bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes and toxicity in older adults with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor targeted (ART) therapies.
Authors: Mellgard George Slade , Chakrani Zakaria , Mccroskery Stephen , Saffran Nathaniel , Taylor Nicole , Liaw Bobby Chi-Hung , Galsky Matt D. , Oh William K. , Tsao Kai , Patel Vaibhav G.
Published: March 2023

117

Background: Prostate cancer (PCa) and especially advanced PCa largely affects older adults with a median age of diagnosis of 67. Despite ART’s role as a mainstay of treatment (tx) in advanced PCa, little is known about its risks/benefits in older adults. We aimed to examine survival outcomes and safety in patients (pts) with mCRPC ≥75 years-old (y.o) on ART. Methods: The records of mCRPC pts treated with ART at the Mount Sinai Hospital between 2010 and 2021 were screened for demographics, medical history, ART course, tx toxicity, and survival outcomes. PSA progression free survival (PFS) between pts ≥75 y.o and pts ≤75 y.o was assessed as the primary outcome. Secondary outcomes were overall survival (os) and tx toxicity. Tx toxicity was evaluated using physician documented tx side-effects (SE)s. Fischer’s exact was used to compare baseline characteristics and tx SEs. Cox proportional hazards models were used to compare survival outcomes. Results: Of 153 pts, 97 were < 75 y.o and 56 were ≥75 y.o. Within the <75 y.o group, 17 (17.5%) were post-chemo compared to 7 (12.5%) in the ≥75 group (p = .493) Relevant baseline characteristics (ECOG ≥2, Race, Gleason 4-5, hospitalizations, and CCI) were not significantly different. Median PSA PFS was 14.2 (≥75 y.o) and 17.3 months (<75 y.o) with no significant difference on univariate or multivariate analysis (HR: 1.1 [0.69, 1.74;] p = 0.697. Median OS was 32.4 months for the ≥75 y.o cohort and 32.3 months for the <75 y.o cohort (HR: 1.38 [0.88, 2.17;] p = 0.156). The 5 most common SEs by group are reported below. Of note, adults ≥75 y.o were more likely to report edema compared to the <75 y.o pts (8.2% vs 21.4%, p-value = .026). Conclusions: Pts ≥75 on ART experienced similar survival benefits compared with pts <75. While older adults were more likely to report edema, overall tx toxicity profiles did not differ significantly. Ultimately, these findings ground evidence-based counseling and tx for older adults with mCRPC considering ART. [Table: see text]
Clinical characteristics and outcomes of trial-ineligible patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving androgen receptor targeted (ART) therapy.
Authors: Mellgard George Slade , Mccroskery Stephen , Chakrani Zakaria , Saffran Nathaniel , Taylor Nicole , Liaw Bobby Chi-Hung , Galsky Matt D. , Oh William K. , Tsao Kai , Patel Vaibhav G.
Published: March 2023

118

Background: mCRPC pts with significant comorbidities or poor performance status (PS) are often excluded from clinical trials for ART. These cohorts may not be representative of or comparable to real-world pts. We aimed to determine whether (1) baseline characteristics or (2) survival outcomes differed in pts with mCRPC categorized as eligible or ineligible for ART clinical trials. Methods: We screened for pts with mCRPC treated with abiraterone (abi-) or enzalutamide (enza-) at our institution between 2010 and 2021. Baseline characteristics were reviewed at treatment start and ART course recorded. We applied the inclusion/exclusion criteria from clinical trials, COU-AA-301, COU-AA-302, PREVAIL, and AFFIRM, to categorize pts as ineligible or eligible. Fischer’s exact was used to evaluate pt characteristics. Cox proportional hazards model was used to compare survival outcomes. Results: We identified 150 pts with mCRPC who initiated abi- or enza-. 54.7% of pts were deemed trial ineligible. Among pts on abi-, 48 of 86 (55.8%) pts were ineligible. Among those on enza-, 34 of 64 (53.1%) were ineligible. Common reasons for ineligibility included poor PS, radiation during treatment, and trial specific comorbidities. Among ineligible pts, 11% were post-chemotherapy compared to 20.6% of eligible pts (p = .162). Notably, trial ineligible pts were more likely to be non-Hispanic black when compared to trial eligible pts (29.3% vs. 17.6%, p = 0.036). Median OS was 30.2 for ineligible pts and 37.1 for eligible pts p = 0.46). for the ineligible pts and eligible pts respectively and there was no significant difference on univariate or multivariate analyses (HR: 0.84 [0.54, 1.32;]. Conclusions: Pts classified as trial ineligible had comparable survival outcomes when compared to trial eligible pts. Consistent with prior research on systemic racism in clinical trials, ineligible pts were more likely to identify as Black compared to eligible pts. Further research is warranted to confirm safety of ART in ineligible pts and identify strategies for reducing racial disparity gaps in cancer clinical trials.
Patient characteristics and safety of radium-223 dichloride in Taiwan: Analysis of real-world clinical practice.
Authors: Pang See-Tong , Huang Chao-Yuan , Huang Chi-Ping , Huang Yu-Yi , Huang Steven Kuan-Hua , Lu Kevin , Huang William J. , Meng En , Huang Shu-Pin , Lee Ming-Yang
Published: March 2023

119

Background: Bone metastases commonly develop in patients with metastatic castration-resistant prostate cancer (mCRPC), leading to poor clinical outcomes. Radium-223 (Ra-223) is a bone-targeting radiopharmaceutical that has been shown to improve the overall survival of these patients. Here, we present data on the safety and effectiveness of Ra-223 in patients with mCRPC and symptomatic bone metastases under routine clinical practice in Taiwan. Methods: This prospective, multicenter, single-arm, non-interventional observational study enrolled patients with mCRPC and symptomatic bone metastases. A total of 224 patients were included from July 2020 to January 2022. The patients received Ra-223 (55 kBq/kg of body weight) once every 4 weeks for a maximum of 6 intravenous injections. An exploratory subgroup analysis was conducted in patients who received Ra-223 either as a first-line, second-line or third-line. This first interim analysis of the study assessed the clinical outcomes observed during 6 months of Ra-223 treatment and 1 month after the final or last tolerated injection. Results: The dataset up until September 2021 (n = 104) was available for analysis. Of the 104 patients, 69 (66.3%) received 5–6 injections of Ra-223 while 35 (33.7%) received 1–4 injections. Sixty percent of enrolled patients were chemotherapy-naive. Furthermore, 22 (21.2%), 43 (41.3%) and 39 (37.5%) patients received Ra-223 as a first-, second- or third-line therapy, respectively; 16 (72.7%), 27 (62.8%) and 26 (66.7%) patients in these subgroups received 5–6 injections of Ra-223, respectively. The incidence of any study drug-related treatment-emergent adverse events (TEAEs), hematologic TEAEs and all fracture events were 10.6%, 9.6% and 1.9%, respectively. When compared with the other subgroups, patients on first-line Ra-223 therapy had lower incidences of any drug-related AEs and discontinuation of therapy owing to AEs. In addition, there was a trend observed that better PSA control occurred in patient population using Ra-223 as mCRPC first-line treatment. Conclusions: The study data showed that under routine clinical practice in Taiwan, the rate of Ra-223-associated AEs were low and no new safety concerns were identified with this therapy. First-line Ra-223 therapy was more likely associated with fewer TEAEs and higher rates of completion with the 6-injection course of therapy. A follow-up observation of up to 2 years after the initial injection is on-going. Clinical trial information: NCT04232761 .
Differential expression of PDL-1 and tumour-associated macrophages in N0 and N+ penile cancer.
Authors: Azhar Fowz , Sachdeva Ashwin , Hart Claire Alexandre , Brown Mick D. , Sangar Vijay , Parnham Arie , Lau Maurice , Oliveria Pedro , Clarke Noel W
Published: March 2023

12

Background: Penile squamous cell carcinoma (PSCC) is rare, representing 0.4-0.6% of all male malignancies in the global-north, as compared with 2-10% in the global-south. Overall survival (OS) dramatically decreases with increased lymph node metastases (LNM). Increased prevalence of pro-tumorigenic M2 CD163+ tumour associated macrophages (TAM) is associated with poor PSCC OS, whereas increased prevalence of the generic M1/2 CD68+ TAMs is associated with better PSCC OS. PDL-1 expression has been noted in 40-60% of PSCC primary lesions. However, there is a paucity of evidence on the overall tumour immune microenvironment (TME) within penile LNM disease. This study describes the relationship between PDL-1 expression and TAMs within the TME of the primary tumour and paired LNMs, with the goal of predicting the utility of PD-1 inhibitors in clinical trials in PSCC. Methods: The Ventana Discovery ULTRA platform was used to optimise a 7-marker multiplex immunofluorescence panel on whole FFPE sections of primary and LNM lesions. Multispectral images were captured using a Vectra 3 microscope. Single cell spatial analysis was performed using HALO software, with statistical analysis of data using R 4.2.1. Results: 52 cases with differing LN stages were identified: N0 (N=20); N1/N2 (N=21); N3 (N=11). Increased expression of PDL-1 was noted at the primary lesion invasive margin (IM) of N+, compared with N0 patients. High expression in inguinal LNMs (iLN+) and pelvic LNMs (pLN+) was also observed, with no expression detected in microscopically normal, tumour free LNs (LN-) in the N0 cohort. More CD163+ M2 TAMs were observed at the IM of N+ compared with N0. However, no significant difference was observed between the three LN groups. M1/2 CD68+ TAMs were more prevalent within pLN+ vs iLN+ or LN-. There was no significant difference in M1/2 CD68+ TAMs number at the IM. Conclusions: Our data highlights increased prevalence of M2 CD163+ TAMs within the IM is associated with LNM. Increased presence of CD68+ M1/2 TAMs in pLN+ may represent active inflammation at the leading microscopic edge of metastatic deposits. A significant difference in the expression of PDL-1 between localised and metastatic disease at both primary and LN location is noted. High PDL-1 expression at the IM of the primary lesion is associated with increased LNMs, where PDL-1 expression is significantly higher as compared to LN-. This study supports the rationale for the use of anti-PD-1/PDL-1 therapies in patients with LNM disease.
Factors related to men’s experience with prostate cancer germline testing.
Authors: Giri Veda N. , Gross Laura , Hartman Rebecca , Leader Amy , Whang Young E. , Couvillon Anna , Cheng Heather H. , Paller Channing Judith , Loeb Stacy , Karsh Lawrence Ivan , Friedman Sue J. , Beer Tomasz M. , Sokolova Alexandra , Keith Scott W.
Published: March 2023

128

Background: Indications for prostate cancer (PCA) germline testing (GT) have greatly expanded, with genetics delivery being implemented in a variety of ways. Here we evaluate factors related to men’s experience with genetic evaluation (GE) in the PCA Genetic Risk, Experience, and Support Study – PROGRESS Registry. Methods: Men took online surveys that covered demographics, PCA history, mode of GE, and measures of patient-reported outcomes (PROs) (satisfaction [Demarco 2004] [Score 6-30; higher=greater satisfaction], decisional conflict [O’Connor 1995] [Score 16-80; higher=greater conflict], attitude re: GT [Marteau 2001] [Score 1-7; higher=perceived benefit], and knowledge of cancer genetics [Erblich 2005] [% correct of 15 questions]). Data were summarized using descriptive statistics. Multiple linear regression modeling assessed relationships between characteristics, mode of GE, and PROs. Significance level was a nominal α = 0.05 (SAS v9.4). Results: PROGRESS reached accrual goal (n=500). Characteristics (among n=414): 87.7% White, 6.0% Asian, 87.7% bachelor’s degree or higher. Among n=422, 46.9% reported PCA diagnosis. Among n=416 who reported genetic results, 27.9% had pathogenic/likely pathogenic variants (P/LPV), 14.7% had VUS, and 9.9% did not know. Mode of GE was delivered: by genetics professional (GP) (24.9% in-person,10.5% phone, 6% telehealth), by doctor (21.1%), from website (20.8%), by genetics lab (5%), and by video (10.8%). Some reported not having pretest discussion (23.7%) or not knowing (8.1%). From multiple regression models, several factors including race, mode of GE, education, and genetic results were related to PROs. Conclusions: Several factors may impact men’s experience with PCA GE, deserving further study into root causes particularly related to diverse populations and genetics care delivery models to support men and their families. [Table: see text]
A retrospective review of the benefits vs. safety implications of prednisolone during docetaxel chemotherapy alongside androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Jameson Molly , Barker Claire , King Jennifer , Liang Hui-Wen , Carey Charles , Cripps Nicole , Jameson Daisy , Patel Kamlesh , Robinson Andrew , Hudson Andrew , Song Yee Pei , Conroy Ruth , Serra Maria , Choudhury Ananya , Logue John , Wylie James , Tran Anna
Published: March 2023

132

Background: A key difference between the landmark trials for docetaxel chemotherapy alongside ADT for mHSPC was the addition of prednisolone in the STAMPEDE but not CHAARTED or GETUG-AFU 15 trials, resulting in varied use in clinical practice. Potential toxicity from prolonged steroid use was recognised in a 2020 NHS England safety alert. This retrospective study compared toxicities in patients treated with docetaxel +/- prednisolone. Methods: Electronic notes of patients treated with docetaxel and ADT +/- prednisolone (per consultant preference) Feb 2018 - Sept 2020, were reviewed. Data was collected on common toxicities using CTCAE v5 grading. Analysis of incidence and severity were carried out using paired T-tests and logistic regression due to small sample sizes at each severity grade. Results: Data on 299 patients was collected; 167 received docetaxel and ADT, 132 also received prednisolone. There was no significant difference in the number of cycles completed between the 2 groups; 66.5% (no prednisolone) v 70.4% (with prednisolone) of patients completed 6 cycles (p=0.41). There was a significant difference in both the incidence and severity of anaemia between patients treated +/- prednisolone. There was no significant difference in the incidence of neutropenia or alopecia between patients treated +/- prednisolone, but prednisolone use was predictive of lower severity scores in neutropenia and alopecia. In contrast, there was a significant difference seen in incidence of neuropathy between the 2 groups, with no impact on severity. There was no significant difference in incidence or severity of thrombocytopenia, neutropenic sepsis, fatigue or nausea/vomiting. The prednisolone group had a significant increase in contacts with an advice hotline or general practitioner (p values <0.001). Review of interactions found many were requesting support with administration of prednisolone. Conclusions: These findings suggest limited clinical benefit in the addition of prednisolone to docetaxel and ADT in patients with mHSPC. Prednisolone is associated with significant potential harms e.g., impaired blood glucose and adrenal insufficiency (blood glucose was not routinely recorded in this group). These preliminary findings would benefit from further study with a larger sample size. [Table: see text]
COVID-19 vaccination behavior and outcomes in patients with genitourinary cancer in comparison with other cancer types.
Authors: Polimera Hyma Vani , Pomerantz Lauren Danielle , Guare Emma , Zhu Junjia , Joshi Monika
Published: March 2023

134

Background: Cancer(ca) and old age are risk factors for developing severe COVID-19 (C19+) disease, related morbidity and mortality. These patients (pts) were excluded from clinical trials evaluating the safety and efficacy of 3 FDA approved C19 vaccines (vax). Genitourinary (GU) ca-prostate, bladder and kidney ca contribute to the majority of non-skin ca and median age of these pts range from 65-75 yrs. We aimed to study these highly vulnerable pts behavior and outcomes regarding C19 vax in comparison to non-GU ca pts (18-89 years). Methods: A prospective and observational single center study. Adult ca pts seen in clinics from Nov 2021-Sept 2022 were randomly interviewed using telephone surveys after a verbal consent. Type of ca and therapy data were collected from pts’ medical records. The survey included C19 disease status, vax status positive (+) or negative (-), reason for vax status, side effects (s.e), impact on ca Rx or ca progression. Data was entered on REDCap. The primary end point was rate of vaccination in adult ca pts. Secondary end points were to quantify C19 vax acceptance vs. hesitance, identify s.e of C19 vax and effect of C19 vax on outcomes in GU and non-GU Ca pts. Results: N=172; GU ca 21 (12.2%) and non-GU ca 151 (87.8%). Among GU ca pts- 9 had prostate ca, 7 had bladder ca and 5 had renal ca. C19+ in 4 (19%) GU and 45 (30.2%) non-GU pts. GU pts: 90.5% received C19 vax (Pfizer 47.6%; Moderna 42.9%, J & J 0%); 9.5% were not vaxed. Non-GU pts: 85.2% received C19 vax (Pfizer 39.1%; Moderna 43%, J & J 2.6%); 14.8% were not vaxed. The top 3 risk factors for serious C19+ were age >65yr (76.2%), heart disease (61.9%) and BMI>30 (42.9%) in GU ca pts and age >65yr (46.4%), BMI>30 (35.1%) and smoking (19.9%) in non-GU ca pts. The top 3 reasons for C19 vax (+) in GU ca pts: protection against C19+ for self (81%), for others (47.6%) and provider recommendation (38.1%). The main reasons for vax hesitancy in C19 vax (-) GU ca pts: concern for allergy to the vax (4.8%) and prior C19 infection (4.8%). The common s.e of C19 vax reported in GU ca pts were injection site inflammation (19%), headache (4.8%), muscle/body aches (4.8%) but no lymphadenopathy. None of GU ca pts reported delay in Rx or progression of the disease due to C-19 vax. Conclusions: C19 vax were overall well tolerated and did not impact ca outcomes in pts with GU malignancies. Oncologists should discuss the importance of C19 vax in the context of ca. Clinical trial information: NCT04953065 . [Table: see text]
Dosing, safety, and pharmacokinetics (PK) of combination therapy with darolutamide (DARO), androgen-deprivation therapy (ADT), and docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study.
Authors: Rezazadeh Arash , Tombal Bertrand F. , Hussain Maha H. A. , Saad Fred , Fizazi Karim , Sternberg Cora N. , Crawford E. David , Kapur Shivani , Zhang Weijiang , Ploeger Bart , Li Rui , Kuss Iris , Zieschang Carsten , Wittemer-Rump Sabine , Smith Matthew Raymond
Published: March 2023

148

Background: In ARASENS (NCT02799602), DARO in combination with ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P<0.001) vs placebo (PBO) + ADT + DOC in patients with mHSPC. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment groups. We report dosing, safety, and PK of coadministration of DARO and DOC with ADT. Methods: Patients with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, plus ADT and DOC (75 mg/m2 q21d for 6 cycles). The effect of DARO on DOC PK was assessed by noncompartmental analysis from the first 25 patients with dense PK data and by population PK (PopPK) for all patients. DARO PK from ARASENS were compared with PK data from ARAMIS (NCT02200614; without DOC) to evaluate the impact of DOC on DARO PK. Results: Of 1306 randomized patients, 1305 were included in the full analysis set (DARO, n=651; PBO, n=654). The median treatment duration was longer with DARO vs PBO (41.0 vs 16.7 months) and more DARO-treated patients (45.9% vs 19.1%) were still receiving treatment at primary analysis cutoff (Oct 25, 2021). Almost all patients completed 6 cycles of DOC in both groups (DARO, 87.6%; PBO, 85.5%). The proportion of patients requiring DOC dose modification (interrupted/delayed or reduced) was similar between groups (DARO, 60.0%; PBO, 62.9%). TEAEs led to discontinuation/reduction of DOC in 8.0%/19.9% of DARO patients and 10.3%/19.5% of PBO patients. PopPK analysis indicated that DOC PK in ARASENS was generally consistent with that in the literature. A slight numeric increase in DOC exposure was observed in the DARO + DOC + ADT arm, with 15% higher maximum plasma concentration (geometric mean, 1.93 vs 1.68 µg/mL) and 6% higher area under the concentration-time curve (AUC0-tlast within an 8-hour sampling interval, 2.10 vs 1.99 µg·h/mL) vs PBO + DOC + ADT. This small numeric increase is likely not clinically relevant given the variability in DOC exposure (coefficient of variation, 23%–54%). PK meta-analysis of ARASENS and, which considered patients’ intrinsic characteristics as covariates (eg, age, body weight, region), indicated a 10% lower AUC0-12ss of DARO in patients receiving DOC vs those not receiving DOC, which is not considered clinically relevant. Conclusions: The combination of DARO + DOC + ADT increases overall survival with similar overall incidence of TEAEs and no observed drug-drug interactions between DARO and DOC. DARO can be effectively and safely administered with DOC in patients with mHSPC without clinically relevant changes in PK of DARO or DOC. Clinical trial information: NCT02799602 .
Therapeutic effect of gedatolisib, a pan-PI3K/mTOR inhibitor, on prostate cancer models with PI3K or PTEN mutational status.
Authors: Sen Adrish , Khan Salmaan A , MacNeil Ian A. , Rich Benjamin E. , Molden Jhomary S , Davis Laura N , Rossetti Stefano , Broege Aaron M , Laing Lance G.
Published: March 2023

149

Background: Metastatic castration-resistant prostate cancer (mCRPrC) is characterized by a loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K, AKT, and mTOR (PAM) pathway. Loss of the PI3K regulator, PTEN, is frequent during prostate cancer (PrC) initiation, progression, and therapeutic resistance. Co-targeting PAM/AR pathways is a promising PrC treatment strategy but hampered by complex PAM-AR pathway crosstalk driving either reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors (PAM-i) selectively spare (or weakly inhibit) one or more key PAM pathway components, potentiating drug resistance depending on the PAM mutation status of patients. AKT-i demonstrated limited efficacy in PTEN-deficient PrC and even less efficacy in PTEN-wild type (wt) in recent clinical studies, suggesting that more comprehensive inhibition of the PI3K isoforms and mTOR may be required. We posited that gedatolisib, a well-tolerated and potent inhibitor of all Class I PI3K isoforms, mTORC1, and mTORC2, would be effective in both PTEN-wt and PTEN-deficient PrC. Methods: A panel of PrC cell lines with different PI3K or PTEN status ( wt: 22RV1, MDA-PCa-2b, DU145; null: LNCaP, PC3, C4-2) were assayed under different conditions for their sensitivity to gedatolisib and other PAM-I ( PI3K: alpelisib, copanlisib; AKT: capivasertib, ipatasertib; mTOR: everolimus; pan-PI3K/mTOR: samotolisib, gedatolisib). A combination of cell viability, growth rate, cytotoxicity and phospho-FACS analytical assays were used. Xenograft studies evaluating gedatolisib with a subset of these models were also performed in castrated mice. Results: We confirmed that AKT-i is more effective in PTEN-null than PTEN-wt PrC. In contrast, the two pan-PI3K/mTOR-i evaluated were effective independent of PI3K or PTEN status. Gedatolisib exhibited superior potency and efficacy compared to each of the other PAM-i for cell proliferation, death, or PAM pathway activation. In vivo, gedatolisib substantively inhibited tumor growth regardless of PTEN or PI3K status. Conclusions: We demonstrated that gedatolisib exerts superior activity regardless of PI3K or PTEN status in all PrC cell lines evaluated compared to the other PAM pathway inhibitors evaluated. Our results indicate potent and simultaneous blockade of all Class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN dependent resistance. Gedatolisib as a single agent and in combination with other therapies reported promising preliminary efficacy and safety in various solid tumor types. In light of the PrC findings reported here, development of gedatolisib may be warranted in PrC patients regardless of their PTEN or PI3K status.
Efficacy and safety of darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) by disease volume and disease risk in the phase 3 ARASENS study.
Authors: Hussain Maha H. A. , Tombal Bertrand F. , Saad Fred , Fizazi Karim , Sternberg Cora N. , Crawford E. David , Shore Neal D. , Kopyltsov Evgeny , Rezazadeh Arash , Boegemann Martin , Ye Ding-Wei , Cruz Felipe Melo , Suzuki Hiroyoshi , Kapur Shivani , Srinivasan Shankar , Verholen Frank , Kuss Iris , Joensuu Heikki , Smith Matthew Raymond
Published: March 2023

15

Background: In ARASENS (NCT02799602), DARO plus ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI: 0.57–0.80; P<0.0001) vs placebo (PBO) + ADT + DOC in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC), with similar overall incidences of treatment-emergent adverse events (TEAEs) between groups. The effect of DARO on overall survival (OS) was consistent across prespecified subgroups, including de novo and recurrent disease. For pts with mHSPC, outcomes based on disease volume and risk provide additional information to clinicians. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, with ADT + DOC. High-volume disease was defined as visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis (CHAARTED criteria). High-risk disease was defined as ≥2 risk factors: Gleason score ≥8, ≥3 bone lesions, and presence of measurable visceral metastasis (LATITUDE criteria). OS for these subgroups was assessed using an unstratified Cox regression model. Results: Of 1305 pts in the full analysis set, 1005 (77%) had high-volume disease, 912 (70%) had high-risk disease, 300 (23%) had low-volume disease, and 393 (30%) had low-risk disease. DARO + ADT + DOC prolonged OS regardless of high- or low-volume disease with HRs of 0.69 and 0.68 vs PBO + DOC + ADT, respectively. OS benefit of DARO vs PBO was also similar for pts with high- or low-risk disease. DARO improved clinically relevant secondary endpoints vs PBO in high/low-volume and risk subgroups, with HRs generally in the range of those observed in the overall population. Incidences of TEAEs were consistent with the overall ARASENS population across subgroups by high/low volume and high/low risk. Conclusions: In pts with mHSPC, the benefits of early treatment intensification with DARO + ADT + DOC on OS and key pt-relevant secondary efficacy endpoints vs PBO + ADT + DOC were similar in patients with high- and low-volume as well as high- and low-risk mH+SPC. The favorable safety profile of DARO was reconfirmed in high/low-volume and high/low-risk populations. DARO + ADT + DOC sets a new standard of care for pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]
The effect of reduced dose of apalutamide on skin adverse events in advanced prostate cancer: A multicenter retrospective study.
Authors: Hatakeyama Shingo , Tabata Ryuji , Fujita Naoki , Tanaka Toshikazu , Yoneyama Takahiro , Sato Satoshi , Ohyama Chikara
Published: March 2023

151

Background: We aimed to evaluate the effect of a reduced dose of apalutamide on skin-related adverse events (AEs) and castration-sensitive prostate cancer (CRPC)-free survival in patients with advanced prostate cancer. Methods: We retrospectively evaluated 35 patients with non-metastatic CRPC and 72 treatment naïve metastatic castration-sensitive prostate cancer (mCSPC) who were treated with apalutamide. The primary outcome was the effect of apalutamide dose-reduction on skin AEs. The secondary outcomes included the effect of apalutamide dose-reduction on skin AE in patents with small body size, post-skin AEs discontinuation rate, and the effect of apalutamide dose-reduction on CRPC-free survival in patients with mCSPC treated with upfront apalutamide plus androgen deprivation therapy. Results: Of 107 patients, 65 (60.7%) and 42 (39.3%) patients were treated with full- and reduced-dose of apalutamide, respectively. The skin AEs rate was not significantly different between the groups (55% vs. 43%, P = 0.761). The incident of skin AEs in the reduced dose of apalutamide were significantly lower in patients with small body size (body weight <67kg and body mass index < 24kg/m2) than those in other body sizes. Apalutamide discontinuation rate after skin AEs was significantly different between the full-dose (50%) and reduced-dose (16.7%) groups. Of 72 patients with mCSPC, the CRPC-free survival was not significantly different between the full- and reduced-dose groups. Conclusions: A reduced dose of apalutamide was not significantly associated with the incident of skin AEs. However, dose reduction for patients with small body size may decrease skin AEs without sacrificing oncological outcome.
A phase 2 randomized open-label study of oral darolutamide monotherapy vs. androgen deprivation therapy in men with hormone-naive prostate cancer (EORTC-GUCG 1532).
Authors: Tombal Bertrand F. , Gomez-Veiga Francisco , Gomez-Ferrer Alvaro , López-Campos Fernando , Ost Piet , Roumeguere Thierry Andre , Herrera-Imbroda Bernardo , D'Hondt Lionel A. , Quivrin Magali , Gontero Paolo , Villà Salvador , Khaled Hussein Mustafa , Fournier Beatrice , Krzystyniak Joanna , Pretzenbacher Yassin , Erkol Hazal , Loriot Yohann
Published: March 2023

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Background: Darolutamide is androgen-receptor (AR) inhibitor with low blood–brain barrier penetration and limited potential for clinically relevant drug–drug interactions. Darolutamide has been shown to increase overall survival in combination with androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone sensitive prostate cancer (PC) and, in combination with docetaxel, in men with non-metastatic castration resistant PC. This phase 2 study assessed the efficacy and safety of DARO as a monotherapy without ADT in patients with non-castrate testosterone (T) levels (≥230 ng/dL). Methods: This was a 24-wk, open-label, randomized study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages, with a max of 4 metastatic lesions) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 y. All patients received DARO 600 mg bid or commercially available LHRH analogue. The primary endpoint is PSA response defined as a ≥ 80% decline at week 24 relative to baseline, in the DARO study arm. The ADT arm is used as an internal control. Secondary endpoints included changes in T levels, safety/tolerability, and quality of life. Results: Among 61 men enrolled, the median (range) age was 72 y (53-86y); 49.2% had metastases; 14.8% and 62.3% had undergone prostatectomy or radiotherapy before study entry. The median (range) of PSA at baseline was 8.9 ng/mL (2.2-333.8). In the DARO arm, the evaluable population with available PSA values at baseline and week 24 consisted of 21 patients. The PSA response rate (>80% PSA decline at wk 24) was 100%, with a median (range) decrease of -99.6% (-94.3, -100) at wk 24 in the DARO arm. Serum T levels increased by a median (range) of 43.4% (5.7-144.0) at wk 24, compared with baseline. In the DARO arm, 45.2% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (19.4%), fatigue (12.9%), and hot flush (12.9%). 3.1% of men experienced SAEs, none of which were drug related. HR-QoL measures and ADT arm results will be presented as internal reference. Conclusions: DARO monotherapy (600 mg bid) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Testosterone level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT02972060 .
Cytoreductive radical prostatectomy (cRP) in the management of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Heidenreich Axel , Rieger Constantin , Kastner Lucas , Seelemeyer Felix , Pfister David
Published: March 2023

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Background: Although still discussed controversially, cRP represents a therapeutic option for mHSPC patients in the context of a multimodality approach. It was the purpose of our study to retrospectively review the oncological and functional outcome of a single-center cohort of cRP patients. Methods: A total of 134 mHSPC patients underwent cRP with pelvic lymphadenectomy. All patients received neoadjuvant androgen deprivation therapy (ADT, n = 34), ADT + docetaxel (n=15), or ADT plus ABI/ENZA/APA (n=85) for 6 months which was continued postop. Follow-up studies were performed at 3-month intervals, new imaging studies with 68Ga-PSMA PET/CT was done at PSA-levels > 1.0 ng/ml. Perioperative complications were evaluated according to Clavien-Dindo classification. Clinical progression free survival (cPFS) and cancer specific survival (CSS) were calculated via Kaplan-Maier analysis. Multivariate regression analysis was used to assess the impact of biopsy ISUP grade, PSA at diagnosis and preop., PSA decrease, T stage, and metastatic burden on PFS and CSS. Results: 115 and 19 had low and high volume mHSPC, resp. Mean age was 64.2 (42-88) years, mean preop. PSA was 3.2 (0.1-21.6) ng/ml. The median Follow-up ist 53.7 (4 – 168) months. M1a, M1b and M1c were present in 28 (20.9%), 98 (73.1%) and 8 (6.0%) men. Pathohistology demonstrated pT0 in 3 (2.2%), pT2a-c in 21 (15.7%), pT3 and pT4 in 105 (78.3%) and 5 (3.7%). pN0 and pN+ was diagnosed in 38 (28.3%) and 96 (71.7%) pts. There was no significant difference between type of ADT and final pathohistology. Clavien-Dindo Grad 3a-b and 4 complications were observed in 13 (9.7%) and 2 (1.5%) pts. CSS was 88.1% and cPFS was 53%. None of the pts developed locally recurrent disease. Overall survival was reduced in M1 high volume (61.9% vs 92.8%, p=0.002) and pN+ (85.7% vs 96.7%, p=0.001). cT≥3b (HR=2.24, p=0.02) and M1 high volume (HR=2.35, p=0.01) were associated with reduced cPFS; M1 high volume (HR=1.49, p=0.03) and relative PSA decrease £60% (HR=1.37, p=0.03) were associated with reduced CSS. Conclusions: cRP can be performed with minimal morbidity. mHSPC patients with clinically localized high risk PCA, low metastatic burden and good response to nADT benefit most from this approach. The risk for symptomatic local relapse is low. Limitation of the study is its retrospective design.
Characteristics of long-term responder (LTR) patients (pts) treated with androgen-receptor signaling inhibitors (ARSI) as a first-line treatment for metastatic castration-resistant prostate cancer (mCRPC): Real-world evidence from four high-volume institutions.
Authors: Caffo Orazio , Buttigliero Consuelo , Cattrini Carlo , Bimbatti Davide , Cani Massimiliano , Cavasin Nicolò , Crespi Veronica , Farinea Giovanni , Kadrija Dzenete , Kinspergher Stefania , Lai Eleonora , Maines Francesca , Mennitto Alessia , Veccia Antonello , Pappagallo Giovanni L. , Maruzzo Marco
Published: March 2023

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Background: ARSI [enzalutamide (ENZA) and abiraterone (ABI)] demonstrated to be efficacious as a first-line therapy for mCRPC, showing a median progression-free survival of 16 and 20 months (mos) in pivotal trials, respectively. Nevertheless, some pts of daily clinical practice show exceptionally prolonged disease control with very long duration of treatment. The present study aimed at identifying the characteristics of LTR pts who received one ARSI as a first-line for mCRPC. Methods: We retrospectively reviewed the clinical records of a consecutive series of 647 pts treated in the daily clinical practice with one ARSI as first-line mCRPC in four Italian high-volume Institutions. Pts who had previously received docetaxel in castration-sensitive setting were excluded. Pts received standard AA or ENZA doses (1,000 mg po daily plus prednisone 10 mg po daily or 160 mg po daily, respectively). ARSI were administered until progression and were followed according to each Institution policy. For each pt we recorded pre and post-ARSI clinical history, baseline characteristics, treatment details and clinical outcomes. Pts were considered as LTR in presence of an ARSI exposure ≥ 36 mos. LTR were compared to the progressed pts with an ARSI exposure < 36 mos. On-treatment pts with an ARSI exposure < 36 mos were not considered. Results: We identified 81 LTR pts (53 treated with ENZA and 28 treated with ABI). The median age was 76 yrs (range 56-89). The median treatment duration was 46.1 mos (range 36.4-88.6) and 52 pts were still on treatment. LTR were compared to no-LTR 415 pts (233 treated with ENZA and 182 treated with ABI). Compared to no-LTR, LTR pts showed longer PSA doubling time (PSADT) (PSADT) (p = 0.001) and time to mCRPC (p < 0.0001), lower levels of basal PSA (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01), better ECOG PS (p = 0.01), lower Gleason score (p = 0.01), and less pain level (p = 0.04). ECOG PS, ALP, time to mCRPC and PSADT were all identified as independent predictors of time to treatment interruption in multivariate analysis. LTR showed an 89% decreased risk of death compared to no-LTR (HR = 0.11 IC95% 0.06-0.18). Conclusions: In our experience, several variables, which are usually considered as having a prognostic value, demonstrated to be able to predict the probability of prolonged disease control in mCRPC pts treated with first-line ARSI.
Real-world outcomes of docetaxel (DOC) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC): First analysis from an Italian multicenter observational study (ECHOS trial).
Authors: Caffo Orazio , Basso Umberto , Cavasin Nicolò , Facchini Gaetano , Catalano Fabio , Nicodemo Maurizio , Sorarù Mariella , Ermacora Paola , Galli Luca , Cattrini Carlo , Borsellino Nicolo , Sirotova Zuzana , Rossetti Sabrina , Grillone Francesco , Zucali Paolo Andrea , Ortega Cinzia , Ricotta Riccardo , Valcamonico Francesca , Vittimberga Isabella , Buttigliero Consuelo
Published: March 2023

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Background: Although CHAARTED trial suggested a survival advantage in de novo (DN) high volume (HV) mCSPC pts, the use of DOC is still debated according to the timing of either metastatic onset [relapsed (REL) vs DN] or disease burden [low volume (LV) vs HV]. In this view, it could be of interest to describe the real-world use of DOC. From 2014, ECHOS multicenter study is collecting real world data from mCSPC pts in Italy, where DOC was the only reimbursed agent until recently. Here, we present study results after first data lock at the end of 2021. Methods: We reviewed the clinical records of the mCSPC pts treated with DOC in 34 Italian Institutions. For each pt we recorded pre and post-DOC clinical history, baseline characteristics, treatment details and clinical outcomes. Results: We identified 568 pts [median age 66.5 yrs (range 43-85)]. Most of them were classified as having a DN/HV disease (78%): the remaining had a REL/LV (2.5%), a REL/HV (8.1%), and a DN/LV disease (11.5%). After a median follow-up of 22 mos, 389 pts experienced disease progression and 227 died. The survival outcomes according to the metastases timing and disease volume is reported in the table. Conclusions: Our real-world experience shows that DOC is proposed not only in DN/HV pts, but also in the other pts regardless of metastases timing and disease volume. The prognosis of DN/HV pts treated with DOC appears to be worse than in CHAARTED trial. These findings need to be confirmed by further analyses made on larger number of pts enrolled in the ECHOS trial. [Table: see text]
Comparative outcomes of metastatic prostate cancer (mPC) patients (pts) with DNA damage response gene alterations (DDR-a): A single-center experience.
Authors: Almunaikh Khalid , Kolinsky Michael Paul , Basappa Naveen S. , North Scott A. , Ghosh Sunita , Niederhoffer Karen Y. , El Hallani Soufiane
Published: March 2023

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Background: DDR-a are prevalent in mPC pts. The clinical behaviour of these pts is not well defined. We sought to investigate how DDR-a affects prognosis and treatment outcomes in mPC pts. Methods: Eligible pts were age ≥18 with mPC who had undergone germline (G) and/or somatic (S) next generation sequencing (NGS) at the Cross Cancer Institute 2016-2021. Pts were considered DDR-a if a pathogenic/likely pathogenic variant (P/LP-v) in a DDR gene was identified on G or S NGS; patients were considered DDR-p if no P/LP-v was identified on S NGS. Data from electronic medical records were collected. The primary endpoint was overall survival (OS) from diagnosis of mPC. Secondary endpoints included: OS and progression free survival (PFS) from initial diagnosis of prostate cancer (PC); PSA response after 12 weeks, and PFS and OS from the start time of 1st and 2nd line therapies. Time based endpoints were analyzed using the Kaplan-Meier (KM) method, and log-rank statistics were used to compare the KM curves. PSA responses were compared using chi-squared testing. Results: 23 DDR-a and 48 DDR-p pts were identified. The most frequent DDR-a were BRCA2 (n=11) and ATM (n=6). Baseline characteristics including age at diagnosis were similar between the two groups. 1st line systemic therapy was androgen deprivation therapy (ADT) alone in 73.9% of DDR-a and 77.0% of DDR-p. 2nd line therapy was abiraterone or enzalutamide in 65% of DDR-a and 92% of DDR-p. Olaparib was received by 52% of DDR-a pts. No difference in OS from mPC (65.7 vs 51.0 mos, p=0.487), OS from initial diagnosis (94.1 vs 88.9 mos, p=0.865), PFS on 1st line therapy (33.2 vs 31.0 mos, p=0.847), OS on 1st line therapy (85.6 vs 78.6 mos, (p=0.799) PFS on 2nd line therapy (8.4 vs 13.1 mos, p=0.569) or OS on 2nd line therapy (32.5 vs 35.8 mos, p=0.901) was seen for DDR-a vs DDR-p, respectively. PSA responses to 1st and 2nd line therapies were similar and will be presented as waterfall plots. Conclusions: In this single-center cohort, no difference in clinical characteristics or outcomes were seen in DDR-a compared to DDR-p pts. While this study is limited by small numbers and retrospective nature, it adds to the growing literature characterizing the clinical behaviour of DDR-a mPC. Collaborative efforts are required to better define this molecular cohort of pts.
A living interactive systematic review and network meta-analysis evaluating systemic therapies in metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Riaz Irbaz Bin , Naqvi Syed Arsalan Ahmed , He Huan , Siddiqi Rabbia , Asghar Noureen , Ravi Praful , Hussain Syed A. , Singh Parminder , Bryce Alan Haruo
Published: March 2023

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Background: We maintain a network meta-analysis for the treatment of mCSPC using a living interactive evidence (LIvE) synthesis framework. Recently, the STAMPEDE trial presented evidence regarding a new triplet regimen (enzalutamide-abiraterone-androgen deprivation therapy [E+AAP+ADT]). Hence, in this report we provide the most-up-to-date evidence to inform the choice of optimal therapy in mCSPC patients. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with androgen pathway inhibitors (API), docetaxel (D), or both in patients with mCSPC were included. Mixed treatment comparisons for overall-survival (OS) and progression-free survival (PFS) were made across randomized comparisons using a frequentist network-meta-analysis. Additionally, subgroup data from three trials (ENZAMET, TITAN, ARCHES) by the receipt of docetaxel were abstracted to evaluate the comparative effectiveness of different triplet regimens. Treatment effects were expressed as hazard ratio (HR) and 95% confidence intervals (CI). Relative treatment rankings were evaluated using P-scores and assessed in congruency with the pairwise estimates. Results: This report includes 10 clinical trials (30 references) and over 11500 patients updated as of 1st October 2022. Using randomized data in overall patient population, AAP+D+ADT (rank 1; HR: 0.50; 95% CI: 0.35-0.72) and E+AAP+ADT (rank 4; HR: 0.76; 0.62-0.93) significantly improved PFS compared to D+ADT (rank 7) but not when compared to E+ADT (rank 2) and APA+ADT (rank 3). Similarly, darolutamide (DARO)+D+ADT (rank 1; HR: 0.68; 0.57-0.81), AAP+D+ADT (rank 2; HR: 0.75; 0.59-0.95) significantly improved OS when compared to D+ADT (rank 7). Efficacy by volume of disease and timing of metastatic presentation was consistent with prior update. Using subgroup data by the receipt of docetaxel, a total of five triplet regimens (DARO+D+ADT, AAP+D+ADT, E+D+ADT, apalutamide (APA)+D+ADT, and E+AAP+ADT) were evaluable for comparisons. E+D+ADT (rank 3) improved PFS compared to D+ADT (rank 9; HR: 0.52; 0.41-0.66) and E+AAP+ADT (rank 6; HR: 0.70; 0.52-0.94). Compared to AAP+ADT (rank 7), E+D+ADT (HR: 0.64; 0.49-0.84) and AAP+D+ADT (rank 2; 0.62; 0.42-0.91) significant improved PFS. However, no significant differences were observed among E+D+ADT, AAP+D+ADT, and APA+D+ADT. Similarly, DARO+D+ADT (rank 1) improved OS compared to APA+D+ADT (HR: 0.47; 0.24-0.93). Conclusions: Current evidence favors the use of emerging triplet regimens over docetaxel doublet but not API doublets in overall population. Among different triplets, E+AAP+ADT may not delay progression compared to docetaxel triplets. Hence, access to treatment, toxicity, disease volume and timing of metastases should be carefully considered in mCSPC patients.
Deep prostate-specific antigen response and overall survival in patients with metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis.
Authors: Naqvi Syed Arsalan Ahmed , Riaz Irbaz Bin , Imran Manal , Bin Zafar Muhammad Daim , Faisal Kunwer Sufyan , Riaz Zaryab Bin , Singh Parminder , Bryce Alan Haruo
Published: March 2023

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Background: Preliminary data suggests that patients with metastatic castration-sensitive prostate cancer (mCSPC) who achieve deep prostate-specific antigen (PSA) response may have improved survival. This finding may have implications for developing treatment de-escalation strategies. Thus, we assessed the overall survival by deep PSA response in mCSPC patients receiving intensified treatments. Methods: MEDLINE and EMBASE were systematically searched from each database’s inception through 1st October 2022. Trials assessing androgen deprivation therapy intensification (doublets, triplets) and reporting overall survival (OS) by deep PSA response were considered eligible for inclusion. Deep PSA response was defined as the PSA level of less than 0.1 or 0.2 ng/ml within eight months after initiation of intensified treatment. Precomputed effect estimates of OS (deep PSA response vs no deep PSA response) were pooled using an inverse-variance approach after logarithmic transformation; a random-effects meta-analysis was conducted within the Bayesian framework using empirical informative priors for heterogeneity parameter as specified by Turner et al. Summary effect was expressed as hazard ratios (HR) with the corresponding 95% credible intervals (CrI). A sensitivity analysis was conducted using the Der Simonian-Lairds random-effects meta-analysis with Hartung-Knapp (HK) adjustment. Results: Five RCTs (PEACE-1, ARASENS, CHAARTED, LATITUDE, TITAN) with 2533 patients were included in this systematic review. A total of 1335 patients experienced a deep PSA response, while 1218 did not achieve a deep PSA response after the initiation of intensified treatment. The pooled incidence of deep PSA response was 49.45% (95% confidence interval: 37.75-61.18). Bayesian meta-analysis showed significantly improved OS in overall mCSPC patient population who achieved a deep PSA response after intensified treatment with either triplet or doublet therapy as compared to those who did not achieve a deep PSA response (HR: 0.39; 95% CI: 0.30-0.50) as shown. The results were consistent with HK adjustment. Conclusions: Excellent overall survival in patients with deep PSA response may offer an opportunity to guide treatment de-escalation trials in carefully selected mCSPC patients. [Table: see text]