific-mortality (8.4%, 6.8%, 6.5% and 5.1% for <=35k, 35-55k, 55-75k, and >=75k, respectively, p<0.001), as well as higher overall mortality (21.2%, 18.0%, 15.0%, and 11.9% for <=35k, 35-55k, 55-75k, and >=75k, respectively, p<0.001). Conclusions: In conclusion, these data suggest that prostate cancer patients with lower household income are diagnosed with more aggressive disease, tend to undergo surgery at lower rates, develop more advanced disease, and endure worse clinical outcomes than those in higher income brackets. Healthcare providers should be made aware of the clear associations between lower income and more aggressive disease at diagnosis, lower rates of surgical treatment and worse cancer-specific and overall mortality. [Table: see text]
Evaluation of PAM50 intrinsic subtypes and risk of recurrence (ROR) scores in premenopausal women with early-stage HR+ breast cancer: A secondary analysis of the SOFT trial.
Authors: Brown Lauren Claire , Luen Stephen James , Molania Ramyar , Caramia Franco , Savas Peter , VanGeelen Courtney , Chic Nuria , Fleming Gini F. , Kammler Rosita , Colleoni Marco , Viale Giuseppe , Speed Terence Paul , Regan Meredith M. , Francis Prudence A. , Loi Sherene
Published: June 2023

504

Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS. The purpose of this study is to assess the prognostic and predictive ability of PAM50 intrinsic subtypes and ROR scores in premenopausal women with HR+/HER2- breast cancer in the SOFT trial. Methods: Gene expression analyses were performed via the NanoString Breast Cancer 360 assay on RNA isolated from FFPE tumor samples from the SOFT trial that were HR+/HER2- (n=1245/3047). PAM50 subtype and ROR score were determined centrally by NanoString Technologies (Seattle, WA, USA), blinded to clinical characteristics, treatment and outcome. Median follow-up was 12 years. Primary endpoint in this study was distant recurrence-free interval (DRFI). Secondary endpoints were breast cancer-free interval (BCFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of PAM50 intrinsic subtypes and ROR categories (low vs intermediate vs high), and secondarily ROR score as a continuous variable. We also investigated differences between very young (<40yrs) vs young (>40yrs) women. Results: Tumor samples from 1084/1245 (87%) patients successfully completed PAM50 testing and are included in this analysis. Patient characteristics in this cohort were similar to the entire SOFT trial population. Intrinsic subtype and ROR category distribution is described below. Subtype distribution significantly differed between very young vs young premenopausal women, with fewer luminal A and more luminal B and non-luminal tumors seen in the very young (p<0.001). The ROR score distribution also differed significantly: in node-negative patients there were significantly more ROR-high scores amongst very young compared to young women (36% vs 14%, p<0.001). Conclusion: Breast cancer diagnosed in very young women has aggressive disease biology. Prognostic and predictive analyses of both intrinsic subtypes and the ROR score are ongoing and will be presented at the meeting. Clinical trial information: NCT00066690 . [Table: see text]
Bone biomarkers and subsequent survival in men with bone-metastatic hormone sensitive prostate cancer (HSPC): Results from the phase III SWOG S1216 trial of androgen deprivation +/- orteronel.
Authors: Lara Primo N , Mayerson Edward , Gertz Erik , Tangen Catherine , Goldkorn Amir , Van Loan Marta , Hussain Maha H. A. , Gupta Shilpa , Zhang Jingsong , Parikh Mamta , Twardowski Przemyslaw , Quinn David I. , LeBlanc Michael Leo , Thompson Ian M , Agarwal Neeraj
Published: June 2023

5048

Background: We previously reported that circulating serum biomarkers of bone metabolism were significantly associated with overall survival (OS) in men with advanced prostate cancer, either in the hormone sensitive (Lara, et al. ASCO 2022) or castration resistant state (Lara, et al. JNCI 2016). In S1216, we showed that elevated bone biomarkers were significantly associated with an increased risk of death in HSPC regardless of bone metastases (mets). We also identified three risk groups (low, intermediate, and poor) with differential OS outcomes (median OS: 8.2, 5.1, and 2.1 years, respectively) based on combinations of bone biomarkers in these patients. Here we report the association of bone biomarkers with OS in men with HSPC and documented skeletal mets as part of a planned analysis of S1216. Methods: Bone resorption [C-telopeptide (CTx) and Pyridinoline (PYD)] and bone formation markers [C-terminal collagen propeptide (CICP) and bone alkaline phosphatase (BAP)] were assessed from patient sera. Patients were randomly divided into training (n=238) and validation (n=475) sets. In the training set, recursive partitioning that maximizes discrimination of OS was used to identify the dichotomous cut-point for each biomarker and for a combination of biomarker split points to define prognostic groups. In the validation set, Cox proportional hazards models were used to assess the impact of biomarkers on OS, adjusted for patient and tumor characteristics. Results: Of 1,279 men in S1216, 713 had both baseline bone mets and evaluable bone biomarkers. Patient characteristics were similar between the overall population and the subset with bone mets. Elevated levels of CICP, CTX, and PYD were strongly prognostic for OS, but not for BAP. Hazard ratios (95% CI) for OS adjusted for treatment arm and baseline clinical variables were: BAP – 1.31 (0.93, 1.84), p=0.12; CICP – 1.58 (1.09, 2.29), p<0.02; CTx – 1.55 (1.12, 2.15), p=0.008; and PYD – 1.66 (1.27, 2.217), p=0.0002. There was no evidence of interaction between elevated biomarkers and treatment (all p>0.2). Recursive partitioning algorithms identified four groups of patients with differential OS outcomes based on bone biomarkers, adjusted for baseline clinical variables, with median OS ranging from 2.3 years (highest risk group) to 7.5 years (lowest risk group). Conclusions: In this subset analysis of men with HSPC and bone mets in S1216, elevated serum markers of bone metabolism were significantly associated with worse OS. Bone biomarker levels alone and in combination with patient and tumor characteristics identify unique subsets of men with differential OS outcomes. Clinical trial information: NCT01809691 .
Impact of synchronous (sync) vs metachronous (meta) metastasis at the presentation on survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor signaling inhibitors (ARSIs).
Authors: Gebrael Georges , Sayegh Nicolas , Tripathi Nishita , Goel Divyam , Brundage James , McFarland Taylor Ryan , Ebrahimi Hedyeh , Nordblad Blake , Chigarira Beverly , Mathew Thomas Vinay , Sahu Kamal Kant , Li Haoran , Chehrazi-Raffle Alexander , Maughan Benjamin L. , Kohli Manish , Swami Umang , Agarwal Neeraj
Published: June 2023

5049

Background: Pts with sync metastatic castration-sensitive prostate cancer (mCSPC) appear to have worse survival outcomes and earlier time to developing castration resistance than pts with meta mCSPC (PMID: 33914595). However, the impact of the initial timing of metastasis on survival in the mCRPC setting is less clear. Herein, our objective was to assess the correlation between the sync/meta metastatic disease presentation and survival in real-world newly diagnosed mCRPC pts. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: confirmed diagnosis of mCRPC, treatment with ARSI (abiraterone or enzalutamide) as first-line (1L) therapy for mCRPC, and no prior exposure to ARSI in the mCSPC or localized states. The disease was considered sync if distant metastasis was diagnosed within 90 days of the initial prostate cancer diagnosis. Study endpoints: progression-free survival (PFS) was defined from the start of therapy for 1L mCRPC to progression (per PCWG-2) or death from any cause. Overall survival (OS) was defined from the start of therapy for 1L mCRPC to the date of death from any cause or censored at the last follow-up. A multivariate analysis using the Cox proportional hazards model was used, adjusting for potential confounders. Results: 323 pts (144 sync and 179 meta) were eligible and included in the analysis. Sync and meta pts had respectively similar baseline characteristics: median PSA (19.6 vs 20.8 ng/ml), liver metastasis (9 vs 12.3%), median alkaline phosphatase (97 vs 95 IU/L), and ECOG performance > 1 (9 vs 3.9%). The difference in median PFS was not statistically significant (8.2 vs. 10.7 months, HR 1.13, 95% CI 0.85-1.49, p=0.4 for sync and meta, respectively). Median OS was significantly shorter in pts with sync compared to meta (26 vs. 38.7 months, HR 1.51, 95% CI 1.11-2.08, p=0.01). In the multivariate analysis, the initial timing of metastasis remained an independent prognostic factor. Conclusions: For the first time, we report the impact of the initial timing of metastasis on mCRPC prognosis in a real-world patient population with sync disease being associated with having a poor prognosis. Initial timing of metastasis may be worth accounting for in future mCRPC clinical trials to explore its prognostic value further. These hypothesis-generating data need external validation. [Table: see text]
Talazoparib (TALA) plus enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC): Safety analyses from the randomized, placebo (PBO)-controlled, phase 3 TALAPRO-2 study.
Authors: Azad Arun , Fizazi Karim , Matsubara Nobuaki , Saad Fred , De Giorgi Ugo , Joung Jae Young , Fong Peter C.C. , Jones Robert J. , Zschaebitz Stefanie , Oldenburg Jan , Shore Neal D. , Dunshee Curtis , Carles Joan , Fay Andre P. , Lin Xun , DeAnnuntis Liza L , Di Santo Nicola , Engelsberg Arne , Agarwal Neeraj
Published: June 2023

5053

Background: The phase 3 TALAPRO-2 study demonstrated a clinically meaningful and statistically significant improvement in radiographic progression-free survival for 1st-line TALA + ENZA versus PBO + ENZA in men with mCRPC, unselected for homologous recombination repair gene alterations (all-comers population). Here, we detail the safety profile of TALA + ENZA. Methods: In this double-blind, randomized, PBO-controlled trial, men received TALA 0.5 mg or PBO, plus ENZA 160 mg once daily (QD). Patient (pts) were ≥18 yrs of age, had Eastern Cooperative Oncology Group performance status ≤1, were receiving ongoing androgen deprivation therapy, and had no prior systemic therapy for mCRPC. Treatment-emergent adverse events (TEAEs) were evaluated: type, severity, timing, and associated dose modifications/discontinuations. Results: The all-comers safety population included 398 pts in the TALA + ENZA arm. Data cutoff was August 16, 2022. The median treatment duration of TALA was 19.8 months. All-cause any-grade TEAEs were observed in 98.5% of pts. Overall, 19.1% of pts discontinued TALA due to TEAEs. The 3 most common hematologic all-cause TEAEs and associated dose modifications are reported. To ensure optimal dosing of TALA at the individual level, the protocol did not require dose modification of TALA until anemia was grade (G) ≥3. Median time to onset of first G≥3 anemia was 3.3 months. At study entry, 49.0% had G1–2 anemia. 43.2% had anemia leading to dose reduction (with or without transfusion) and 8.3% discontinued TALA due to anemia. Despite dose reduction, the relative dose intensity of talazoparib remained >80% (approx. 0.4 mg/day). The 3 most common nonhematologic TEAEs were fatigue (33.7%; 4.0% G3), back pain (22.1%; 2.5% G3), and decreased appetite (21.6%; 1.3% G3). Conclusions: TALA 0.5 mg QD + ENZA 160 mg QD was generally manageable, with dose modifications of TALA and/or standard supportive care. Anemia was the most common TEAE and led to discontinuation of TALA in 8.3% of pts. G≥3 hematologic AEs typically occurred within 6 months of starting therapy and resolved in <1 month. A detailed understanding of the onset, duration, and severity of AEs, as well as the impact of dose adjustments in the TALAPRO-2 study, will optimize the management of pts receiving TALA + ENZA for mCRPC. Clinical trial information: NCT03395197 . [Table: see text]
The impact of circulating tumor cell HOXB13 RNA detection in men with metastatic castrate-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide.
Authors: Guo Siyuan S , Halabi Susan , Nanus David M. , George Daniel J. , Antonarakis Emmanuel S. , Danila Daniel Costin , Szmulewitz Russell Zelig , McDonnell Donald P. , Norris John D. , Lu Changxue , Luo Jun , Armstrong Andrew J.
Published: June 2023

5060

Background: It has been shown that HOXB13 is an important androgen receptor (AR) coregulator. The primary objective of this analysis was to correlate HOXB13 expression with clinical outcomes in men with mCRPC. Methods: We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (n=118) treated abiraterone (abi) or enzalutamide (enza). CTC detection and specific HOXB13 cDNA detection and expression was measured using a modified Adnatest using appropriate controls. CTC HOXB13 status was categorized into 3 groups: undetectable CTCs (CTC=0 based on CTC PSMA & PSA=0); CTC+ but HOXB13 CTC negative (<4 copies) or positive (≥4 copies) where the HOXB13 cutoff point was determined by the maximally selected rank statistic for prognostic associations. The association between HOXB13 and overall survival (OS) and radiographic progression-free survival (rPFS) were explored using the proportional hazards model. We also explored the association between the two endpoints and multigroup of HOXB13 at cutoff 0 and CellSearch CTC at cutoff 1 and 5. Results: 102 men who had sufficient CTC cDNA sample for HOXB13 detection. Of those men with detectable CTCs, 19% (n=19) had no detectable HOXB13, while the majority of men at 67% (n=58) had both CTC and HOXB13 detection. The proportion of patients with CTC=0, CTC+ HOXB13-, and CTC+ HOXB13+ using the optimal HOXB13 threshold were 25%, 31% and 44%, respectively. Men with HOXB13- CTCs were more likely to have low PSA (median 3 vs 79 copies), low CTC PSMA (0 vs 99 copies), low AR-FL (47 vs. 89 copies) and CTC AR-V7 (5.9 vs. 42 copies), and more likely to have liver/lung metastases (41% vs 25%). Median OS were 25.7, 25 and 12.1 months while the median rPFS of the three groups were 9.0, 7.2 and 4.7 months, respectively. Compared to CTC=0, men with HOXB13- CTCs did not have a worse hazard rate for OS (HR: 0.9, 95% CI: 0.4-1.9), while HOXB13+ CTC patients had a worse hazard for OS (HR: 2.0, 95% CI: 1.0-3.9), adjusting for prior abi/enza treatment and Halabi clinical risk score. The positive HOXB13 had also statistically significant increased hazard for progression/death (HR: 2.31, 95% CI: 1.24-4.30). Compared to the group with both HOXB13=0 and CellSearch CTC=0, men with HOXB13>0 and CellSearch CTC≥5 had increased hazard on both OS and rPFS (OS: HR:2.39, 95% CI: 1.06-5.4; rPFS: HR: 2.78, 95% CI: 1.38-5.59). Conclusions: Higher CTC HOXB13 expression is associated with AR dependent biomarkers in CTCs and is adversely prognostic in the context of potent AR inhibition in men with mCRPC, and this assay could be useful to select for patients appropriate for AR or future HOXB13 targeted therapies. Clinical trial information: NCT02269982 .
Phase I trial of enzalutamide (Enz) plus the glucocorticoid receptor antagonist relacorilant (Rela) for patients with metastatic castration resistant prostate cancer.
Authors: Desai Kunal , Serritella Anthony V. , Stadler Walter Michael , O'Donnell Peter H. , Sweis Randy F. , Szmulewitz Russell Zelig
Published: June 2023

5062

Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I study of the combination of rela and enz in patients with mCRPC. Methods: The study used a 6+3 design to assess safety and pharmacokinetics (PK) of the 2-drug combination. The starting dose of rela 100mg/day was chosen based on current clinical studies indicating this dose was both safe for daily dosing and pharmacologically active and the starting dose for Enz was 120mg based on anticipated drug-drug interactions. Escalating doses of rela were combined with Enz 120 using pre-specified dose escalation rules. An additional 12 patients were to be assessed at the MTD to refine safety and PK profiles. Primary endpoint was safety of the combination and to establish safe and pharmacologically active doses of both agents. Key secondary endpoints were tumor response per RECIST 1.1 criteria and progression-free survival (PFS; defined as either PSA progression, radiographic progression or death). PSA was measured after 12 weeks or at the last time at which PSA data was available, including times <12 weeks. Results: 35 pts were enrolled. Pts had a median age of 74 (range 62-85) and baseline PSA of 89.5 (range 7.3-2391). 100% had prior potent AR signaling inhibitor (abi or enz) with 89% receiving prior enz, 94% prior abi, 83% prior both. 69% of pts received prior docetaxel. Median PSA change was 0.1%. Enz 120mg + Rela 100mg and Enz 120+Rela 150 were found to be safe and tolerable and achieved desirable Enz PK. DLTs were noted in 3 pts at the 200mg Rela dose, which was deemed to have exceeded the MTD, which was thus defined as 150mg Rela+120mg Enz. Most common ≥ grade 3 treatment related adverse events (TRAEs) were fatigue (11% of pts), anemia (9%), abdominal pain (6%) and pericardial effusion (6%). Median PFS was 2.5 months for 21 of 35 evaluable pts. Best response per RECIST 1.1 were Not Evaluable (40%), SD (34%) & PD (26%). No CR or PR were noted. Most common reasons for discontinuation from trial included progressive disease/hospice (82%), AEs (12%), physician discretion (3%) & death (3%). 2 pts remain on trial as of data cutoff (12/31/22). Conclusions: The combination of enzalutamide and relacorilant was safe & largely well tolerated. The majority of pts were discontinued from trial due to progressive disease or hospice. Further analyses of secondary & correlative endpoints such as translational/endocrine biomarkers, GR target gene expression and circulating tumor cells are ongoing. Clinical trial information: NCT03674814 .
Enzalutamide vs abiraterone in patients with prostate cancer with and without type 2 diabetes mellitus.
Authors: Shaver Amy L , Nikita Nikita , Gandhi Krupa , Sharma Swapnil , Keith Scott W. , Yang Christopher C. , Lu-Yao Grace L.
Published: June 2023

5066

Background: Estimations are that 8-18% of newly diagnosed cancer patients have Type 2 Diabetes Mellitus (T2DM). Current guidelines offer no clarification on the choice of therapy for prostate cancer (PCa) patients with T2DM. Since the comorbid PCa—T2DM population is increasing and these patients face unique challenges from adverse events requiring acute care utilization (ACU) it is important to ascertain which medication poses less of a threat of adverse events. The objective of this study was to describe the SEER-Medicare T2DM-PCa population in terms of those with and without complications and determine if T2DM influences ACU and PCa medication choice. Methods: We identified men with primary PCa treated with abiraterone (ABI, 2011) or enzalutamide (ENZ, 2012) with comorbid T2DM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (1999-2019). Patients with a missing date of diagnosis, those diagnosed at death, having HMO or no continuous A and B coverage 12 months before diagnosis and 6 months continuous part D coverage before starting treatment as well as 6 months following treatment or until death were excluded. T2DM was identified using ICD-9 and ICD-10 codes. ACU was calculated utilizing the CMS Research Data Assistance Center definition focusing on emergency room visits resulting in in-patent hospitalization during the 6 months following treatment initiation. Differences in emergency room in-patient visits were evaluated using negative binomial models adjusted for age, race, SEER region, marital status, state-buyin, education, income, and modified Charlson Comorbidity Index (excluding T2DM). Results: The sample of 11,163 men included 61.8% treated with ABI and 38.2% with ENZ. We identified 3,044 (27.3%) men with T2DM, of which, 59.1% were treated with ABI and 40.8% with ENZ. Compared to those without T2DM those with T2DM had more ACU, regardless of medication, with a higher rate in the ABI than ENZ group, see table. Among diabetics, those with complications related to T2DM compared to those without also experienced a higher rate of ACU. The rate of ACU was 43% higher among those treated with ABI compared to ENZ (IRR 1.43; 95% CI 1.28, 1.61). Overall mortality (15.7% vs 10.1%, p<0.01) and PCa-specific mortality (8.2% vs 5.3%, p<0.01) were worse in those with T2DM treated with ABI compared to ENZ. Conclusions: Outcomes for PCA patients with T2DM are worse than for those without. ACU is higher in men treated with ABI compared to ENZ regardless of T2DM status. Given the worse outcomes for comorbid T2DM patients, further study to evaluate comorbidity management in this population is warranted. [Table: see text]
Assessing PSA levels as prognostic of overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Halabi Susan , Roy Akash , Guo Siyuan S , Rydzewska Larysa , Godolphin Peter , Hussain Maha H. A. , Tangen Catherine , Thompson Ian , Xie Wanling , Carducci Michael Anthony , Smith Matthew Raymond , Morris Michael J. , Gravis Gwenaelle , Dearnaley David P. , Verhagen Paul , Goto Takayuki , Tierney Jayne F. , James Nicholas D. , Buyse Marc E. , Sweeney Christopher
Published: June 2023

5070

Background: Prior data have shown that prostate specific antigen (PSA) ≤ 0.2 ng/dL at 6-7 months with androgen deprivation therapy (ADT) with testosterone suppression (TS) alone is prognostic of OS. We hypothesized that PSA ≤0.1 ng/dL at 7 months would be a stronger prognostic for OS in men with mHSPC treated with TS alone. This hypothesis was investigated by the STOPCAP M1 collaborators. Methods: Individual patient data from 13 eligible randomized trials comparing treatment regimens (TS or TS + docetaxel in the control or research arms in mHSPC trials were utilized. Landmark survival analyses were performed at 7 months after ADT initiation. Overall survival was computed as the time from 7 months after start of initial TS to death or date of last follow for patients who started TS prior to randomization or 7 months after randomization to death or date last follow-up for patients who started TS after randomization. PSA measurements between 4-7 months after ADT were selected and cut off-points of PSA ≤0.2, 0.2-4, and >4 ng/dL or PSA ≤0.1, 0.1-0.2, 0.2-4, and >4 ng/dL were considered. The proportional hazards model was utilized to explore the prognostic significance of PSA levels in predicting OS adjusting for treatment in all patients and patients who were enrolled on docetaxel trials. Results: IPD from 5,438 patients randomized 1994-2012 from 13 trials were pooled. At 7 months, the proportion of patients who had PSA≤0.1 and PSA ≤0.2 were 18.1% and 26.1%. The median OS in patients who experienced PSA ≤0.1 and PSA≤0.2 and in patients enrolled on docetaxel trials are presented in the table below. The hazard ratios (HR) for death for PSA≤0.1 and PSA≤0.2 vs. those PSA>4 at 4-7 months were 0.26 and 0.27, respectively. In patients enrolled on docetaxel, HRs for death for PSA≤0.1 and PSA≤0.2 vs. those PSA>4 at 7 months were 0.35 and 0.34, respectively. Conclusions: PSA≤0.1 and PSA≤0.2 at 7 months have similar prognostic value of OS in men with mHSPC treated with weak ADT (TS alone) without and with docetaxel. Clinical trial information: NCT00309985 ; NCT00268476 ; NCT00104715 ; NCT00079001 ; NCT00002651 ; NCT00685646 . [Table: see text]
Early results from CASCARA: A phase 2 study of cabazitaxel/carboplatin plus abiraterone in high-volume metastatic castrate-sensitive prostate cancer (mCSPC).
Authors: Ryan Charles J. , Cao Qing , De Souza Andre Luiz , VanderWeele David James , Bryce Alan Haruo , Kelly William Kevin , Jha Gautam Gopalji , Barata Pedro C. , Sartor A. Oliver , Stadler Walter Michael , Dhawan Mallika Sachdev , Morgans Alicia K. , Antonarakis Emmanuel S.
Published: June 2023

5071

Background: Best treatment of mCSPC involves doublet therapy (ADT + novel hormonal agent) or triplet therapy (ADT + novel hormone + docetaxel); however, opportunity remains for further improvement. Studies show that homologous recombination repair (HRR) gene mutations are enriched in metastatic prostate cancer, and may portend resistance to docetaxel. CASCARA tested quadruplet therapy (ADT + cabazitaxel/carboplatin + abiraterone) in high-volume mCSPC, aiming to enhance PSA responses and decrease progression at 1 year. Methods: This phase 2 study enrolled 61 mCSPC patients with high-volume disease who received ADT plus cabazitaxel (20 mg/m2 q21d x 6) and carboplatin (AUC=4 q21d x 6) followed by abiraterone (1000 mg, plus prednisone 5 mg). Primary endpoint was freedom from PSA/radiographic progression at 1 year. Other endpoints included PSA50 response, freedom from PSA progression, and safety. Archival biopsies were retrospectively evaluated for HRR ( BRCA1/2, ATM, CHEK2, CDK12, BRIP1, RAD51B) mutations at a CLIA-certified lab. A sample size of 61 was determined using a Simon two-stage design (stage 1: 32 men, stage 2: 29 men) with a null hypothesis of a 1-year PSA/radiographic progression-free rate of 0.80 against a one-sided alternative of 0.92. Results: From 11/2019 to 06/2022, 61 men enrolled at 7 sites. Median age was 64 (range, 45–76) years; 21% were African American. Median baseline PSA was 8.9 (range, 0.1–1021) ng/mL. 44% of men had ECOG=1. 91% had Gleason sum 8–10. Prevalence of DNA alterations (50 evaluable pts) was 18% for HRR mutations, 38% for TP53 muts, 22% for ERG fusions, 10% for SPOP muts. Freedom from PSA/radiographic progression at 1 year was 77% (95% CI, 63–87%), and freedom from PSA progression at 1 year was 81% (95% CI, 67–90%). The PSA50 rate response was 97%. PSA ≤0.2 ng/mL at month-7, a surrogate for survival in other mCSPC studies, was 61%; PSA ≤4 ng/mL at month-7 was 82%. Outcomes according to mutation status are shown. AEs included 7% grade (Gr)-3/4 myelosuppression, 8% Gr-3/4 infections, 10% Gr-3 GI disorders, and 3% Gr-3 fatigue. There were 4 treatment-related discontinuations. Conclusions: Quadruplet therapy with ADT + cabazitaxel/carboplatin + abiraterone was well tolerated. At 1 year, 77% of pts were progression-free. PSA ≤0.2 ng/mL at month-7 was 61%, exceeding the historical month-7 PSA ≤0.2 ng/mL rate of 45% in CHAARTED–docetaxel arm. Further exploration of this quadruplet strategy in randomized phase III studies is warranted. Clinical trial information: NCT03934840 . [Table: see text]
The relationship between a priori defined prognostic risk groups and and overall survival (OS) in men with metastatic hormone sensitive prostate cancer (mHSPC).
Authors: Halabi Susan , Guo Siyuan S , Roy Akash , Rydzewska Larysa , Godolphin Peter , Hussain Maha H. A. , Tangen Catherine , Thompson Ian , Xie Wanling , Carducci Michael Anthony , Smith Matthew Raymond , Morris Michael J. , Gravis Gwenaelle , Dearnaley David P. , Verhagen Paul , Goto Takayuki , James Nicholas D. , Parmar Mahesh , Buyse Marc E. , Sweeney Christopher
Published: June 2023

5073

Background: Prior analyses have shown that men who present with high volume (HV) disease and de novo metastases have shorter OS compared with other mHSPC subgroups. The objective of this analysis was to determine the prognostic relationship between a-priori defined 4-prognostic groups and OS in men with mHSPC and in a subset of trials in patients treated with androgen deprivation therapy (ADT) +docetaxel. This hypothesis was investigated by the STOPCAP M1 collaborators. Methods: We obtained individual patient data (IPD) from 13 randomized trials comparing treatment regimens (ADT or ADT + docetaxel in the control or research arms) in mHSPC. OS was defined as the time between date of randomization and date of death/or last follow-up. Patients (pts) were classified into 4 mutually exclusive groups. Poor prognostic risk-group was defined as HV (presence of visceral metastases, and/or > 4 bone metastases or presence of bone metastases beyond pelvic or vertebral bones) plus synchronous diagnosis (SYN); whereas intermediate risk groups were patients with HV and metachronous (MET; intermediate A) or low volume plus SYN (intermediate B); and lastly good risk group had LV plus MET. The proportional hazards model was used to estimate the hazard ratio (HR) and assess the prognostic significance of risk groups in predicting OS adjusting for treatment. Results: Of 6041 pts included in this analysis, 60% (3622 pts) had died. Median follow-up time=5-years. Overall 11%, 8%, 47% and 34% were in the good, intermediate A, intermediate B and poor risk groups, respectively and for trials including docetaxel (n=2627 pts) 9%, 5%, 39% and 47% respectively. HRs for risk groups are shown in the table. Conclusions: Differences in OS across the risk groups were observed. Further work is needed to investigate if more precise prognostic groups can be defined such as better characterization of patients' groupings of extent of bone metastases and visceral metastases. Clinical trial information: NCT00309985 ; NCT00268476 ; NCT00104715 ; NCT00079001 ; NCT00002651 ; NCT00685646 . [Table: see text]
Prostate-specific antigen value at 3 & 7 months (PSA-3mo, PSA-7mo) and overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation (ADT) with or without orteronel (SWOG S1216).
Authors: Parikh Mamta , Tangen Catherine , Hussain Maha H. A. , Gupta Shilpa , Jo Yeonjung , Harzstark Andrea , Paller Channing Judith , George Saby , Zibelman Matthew R. , Cheng Heather H. , Maughan Benjamin L. , Zhang Jingsong , Pachynski Russell Kent , Bryce Alan Haruo , Lin Daniel W. , Quinn David I. , Thompson Ian M , Dorff Tanya B. , Lara Primo N , Agarwal Neeraj
Published: June 2023

5074

Background: Analysis of phase 3 studies of patients (pts) with mHSPC in the era of ADT, including in combination with docetaxel and/or androgen receptor axis targeted therapies have established PSA-7mo as a key prognostic marker. Our objective was to evaluate the association between PSA-3mo, PSA 7-mo and OS measured in the phase 3 S1216 trial in mHSPC comparing ADT + orteronel (treatment arm) vs ADT + bicalutamide (control arm) [NCT01809691]. Methods: Pts enrolled in the S1216 trial with available PSA-3mo & PSA-7mo were included in this analysis. PSA responses were defined as complete response (CR) if PSA ≤ 0.2 ng/mL, partial response (PR) for PSA >0.2 and ≤ 4ng/mL, and no response (NR) as PSA >4 ng/mL at month 3 or 7. Landmark OS was measured and Cox regression model applied adjusting for stratification (performance status, extent of disease, early vs late start of treatment, treatment arm). Results: 1251 pts were alive and evaluable for PSA-3mo and 1231 pts were evaluable at 7 mo, out of a total of 1279 pts. The median age was 67 (range: 43-92), 10% of patients were black, 96% had a Zubrod performance status of 0-1. Median PSA at baseline was 29 ng/ml (range: 2-6710). Of pts on treatment vs.control arm, PSA-3mo CR, PR, and NR occurred in 52% vs 35%; 31% vs 42%, and 17% vs 23%, respectively. Of pts on treatment vs control arm, PSA-7mo CR, PR, and NR occurred in 61% vs 46%, 20% vs 26%, and 19% vs 29%, respectively. CR or PR at either timepoint led to significantly better outcomes than those with NR. No interaction between treatment arm and PSA response was observed in terms of OS. Conclusions: PSA-3mo and PSA-7mo are strong prognostic markers for pts with mHSPC. More pts on ADT with orteronel achieved CR at 3 and 7 mo. In addition to its use in counseling patients in the clinic, PSA-3mo and PSA-7mo may be used as parameters for designing future trials in pts with mHSPC, utilizing the next generation of intensification or de-intensification treatment regimens. Clinical trial information: NCT01809691 . [Table: see text]