bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of care for patients with non-metastatic castration-resistant prostate cancer: Population-based study in Ontario, Canada.
Authors: Malone Shawn , Wallis Christopher J.D. , Lee-Ying Richard M. , Basappa Naveen S. , Cagiannos Ilias , Hamilton Robert James , Fernandes Ricardo , Ferrario Cristiano , Gotto Geoffrey , Morgan Scott Carlyle , Morash Chris , Niazi Tamim , Noonan Krista , Rendon Ricardo A. , Hotte Sebastien J. , Saad Fred , Zardan Anousheh , Osborne Brendan , Chan Katherine , Shayegan Bobby
Published: February 2022

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Background: To describe patterns of practice of PSA testing and imaging for Ontario men receiving continuous androgen deprivation therapy (ADT) for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). Methods: This was a retrospective, longitudinal, population-based study of administrative health data from 2008 to 2019. Men > 65 years old receiving continuous ADT with documented CRPC were included. An administrative proxy definition was applied to capture patients with nmCRPC patients and excluded those with metastatic disease. Patients were indexed upon progression to CRPC and were followed until death or end of study period to assess frequency of monitoring with PSA tests and conventional imaging. A 2-year look-back window was used to assess patterns of care leading up to CRPC, as well as baseline covariates. Results: At a median follow-up of 40 months, 944 patients with CRPC were identified. Their median time from initiation of ADT to CRPC was 26 months, 61% of patients had their PSA measured twice or fewer in the year prior to index and 71% patients did not receive any imaging in the year following progression to CRPC. Almost all patients (98%, n = 921/944) in the study progressed to high-risk CRPC (HR-CRPC) during the study period, of which more than half received fewer than 3 PSA tests in the year prior to progression to HR-CRPC, and 31% received no imaging in the subsequent year. Conclusions: PSA testing and imaging studies are under-utilized in a real-world setting for the management of nmCRPC, including those at high-risk of developing metastatic disease. Infrequent monitoring impedes proper risk stratification, disease staging, detection of treatment failure and/or metastases, likely delaying necessary treatment intensification with life-prolonging therapies. Adherence to guideline recommendations and the importance of timely staging should be reinforced to optimize patients’ outcome.
The association of the use of anxiety and depression medications with PSA testing.
Authors: Khan Areeb , Goldberg Hanan , Pinkhasov Ruben , Shapiro Oleg , Jacob Joseph M , Bratslavsky Gennady
Published: February 2022

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Background: Mental illness is a growing issue in the USA. More individuals continue to be diagnosed with illnesses such as depression and anxiety and placed on necessary medications. Studies have shown that the psychological makeup of an individual greatly impacts their health behavior and usage of preventative measures. However, there is limited research on the effect of anxiety and depression on PSA testing. This study explores the associations between the use of anxiety and depression medications and PSA testing. Methods: We used data from the National Health Interview Survey during the year 2018, and assessed responses to the question “Have you ever had a PSA test?” and “What is the number of PSA tests you had in the last 5 years?”. Responses were stratified by whether men were taking medications for anxiety, depression, both or none. We performed multivariable logistic regression analysis to define adjusted odds ratios of undergoing PSA testing adjusting for relevant socio-economic and demographic parameters. Results: Among the 5,035 male participants, 89.4% did not take any medication, 2.9% reported they took anxiety medication, 2.1% took depression medication and 5.5% took both medications. There was a significantly higher rate of PSA testing in men who took medications for both anxiety and depression compared to men taking no medications (p=0.002). Furthermore, the average number of PSA tests in the last 5 years was highest in the group of men taking both medications ( p < 0.0001). Multivariable analysis showed that men who took medications for both depression and anxiety were more likely to undergo PSA testing in comparison to men, not on any of these medications (OR=1.755, p=0.001). The multivariable analysis also showed that age, living with a spouse, and prior cancer history were associated with an increased likelihood of PSA testing while being a minority, living in the south of the USA, and being a current smoker was associated with a lower likelihood of undergoing PSA testing. Conclusions: Taking both anxiety and depression medications in men may be associated with a higher likelihood of undergoing PSA testing. Despite obvious limitations of this analysis including its retrospective nature and recall bias, this association needs to be further explored, especially due to rising use of these medication in the current era of the COVID-19 pandemic.[Table: see text]
Evaluating the contribution of virtual peer-led support to comprehensive prostate cancer (PCa ) care: The AnCan experience.
Authors: Geller Herbert M. , Ivory John , Wolinsky Howard , Schraidt James , Davis Rick
Published: February 2022

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Background: Comprehensive care for PCa patients extends well beyond selecting therapies based on available guidelines. Patients should be supported to understand the disease, diagnostics, optimal treatment strategies, side-effects, avert morbidity and improve diet and exercise while combating stress. We present data supporting that patient participation in a video peer-led support group is integral to attaining these goals. Face-to-face peer groups are not readily accessible to many patients. AnCan has hosted virtual meeting support groups across the spectrum of malignancies and stages since 2010. We offer navigation, advocacy, and educational webinars. PCa is our cornerstone, including groups focusing on active surveillance/ high risk/recurrent/advanced disease, as well as under-60 patients. Methods: During spring 2021, a survey questionnaire focused on all disease stages was sent to 1174 men in the AnCan database; a second survey focused on active surveillance was send to 1200 active surveillance patients in the AnCan, Active Surveillance Patients International and Prostate Cancer International databases. We evaluated patient experience and how information acquired informed their treatment, interactions with their medical team, lifestyle, stress, and quality of life (QoL). Results: 238 responses were received for the AnCan survey, and 165 for the active aurveillance Survey, totaling. 389 independent responses. 228 (33%) were on Active Surveillance for low risk, and 93 (23%) had advanced PCa, largely distributed across North America. 154 (40%) repeatedly attend AnCan meetings. All (100%) indicated that meetings helped understand disease, navigate their treatment options, improve interaction with their medical teams and improve their quality of life (QoL). In the AnCan Suvey, 48 (19%) patients opted to move to different care teams and 32 (13 %) of those elected PCa specialists. 138 (58%) improved exercise, 90 (38%) improved diet, and 119 (50% ) reported stress reduction. 202 patients (85%) felt the groups to be welcoming, 102 (43%) connected with others, and 70 (30%) developed friendships. Of those who attend Active Surveillance meetings, 75 (68%) said that attendance helped them be their own best advocate, while 25 (23%) said that attendance informed them of new insights and treatments. Conclusions: The AnCan Support Group model increases patient knowledge, positively impacts treatment planning, and promotes lifestyle improvements while providing support to reduce stress, boosts confidence in navigating the disease, and improves QoL. AnCan empower patients to self-advocate and improve their disease experience. This is integral to optimize physician/patient interactions and improve outcomes. We advocate that virtual peer group attendance, based on our model, be included in NCCN treatment recommendations for PCa patients, especially with advanced disease.
Mental health implications in urologic cancer hospitalizations.
Authors: Das Sanjay , Kilaru Sai Srikar , Bailey Beth
Published: February 2022

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Background: Increased mortality from urologic cancers coupled with an aging population has resulted in patient care becoming more specialized to improve patient outcomes. Though family history, lifestyle behaviors, and genetics are all used to determine risk and treatment, there is a knowledge gap of whether mental illness (MI) should also be considered. Therefore, this study seeks to determine whether hospitalizations of urologic cancers plus MIs are associated with increased all-cause mortality, length of hospital stay (LOS), costs of hospitalization and nosocomial infection rates. Methods: Inpatient data from 2016-2017 was obtained from the National Inpatient Sample database. This included all hospitalizations with at least one diagnosis of urologic cancer including prostate, bladder, kidney, renal pelvis, ureteral, urethral, testicular, and penile cancers. MIs of interest were depression, anxiety, substance abuse, and schizophrenia and related disorders. Data analysis and regression models were performed using SPSS Statistics. Reported odds ratios and significance values were controlled for Age, Sex, Income, Race, Insurance, Location, Mortality Risk, and Illness Severity. Results: There were 146,706 hospitalizations involving urologic cancers between 2016-2017. For these hospitalizations, depression and anxiety were associated with a decreased likelihood of death, and all MIs were associated with increased LOS. For hospitalizations involving prostate cancer, Depression and Substance Abuse were associated with decreased likelihood of death (all-causes). Hospitalizations involving kidney cancer had increased total charges and increased LOS. Hospitalizations involving bladder cancer were associated with decreased likelihood of death, and increased LOS for all MIs except, notably, those with substance abuse. Penile Cancer hospitalizations coded for anxiety showed increased LOS, and testicular cancer hospitalizations coded for substance abuse had increased likelihood of death. Conclusions: MIs can affect hospitalization outcomes of patients with urologic cancer differently based on the type of urologic cancer. Interestingly, our analysis showed that Depression was associated a decreased likelihood of death in hospitalizations coded for Prostate Cancer and Bladder Cancer. Though unexpected, we hypothesize that this finding may be partially due to implicit bias from healthcare providers that lead to enhanced care (e.g. increased patient monitoring, better support from auxiliary units such as Social Work). However, there is an absence of research in substantiating this claim. Further research is warranted to better assess the effect of Depression on the mortality of Urologic Cancer patients, and on how to best incorporate mental health status in the overall management of these patients.
Understanding what matters to metastatic castration-resistant prostate cancer (mCRPC) patients when considering treatment options: A US survey.
Authors: George Daniel J. , Mohamed Ateesha F. , Tsai Jui-Hua , Karimi Milad , Ning Ning , Jayade Sayeli , Botteman Marc
Published: February 2022

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Background: Nine new treatments for mCRPC, each varying in efficacy and safety, have been approved over the last 10 years, changing the landscape of patient management. Understanding how patients perceive and value the efficacy, safety, and administration burden of these treatments can facilitate shared-decision making to determine optimal management. To our knowledge, this study is the first to elicit patient preferences for mCRPC treatments in the US. Methods: We conducted a cross-sectional survey using the discrete-choice experiment (DCE) method, in which participants were asked to state their choices over successive sets of treatment alternatives, defined by varying levels of treatment characteristics (i.e., attributes). Six treatment attributes in this DCE were examined: overall survival (OS), months until patients develop a fracture or bone metastasis, likelihood of requiring radiation to control bone pain, fatigue, nausea, and mode of administration. The levels taken by each of these attributes were selected to reflect clinical practice. Quota sampling was used in an online panel for recruitment to ensure that study sample is representative of the US prostate cancer population by age distribution. The choice responses were used to determine the value (i.e., preference weights) respondents placed on each attribute via the use of conditional and mixed logit models. The importance of attributes and marginal rates of substitutions were also calculated in order to understand how much patients were willing to trade off between different attributes. Results: The final dataset included 160 participants, with a mean age of 71.6 years old and a mean of 8.96 years since prostate cancer diagnosis. Participants noted their preferences for mCRPC treatments characteristics as follows (in decreasing order of importance over the attribute ranges included in the study): OS (relative attribute importance [RAI]: 31%), reduction in the need for bone pain control (23%), nausea (16%), months until patients develop a fracture or bone metastasis (15%), fatigue (11%), and mode of administration (3%). The marginal rates of substitution demonstrated that eliminating moderate nausea was perceived as equivalent to a 1.9-month reduction in OS, and a reduction of fatigue from severe to mild was perceived as equivalent to a reduction in OS of approximately 3.3 months. Conclusions: Improving OS remains the highest priority, but patients are willing to sacrifice some survival to avoid declines in quality of life, including avoiding bone pain/fracture, nausea, and fatigue, in the mCRPC disease state.
PSA-progression only in high-risk, metastatatic hormone-sensitive prostate cancer patients treated with abiraterone in the LATITUDE trial.
Authors: Lorente David , Romero Nuria , Lozano Rebeca , Rubio Novella Silvia , Montes Angela , Mateo Joaquin , Castro Elena , Sanchez Alfredo , Olmos David
Published: February 2022

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Background: The LATITUDE (NCT01715285) trial established the survival benefit of abiraterone (AA) over placebo (PBO) in combination with ADT as first-line therapy in high-risk mHSPC patients. By PCWG3 guidelines, pts with PSA progression and no clinical or radiographic progression should not discontinue therapy. We aimed to evaluate the proportion of patients experiencing PSA progression only in the LATITUDE trial and its prognostic significance. Methods: We performed a retrospective, post-hoc analysis of pts treated in the LATITUDE trial (YODA project #2020-4298). Confirmed PSA progression (PSAProg) and radiographic progression (RadProg) were defined by PCWG2 criteria. Patients with PSA progression with a coinciding radiographic evaluation showing no radiographic progression were defined as progressing by PSA only. In these patients, time from PSA to radiographic progression was defined as the time (months) from the date of confirmed PSAProg to the date of RadProg. Kaplan-meier and Cox models were used to define median survival times and comparison of outcomes in the AA vs PBO groups. Results: 771 patients (63.7%) experienced PSAProg; AA: 302 pts (49.9%); PBO: 469 pts (77.6%). In 501 pts (64.5%) there was no RadProg on the coinciding radiographic evaluation (PSA only progression), 187 (61.9%) in the AA and 314 (67%) in the PBO arm (p = 0.153). 207 (41.3%) pts had measurable disease at baseline, a similar proportion to that in the overall study population (43.8%). 315 (62.9%) of pts with PSA progression only developed subsequent radiographic progression, 105 (56.1%) in the AA and 210 (66.9%) in the PBO arm (p = 0.017). Median time from PSAProg to RadProg was 8.4 months (95%CI: 8.1-9.2); no significant difference was observed in pts in the AA vs PBO arm (9.2 vs 8.3 months; HR: 0.88 [95%CI: 0.7-1.1]; p = 0.287). Median OS from the time of PSAProg was 19.8 months (95%CI:17.2-24) in AA-treated pts. OS from time to PSAProg was longer in AA-treated pts with PSAonly progression than those with simultaneous PSAProg & RadProg (24 vs 15.3 months; HR: 0.62; p = 0.007). Conclusions: A significant proportion of high-risk mHSPC patients experience a PSA rise as the only initial feature of disease progression. In these patients, there appears to be no significant difference in time from PSA to radiographic progression in AA vs PBO treated-patients. These results highlight the need to ensure an appropriate follow-up in pts progressing by PSA, in order to identify radiographic or clinical progression and initiate subsequent therapy early, thereby maximizing benefit from the treatment sequence.
Testosterone recovery for relugolix versus leuprolide in men with advanced prostate cancer: Results from the phase 3 HERO study.
Authors: Tutrone Ronald F. , Saad Fred , George Daniel J. , Tombal Bertrand F. , Bailen James L. , Cookson Michael , Saltzstein Daniel , Brown Bruce , Lu Sophia , Shore Neal D.
Published: February 2022

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Background: In the phase 3 HERO study, the oral GnRH receptor antagonist, relugolix, showed sustained testosterone suppression superior to that of leuprolide (96.7% vs 88.8%; difference: 7.9% [95% CI, 4.1 to 11.8; P < 0.001]). Herein, we provide an analysis of the testosterone recovery data in a subgroup of 184 men from the HERO study who were not indicated to continue androgen deprivation therapy. Methods: The phase 3 HERO study was designed to evaluate relugolix in men with advanced prostate cancer. Overall, 934 men were randomized 2:1 to receive relugolix 120 mg orally once daily after a single oral loading dose of relugolix 360 mg on Day 1 or leuprolide injections every 12 weeks for 48 weeks. Testosterone recovery was assessed in 184 patients who completed 48 weeks of treatment and who did not plan to start alternative androgen deprivation therapy within the following 12 weeks (or within 24 weeks following the last injection of leuprolide 3-month depot). During the 90-day recovery period, assessments included time to testosterone recovery (≥ 280 ng/dL, the lower limit of the normal range) using the Kaplan-Meier method, PSA concentrations in testosterone recovery phase, and adverse events during the recovery phase. All analyses were conducted in a modified intent to treat population. Results: Overall, 137 men in the relugolix group and 47 men in the leuprolide group were included in these analyses. Mean (standard deviation) testosterone levels for men entering the recovery assessment were 427±142 ng/dL and 404±127 ng/dL in the relugolix and leuprolide groups, respectively. The cumulative incidence rate of testosterone recovery to ≥280 ng/dL at 90 days after drug discontinuation was 53.9% in the relugolix group compared with 3.2% in the leuprolide group (nominal p = 0.0017). Overall, 74 of the 137 men in relugolix group recovered testosterone with a median time to recovery of 86.0 days (95% CI: 65.0, 92.0), versus 2 of the 47 men in leuprolide group with a median time to recovery of 112.0 days (95% CI: 112.0, not estimable). At the 90-day follow-up visit, the median PSA values were 0.39 ng/mL (range: 0 to 233.1) and 0.06 ng/mL (0 to 14.0) in the relugolix and leuprolide groups, respectively. Incidence of adverse events were generally similar in the treatment groups during the recovery phase, with 96% of men experiencing at least one adverse event and 15% of men experiencing a grade ≥3 adverse event in both treatment groups during the recovery phase. Conclusions: Relugolix, an oral nonpeptide GnRH receptor antagonist, had a faster and more complete recovery of testosterone to normal levels after treatment discontinuation versus leuprolide in a subgroup of men from the phase 3 HERO study. Clinical trial information: NCT03085095.
Pembrolizumab (pembro) plus abiraterone acetate (abi) and prednisone (p) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from KEYNOTE-365 cohort D.
Authors: Ferrario Cristiano , Piulats Josep M. , Linch Mark David , Stoeckle Michael , Laguerre Brigitte , Arranz José A. , Todenhöfer Tilman , Fong Peter C.C. , Berry William R. , Emmenegger Urban , Mourey Loic , Mar Nataliya , Appleman Leonard Joseph , Joshua Anthony M. , Conter Henry Jacob , Li Xin Tong , Schloss Charles , Poehlein Christian Heinrich , De Bono Johann S. , Yu Evan Y.
Published: February 2022

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Background: Abi + p is a standard of care for mCRPC. Cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573) was used to evaluate safety and efficacy of the PD-1 inhibitor pembro + abi and p in patients (pts) who had not received chemotherapy for mCRPC. Methods: Chemotherapy-naive pts who had not previously used next-generation hormonal agents (NHAs) for mCRPC or were intolerant to enzalutamide or for whom enzalutamide was ineffective for mCRPC, whose disease progressed ≤6 months before screening, and who had ECOG PS score 0/1 were eligible. Enrolled pts received pembro 200 mg IV Q3W + abi 1000 mg PO QD and p 5 mg PO BID. Primary end points were PSA response rate (PSA decrease ≥50% from baseline), confirmed ORR per RECIST v1.1 by blinded independent central review, and safety. Secondary end points included rPFS per PCWG3-modified RECIST v1.1, DCR (CR + PR + SD or non-CR/non-PD ≥6 mo), DOR, OS, time to symptomatic skeletal-related event, radiographic bone progression, and radiographic soft tissue progression. Results: Of 103 treated pts, 35.9% had RECIST-measurable disease and 26.2% had previously received enzalutamide. Median (range) time from enrollment to data cutoff was 17.6 (9.7-27.0) months. Confirmed PSA response rate in all 103 pts was 56.3%. Overall, 78.6% of pts had a reduction in PSA level from baseline (confirmed and unconfirmed). For 37 pts with RECIST-measurable disease, ORR was 16.2% (1 CR; 5 PRs) overall, 7.7% for those who previously received enzalutamide (n = 13) and 21.7% for those who had not previously received NHAs (n = 23). Two pts with RECIST-nonmeasurable disease had a CR. DOR was not reached (NR; range, 2.1+ to 19.4+ mo); 4 pts had a response ≥12 months. DCR was 44.7% overall, 11.1% in pts who previously received enzalutamide (n = 27), and 57.3% in pts who had not previously used NHAs (n = 75). Additional analyses are listed in the table. Treatment-related AEs (TRAEs) were experienced by 90.3% of pts; 36.9% experienced grade 3-5 TRAEs. Overall, 18.4% of pts had a grade 3/4 ALT laboratory elevation and 12.6% had a grade 3/4 AST elevation. Five pts died of AEs; 1 was treatment-related (myasthenic syndrome). Conclusions: Pembro + abi and p showed antitumor activity in chemotherapy-naive pts with mCRPC. Safety was generally consistent with individual profiles of each agent, although there was an increased incidence of grade 3/4 ALT/AST laboratory elevations than reported for the individual treatments. Clinical trial information: NCT02861573. [Table: see text]
Progression-free survival (PFS) and overall survival (OS) in patients (pts) with de-novo, high-volume metastatic castration-sensitive prostate cancer (dn-hv-mCSPC) undergoing intensified androgen deprivation therapy (ADT).
Authors: Swami Umang , Chigarira Beverly , Sayegh Nicolas , McFarland Taylor Ryan , Tripathi Nishita , Nussenzveig Roberto , Kessel Adam , Tandar Clara , Goel Divyam , Cheney Jackson , Nordblad Blake , Thomas Vinay Mathew , Sirohi Deepika , Maughan Benjamin L. , Agarwal Neeraj
Published: February 2022

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Background: In the PEACE-1 trial (Fizazi, ESMO 2021), in pts with dn-hv-mCSPC, the addition of abiraterone to ADT + docetaxel (triplet therapy arm) resulted in a median OS of 61 months (OS on ADT + docetaxel arm was 42 months). However, independent contribution of docetaxel to efficacy of ADT + abiraterone in the triplet therapy arm of PEACE-1 trial is not clear. Furthermore, the efficacy of an novel hormonal therapy (NHT) specifically in dn-hv-mCSPC population has not been reported (LATITUDE trial’s eligibility did not include volume status). Herein, our objective was to assess PFS and OS in a cohort of dn-hv-mCSPC pts undergoing intensified ADT with either NHT (i.e. novel androgen receptor or androgen synthesis inhibitors) or docetaxel. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: presence of dn-hv-mCSPC (hv per CHAARTED criteria) undergoing intensified ADT with either NHT or docetaxel started within 3 months of diagnosis. Study endpoints: PFS was calculated per PCWG-2 - defined PSA progression or radiographic progression or clinical progression whichever occurred first; OS was defined as start of therapy to date of death or censored at last follow-up. A multivariate analysis using the Cox proportional hazards (Cox-ph) model was used; the relationship between treatment intensification with both PFS and OS was assessed and adjusted for age at diagnosis, Gleason score, presence of visceral metastases, and PSA at baseline. Results: 85 pts with dn-hv-mCSPC were included: 45 received ADT + NHT; 40 received ADT + docetaxel. In the NHT vs docetaxel arms: median PFS were 23 vs 14 months; and median OS were 63 vs 36 months respectively. See the table for Cox-ph and adjusted co-variate results. Conclusions: We for the first-time report the real-world survival outcomes with ADT + NHT specifically in pts with dn-hv-mCSPC. In addition, in these hypothesis-generating data, the OS of pts with dn-hv-mCSPC undergoing ADT + NHT or ADT + docetaxel were similar to those in the triplet therapy arm or ADT + docetaxel arm of PEACE-1 trial respectively. A randomized trial in pts with dn-hv-mCSPC comparing ADT + NHT vs triplet therapy may better characterize the benefit of the docetaxel component in the triplet therapy.[Table: see text]
Implications of androgen receptor (AR) alterations identified by genomic testing of tissue and blood from advanced prostate cancer (aPC) patients (pts).
Authors: Zengin Zeynep Busra , Henderson Nicholas , Park Joseph J. , Ali Alicia , Hwang Clara , Barata Pedro C. , Bilen Mehmet Asim , Graham Laura , Kilari Deepak , Tripathi Abhishek , Labriola Matthew , Rothstein Shoshana , Garje Rohan , Koshkin Vadim S , Patel Vaibhav G. , Schweizer Michael Thomas , Armstrong Andrew J. , McKay Rana R. , Alva Ajjai Shivaram , Dorff Tanya B.
Published: February 2022

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Background: AR alterations such as ligand binding domain mutations and amplification evolve under the selective pressure of testosterone suppression and AR targeted agents (ARTA) such as abiraterone or enzalutamide, but their relevance to ARTA treatment outcomes remain unclear. Methods: PROMISE is a multi-institutional retrospective clinical-genomic database inclusive of aPC pts who had tissue and/or blood based genomic testing by commercially available CLIA-certified platforms. We analyzed men who received second generation ARTA and stratified patients according to genomic testing timing (pre-/post-ARTA), castration resistance, type of AR alteration, and PSA decline ≥50% on first ARTA. Time to progression (TTP) from first ARTA initiation was estimated using the Kaplan-Meier method and differences between subgroups defined by AR alteration status were assessed using the log-rank test. Results: 854 pts who received ARTA and had tissue-based (n = 600) or blood-based (n = 335) genomic testing were included. Median age was 62 (range, 33-93). Pre- and post-ARTA genomic testing was available in 387 and 467 pts, respectively. AR alterations were identified in 16% (61/387) of pre-ARTA and 48% (226/467) of post-ARTA pts with AR amplifications in 10% (38/387) and 35% (161/467) of the pts, respectively. 15/52 pts who had pre- and post-ARTA testing developed a new AR alteration. In pre-ARTA cohort; castration status, median TTP, and PSA response for 1st ARTA according to alteration status are summarized in the table. In the post-ARTA group, the most common AR mutations were L702H (53%), followed by T878A (33%); whereas, in the pre-ARTA group, the H875Y (26%) mutation was most common. AR mutations in post-ARTA group were seen at similar rates regardless of prior docetaxel exposure (14.3% vs 18.0%, p = 0.46) and following first abiraterone vs enzalutamide/apalutamide exposure (48.6% vs 48.3%, p = 1.0). Conclusions: AR mutations, unlike amplifications, were associated with shorter TTP on abiraterone. Genomic testing should be considered before second line ARTA.[Table: see text]
HSD3B1 polymorphism in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate and prednisone (AAP): Pharmacodynamics and therapeutic implications.
Authors: Bastos Diogo Assed , Camargo Anamaria Aranha , Zylberberg Ricardo , Fontes Jardim Denis Leonardo
Published: February 2022

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Background: AAP prolongs survival in pts with mCRPC. Although it is widely used for mCRPC, no predictive biomarker for response has been identified so far. Methods: This study evaluated HSD3B1 genetic polymorphism and pharmacodynamic parameters from serum samples of mCRPC pts with disease progression after diethylstilbestrol (DES) treated with AAP in the AAP-DES study (NCT02217566). Peripheral blood samples were collected before initiating AAP therapy, after 12 weeks, and at disease progression. Sample analysis included HSD3B1 genotyping, abiraterone acetate (AbA) and D4-abiraterone serum levels, testosterone and dehydroepiandrosterone sulfate (DHEA-S) ultrasensitive analysis. Clinical characteristics, overall survival (OS), progression-free survival (PFS) and the rate of PSA decline ≥ 50% were assessed considering homozygous wild-type (AA) versus heterozygous variant (AC) + homozygous variant (CC) HSD3B1 genotypes. Results: Serum samples of 42 pts were analyzed. AA and AC + CC HSD3B1 genotypes were 50.0% each (95% CI:34.2-65.8). Mean ages at baseline was significantly higher in the AA group (71.1 years) compared to the AC+CC group (66.3 years) (p=0.047). Gleason score ≥8 was observed for 38.1% and 47.6% of AA and AC+CC genotypes, respectively (p<0.001). No statistically significant difference was observed between AA and AC+CC groups related to testosterone and DHEA-S level at baseline, week 12, and PSA progression. Serum levels of AbA and D4-abiraterone were similar, throughout treatment despite HSD3D1 genotype. Median OS was 21.3 months (95% CI: 14.8 - ; 14 events) for the AA genotype, and it was not reached at the AC+CC genotype group (9 events) (p=0.154). Regarding PFS, median estimates were 7.3 months (95% CI: 4.6 – 9.4; 16 events) for AA genotype and 7.9 months (95% CI: 5.6 – 14.4; 16 events) for AC+CC genotype (p=0.519). PSA decline ≥ 50% was 71.4% for AA genotype and 42.9% for AC+CC genotypes and the chance of PSA response in patients with AA genotype is 3.33 (95% CI: 0.93; 12.11) times greater than that in patients with AC or CC genotypes, despite not statistically significant differences (p=0.0614). Conclusions: In our study, the presence of HSD3B1 (1245C) was not significantly associated with clinical response during AAP treatment, as well as testosterone, DHEA-S, AbA and D4-abiraterone levels. The role of HSD3B1 polymorphism to predict clinical outcome of AR blockade for mCRPC patients still needs to be further analyzed in larger translational studies. [Table: see text]
Effect of PSMA-positive membranes secreted from prostate cancer cells on vascular endothelial cells.
Authors: Watanabe Ryuta , Maekawa Masashi , Kiyoi Takeshi , Kurata Mie , Miura Noriyoshi , Kikugawa Tadahiko , Higashiyama Shigeki , Saika Takashi
Published: February 2022

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Background: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. Methods: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected from patients with prostate cancer via robotic surgery in 2019 at Ehime University. In vitro, we prepared conditioned medium derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the conditioned medium. We assessed angiogenic activities by treating HUVECs with LNCaP-derived conditioned medium using a tube formation assay that mimics angiogenesis. Results: Immunohistochemical positivity of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in four of 33 prostate cancer patients (12.1%). We also found that the 10,000 ´ g pellet fraction of the LNCaP-derived conditioned medium containing PSMA-positive membranes, including microvesicles, transformed HUVECs from “PSMA-negative” to “PSMA-positive.” Mass spectrometry revealed that the fraction contained an important growth factor. Furthermore, treating HUVECs with the 10,000 ´ g pellet fraction of the LNCaP-derived conditioned medium significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. Conclusions: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which were found to enhance tumor angiogenesis in prostate cancer tissues. The endocytic process related to these PSMA-positive microvesicles in normal endothelial cells might be an attractive target to develop novel anti-angiogenic drugs, which could inhibit the transformation of normal endothelial cells into tumor endothelial cells (Watanabe et al., The Prostate. 2021. in press).
Germline BRCA2, ATM and CHEK2 alterations shape somatic mutation landscapes in prostate cancer.
Authors: Nakazawa Mari , Fang Mike , Lotan Tamara L. , Luo Jun , Isaacs William B. , Paller Channing Judith , Antonarakis Emmanuel S.
Published: February 2022

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Background: Prostate cancer (PCa) is a highly heritable malignancy. Germline mutations in homologous recombination repair (HRR) genes, especially in in ATM, BRCA2 and CHEK2, are common in men with PCa, but how these influence somatic mutations is unknown. Characterizing the somatic landscape of tumors from germline HRR-altered PCa patients may provide insights into further therapeutic strategies and identify individuals most likely to benefit from existing therapies. Methods: We retrospectively identified 118 men with germline HRR-altered PCa from Johns Hopkins with available somatic mutation data (g ATM, n = 30; g BRCA2, n = 58; g CHEK2, n = 30). In these patients, somatic NGS analysis were done primarily using prostatic (rather than metastatic) tissues. The proportion of patients in each group with somatic biallelic inactivation was determined. We then compared the somatic mutation landscapes of the 3 groups, focusing on key PCa-relevant genes including AR, TMPRSS2-ERG, PTEN, TP53, BRCA2, ATM, CDK12, APC, FOXA1, AKT1, PIK3CA, and KDM6A among others. Somatic mutation data from primary prostate cancer specimens (n = 3965) found in pooled studies (n = 23) from cBioPortal were included as a reference standard for comparison. Results: Biallelic somatic inactivation was detected in 59% (34/58) of g BRCA2-altered, 47% (14/30) of g ATM-altered, and 0% (0/30) of g CHEK2-altered patients. In all 118 germline HRR-altered individuals, the most common somatic mutations were in BRCA2 (31%), FOXA1 (26%), TMPRSS2-ERG (20%), TP53 (16%), PTEN (15%), and ATM (15%). g BRCA2-altered patients had a higher prevalence of somatic mutations in AR (9% vs 3% in cBioPortal, P < 0.05) and FOXA1 (29% vs 13% in cBioPortal, P > 0.05), suggesting a greater dependency on AR signaling, but a lower prevalence of TMPRSS2-ERG fusions (17% vs 33% in cBioPortal, P < 0.05). g ATM-altered patients had a strikingly low prevalence of somatic TP53 mutations (3% vs 25% in cBioPortal, P < 0.01), indicating mutual exclusivity between these genes. g CHEK2-altered patients had a higher prevalence of somatic CDK12 mutations (10% vs 0% in gATM/gBRCA2 patients, P < 0.05), implying an interaction between CHEK2 and CDK12. No differences were seen between the three groups with respect to alterations in the PI3K/PTEN pathway, WNT pathway, or chromatin-related genes. Conclusions: Biallelic inactivation was frequently observed in PCa patients harboring g ATM and g BRCA2 mutations, but not in those with g CHEK2 mutations. g BRCA2-altered patients were enriched for somatic AR (and FOXA1) mutations and were depleted for TMPRSS2-ERG fusions. g ATM-altered patients were depleted for somatic TP53 mutations, while g CHEK2-altered patients were enriched for somatic CDK12 mutations. Thus, germline mutations appear to impose selective pressures that influence somatic mutation landscapes in PCa.
Age-based assessment of cell-free DNA genomic profiles in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Knox Andrea , Fettke Heidi , Hauser Christine , Bukczynska Patricia , Ng Nicole , Foroughi Siavash , Graham Lisa-Jane K. , Mahon Kate Lynette , Tan Winston , Zheng Tiantian , Dai Chao , Du Pan , Jia Shidong , Horvath Lisa , Kohli Manish , Azad Arun , Kwan Edmond Michael , Wang Amy
Published: February 2022

150

Background: With the evolving use of targeted therapies exploiting genomic vulnerabilities in mCRPC, screening patients for sensitizing alterations is of increasing relevance. However, the influence of age on the detection of relevant genomic alterations is incompletely understood. In this study, we compared the cell-free DNA (cfDNA) profiles of younger (age <70) versus older (age ≥70) men with mCRPC and assessed the relative prognostic impact of common genomic alterations. Methods: A next-generation sequencing-based Predicine cfDNA assay was used to profile 276 mCRPC patients from two independent international cohorts. The frequency of genomic alterations across age categories was compared using the chi-squared test, while circulating tumour DNA fraction (ctDNA%) was compared using the Mann–Whitney U test. Cox proportional hazards analysis with interaction testing was used to assess the association between age, genomic alteration and overall survival. Results: The median age of the combined cohort was 72 years (IQR 66-78), with 170 (62%) patients ≥70 years old. Despite differences in baseline characteristics (poorer performance status in older patients, higher Gleason score and de novo metastatic disease in younger patients), there was no significant difference in ctDNA% (median 22% vs 30%, p=0.6). We observed similar frequencies of genomic alterations across the 10 most commonly aberrant genes, including AR (<70 vs ≥70: 46% vs 49%, p=0.6), TP53 (40% vs 36%, p=0.6), BRCA2 (29% vs 21%, p=0.13) and PTEN (39% vs 35%, p=0.5). This similarity persisted when analysing mutations and copy number alterations in isolation. While driver alterations in both age categories were strongly associated with unfavourable outcomes (Table), an exploratory analysis revealed that copy number gain in PIK3CA may have a worse prognostic impact in younger men ( p for interaction = 0.03), with a lesser effect observed in AR gain ( p = 0.1) and MYC gain ( p = 0.1). Conclusions: The genomic profiles of pertinent alterations between younger and older men are comparable. Certain genomic alterations may carry a worse prognosis in younger men. Patients should be considered for precision medicine assessment and directed therapies, regardless of age. [Table: see text]
Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort.
Authors: Pagadala Meghana , Lynch Julie Ann , Karunamuni Roshan , Alba Patrick , Lee Kyung Min , Agiri Fatai , Anglin-Foote Tori , Carter Hannah , Gaziano J. Michael , Jasuja Guneet Kaur , Deka Rishi , Rose Brent S. , Panizzon Matthew , Hauger Richard , Seibert Tyler
Published: February 2022

155

Background: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man’s risk of dying from prostate cancer and thus inform screening decisions. This might be especially useful in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Our object was to determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Methods: We analyzed the Million Veteran Program (MVP), a multi-ancestry population of over 500,000 individuals participating in the VA healthcare system. Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer (first-degree relative) and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. The primary outcome studied was age at death from prostate cancer. The key secondary outcome was age at diagnosis of prostate cancer metastases. Cox regression was used to test associations. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group ( p <10-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio (HR80/20) for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer (Table). PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.[Table: see text]
Abiraterone decanoate (PRL-02): Pharmacology of a single intramuscular (IM) depot injection compared to oral abiraterone acetate (AA) in intact male rats.
Authors: Moore William R. , Sharp Matthew , Eisner Joel Robert , Bell Caroline , Freeman Stuart , Leesnitzer Tony , Schotzinger Robert
Published: February 2022

160

Background: Oral AA is a standard of care for metastatic prostate cancer. The recommended daily AA 1000 mg dose produces high peak and low trough plasma concentrations that are associated with safety issues (e.g., hepatotoxicity) and inadequate efficacy, respectively. PRL-02 is a novel abiraterone prodrug undergoing evaluation in patients with advanced prostate cancer (NCT04729114). In chemically-castrate monkeys, single doses of PRL-02 suppressed androgens for 14 weeks at much lower plasma exposures than AA (Moore et al, ASCO GU 2021). The present study in intact male rats evaluated the systemic exposures and activity of PRL-02 compared to daily oral AA at 7 and/or 14 days post-treatment start. Methods: Sexually mature male rats (n=4 per timepoint) were administered a single IM dose of PRL-02 (90 mg/kg), daily AA (90 mg/kg) or IM/oral vehicle (VEH). Biological samples were collected on Day 7 (PRL-02/VEH; 0h) or Day 14 (PRL-02/AA/VEH; 2, 6 and 24h) post-dosing. Drug and androgen concentrations were determined by LC-MS/MS. Testicular CYP17 hydroxylase activity was measured ex vivo on Day 14. Results: The Day 14 plasma exposure from abiraterone was greater from AA (5.6 - 210 ng/mL) than from PRL-02 (1.15 – 1.37 ng/mL). However, for Day 14 tissue exposures (AUC0-24) from ‘total abiraterone equivalents’ (TAE; concentration of free abiraterone plus abiraterone from prodrug) were greater from PRL-02 in adrenal, testes, lymph node and bone target tissues than from oral AA; exposures from AA were only greater in non-target tissues such as liver and brain (Table). There was no measurable Day 14 CYP17 hydroxylase activity in testes following PRL-02 or AA dosing; inhibition appeared irreversible from PRL-02 and AA. Compared to VEH, a single IM dose of PRL-02 resulted in 81% and 75% reductions in plasma testosterone (T) on Days 7 and 14 post-dose, and an 80% reduction in testicular T on Day 14. Daily AA resulted in a 98% reduction in plasma T after 14 days. Conclusions: Single-dose IM PRL-02 blocked testicular CYP17 enzyme activity as effectively as daily AA in intact male rats and produced a durable large reduction in plasma T. The pharmacological activity, tissue and plasma distribution of TAE from IM PRL-02 in the rat model, along with results from prior monkey model studies, suggest the potential for a greater therapeutic index than from daily oral AA and support the ongoing evaluation of IM PRL-02 in patients with advanced prostate cancer.[Table: see text]
Quantifying molecular imaging patterns of treatment response or progression using a novel traffic light workflow within a prospective phase I/II trial of 177LuPSMA-617 and NOX66 (LuPIN).
Authors: Pathmanandavel Sarennya , Crumbaker Megan , Yam Andrew O. , Nguyen Andrew , Niman Remy , Wilson Peter , Sharma Shikha , Ayers Maria , Eu Peter , Stockler Martin R. , Martin Andrew James , Joshua Anthony M. , Emmett Louise
Published: February 2022

166

Background: 177Lutetium PSMA-617 (LuPSMA) is an effective therapy for metastatic castrate-resistant prostate cancer (mCRPC). However, treatment resistance may occur. We developed a quantitative workflow for serial PSMA PET/CT to optimise predictive and prognostic imaging biomarker capability for progression free (PFS) and overall survival (OS). Methods: 56 men with mCRPC previously treated with taxane chemotherapy and androgen signaling inhibitor were enrolled, receiving up to 6 doses of LuPSMA and a radiation sensitizer idronoxil (NOX66). 68Ga-PSMA-11 PET/CT was performed at study entry and exit. Traffic Light (TL) quantification workflow was developed to track changes in both tumour volume and intensity at a total body and lesional level. Lesions were classified as responding in green (>30% decline in volume), stable in yellow (<30% change in volume/intensity), progressive in red (>30% increase in volume/intensity, or new). Overall response pattern was categorised as responding ( green/yellow), low volume red (<50% progressive disease) or high volume red (>50% progressive disease). TL workflow results were correlated with PFS and OS. Results: 37/56 men underwent both entry and exit imaging. The median PSA decline was 77% (IQR 34-92%), and 70% (26/37) achieved PSA response >50%. PSA progression occurred in 54% (20/37) at exit imaging. Median PFS was 8.6 months (95%CI 5.6-11.6) and median OS 22 months (95% CI 18.6-25.6). 95% (35/37) had reduction in PSMA SUVmax (-26.1 (IQR +11.7 to -89.4)) and SUVmean (-3.3 (+2.9 to -14.2)). PSMA total tumor volume reduced in 68% (25/37) (median -0.64 liters (range +1.44 to -1.1)). On TL workflow, 24% (9/37) had responding/stable disease ( green/ yellow), 76% (28/37) had progressive disease ( red) of whom 41% (15/37) had low volume progression and 35% (13/37) high volume progression. Men with high volume progression had worse OS compared to responders (HR 0.18 (0.05-0.59), p 0.005), and low volume progression (HR 0.30 (0.11-0.80), p 0.02). 68% (19/28) had progression on both TL workflow and PSA, while 32% (9/28) had progression on TL workflow without PSA progression. In multivariable analysis, TL workflow and PSA progression at time of exit scans were independent predictors of OS (Table). Conclusions: This study demonstrates the feasibility of characterizing lesional response on molecular imaging with a quantification TL workflow. TL workflow response independently correlated with survival outcomes, indicating serial PSMA PET has prognostic biomarker potential. Clinical trial information: ACTRN12618001073291.[Table: see text]