bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II, double-blind, randomized study of salvage radiation therapy (SRT) plus enzalutamide or placebo for high-risk PSA-recurrent prostate cancer after radical prostatectomy: The SALV-ENZA Trial.
Authors: Tran Phuoc T. , Lowe Kathryn , Wang Hao , Tsai Hua-Ling , Song Daniel Y. , Hung Arthur , Hearn Jason W.D. , Lotan Tamara L. , Paller Channing Judith , Markowski Mark Christopher , Denmeade Samuel R. , Carducci Michael Anthony , Eisenberger Mario A. , Orton Matthew , Deville Curtiland , Liauw Stanley L. , Heath Elisabeth I. , Desai Neil B , Beer Tomasz M. , Antonarakis Emmanuel S.
Published: June 2022

5012

Background: We sought to investigate whether enzalutamide (ENZA) treatment, without androgen deprivation therapy, increases freedom-from-PSA-progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer post-radical prostatectomy (RP). Methods: Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double-blind, phase II, placebo-controlled, multicenter study of SRT + placebo vs SRT + ENZA. The randomization (1:1) was stratified by center, surgical margin status (R0 vs R1), PSA prior to salvage treatment (PSA ≥0.5 vs < 0.5 ng/mL), and pathologic Gleason sum (7 vs 8-10) using a minimization algorithm. Following randomization, patients received either placebo or ENZA 160 mg PO once daily for 6 months. Following 2 months of study drug therapy, external beam radiotherapy to 66.6-70.2 Gy was administered to the prostate bed (no pelvic nodes). The primary endpoint was FFPP. The trial design was powered for a HR 0.44 FFPP benefit with intended enrollment of 96 subjects and was closed as planned to enrollment on March 2020 short of that goal. Secondary endpoints were time to local recurrence (LR) within the radiation field, metastasis‐free survival (MFS), and safety as determined by frequency and severity of adverse events (AEs). Results: A total of 86 patients were randomized with a median follow-up of 34 (range 0-52) months. The median pre-SRT PSA was 0.3 (range 0.06-4.6) ng/mL, 56/86 (65%) had extra-prostatic disease (pT3), 39/86 (45%) had Gleason Grade Group 4 or higher and 43/96 (50%) had positive surgical margins. Trial arms were well balanced. FFPP was significantly improved with ENZA vs placebo, for example 2-year FFPP was 87.1% vs 68.1%, respectively, and overall with a HR 0.40 [95% confidence interval (CI), 0.17-0.92, p-value = 0.026]. Subgroup analyses demonstrate differential benefit (p-value of interaction = 0.031) of ENZA in men with pT3 (HR 0.19, 95%CI 0.05-0.67) vs pT2 disease (HR 1.29, 95%CI 0.34-4.81). There were insufficient secondary endpoint events for analysis. The most common adverse events were grade 1-2 fatigue (13% ENZA vs 9%) and urinary frequency (6 % ENZA vs 8%). Conclusions: SRT plus ENZA monotherapy for men with PSA recurrent high-risk prostate cancer following RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time. Additional molecular biomarker analyses are being pursued. Clinical trial information: NCT02203695.
Racial concordance and trust in health communications: A randomized trial of videos about prostate cancer.
Authors: Loeb Stacy , Ravenell Joseph , Gomez Scarlett Lin , Borno Hala , Siu Katherine , Sanchez Nolasco Tatiana , Byrne Nataliya , Wilson Godfrey , Griffith Derek , Crocker Rob , Sherman Robert , Langford Aisha
Published: June 2022

5014

Background: Black men have a significantly higher risk of prostate cancer and more aggressive disease compared to White men. The Internet is a popular source of health information and is commonly used by Black adults. However, Black adults are underrepresented in online content about prostate cancer. Given that medical mistrust is greater among Black compared to White adults, this study sought to evaluate the association between racial representation in online content about prostate cancer and trust in the content. A secondary objective was to identify additional attributes that influence trust in online content. Methods: This was a randomized trial of 2904 U.S. adults age ≥40. Participants were randomly assigned to view one of 8 different online videos. Videos used an equivalent script about either prostate cancer screening or clinical trials presented by one of 4 different presenters: Black physician, Black patient, White physician, or White patient. The primary outcome of the study was trust in the information using a Likert scale. Logistic regression models were applied to compare trust in the videos, based upon the characteristics of the speaker and topic of the video. Results: Study participants were 1703 (59%) Black and 1201 (41%) White adults. Black adults were 1.5 times more likely to trust a Black presenter compared to a White presenter (p<0.001). For White adults, no significant difference in trust was identified between Black or White presenters (p=0.21). For both Black and White adults, a physician presenting the information was more trusted than a patient, and videos discussing screening were more likely to be trusted than those discussing clinical trials (Table). Conclusions: Racial concordance is significantly associated with trust in prostate cancer information among Black adults. Additionally, health information is considered more trustworthy when delivered by a physician. These results highlight the importance of physicians in disseminating health information to the public, and of increasing racial diversity among healthcare providers. They also suggest an ongoing need for public education about clinical trials to prioritize issues of mistrust and distrust. [Table: see text]
BRCAAWAY: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects.
Authors: Hussain Maha H. A. , Kocherginsky Masha , Agarwal Neeraj , Zhang Jingsong , Adra Nabil , Paller Channing Judith , Picus Joel , Reichert Zachery R , Szmulewitz Russell Zelig , Tagawa Scott T. , Whang Young E. , Dreicer Robert , Kuzel Timothy , Bazzi Latifa , Gerke Travis A. , Daignault-Newton Stephanie , Chinnaiyan Arul , Antonarakis Emmanuel S.
Published: June 2022

5018

Background: The PARP-inhibitor olaparib is approved for mCRPC patients (pts) with deleterious germline or somatic homologous recombination repair gene mutations (HRRm). PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically PARP1-inhibition synergizes with androgen receptor (AR) targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating efficacy of targeting AR vs PARP vs combination in first line mCRPC patients with germline and/or somatic HRRm in BRCA1, BRCA2, or ATM. Methods: Eligible mCRPC pts underwent tumor next generation sequencing and germline testing. Pts with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (Abi/pred), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + Abi/pred. The primary end point is progression-free survival (PFS) analyzed using Kaplan-Meier estimates and Cox regression. Secondary endpoints include measurable disease response rate (RR) by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml) and toxicity. Arms 1 and 2 pts were allowed to cross over at progression. Pts with other HRRm were treated with olaparib; Arm 4 (ongoing). Results: 161 pts were registered and had NGS testing; 60 pts were randomized to Arms 1-3; to date 59 are evaluable for toxicity and 53 are evaluable for PFS. Baseline median age 67 (range 42-85) years; 54 pts were White, 6 were Black; sites of disease: bone only (n=31), soft tissue only (n=18), bone and soft tissue (n=10); median PSA 14.61 ng/ml (range 0.15-4036.8). Mutational status: BRCA1 only n = 2, BRCA2 only n = 39, ATM only n = 8, and > 1 HRRm n = 11. 34 pts had germline and 26 had somatic mutations. Median (range) follow-up time: 8.3 (0.8, 33.3), 12.2 (2.7, 21.8) and 16.8 (2.9, 41.7) months in Arms 1, 2 and 3. 43 pts had treatment-related adverse events; most common were fatigue (23 pts; 1 Grade (G) 3, 22 G1/2), nausea (17 pts, G1/2), and anemia (9 pts, 2 G3, 7 G1/2). ≥50% PSA decline was 79%, 67%, and 85% of pts in Arms 1, 2, and 3, respectively. Median PSA nadir (ng/mL) (95% CI) Arms 1-3: 2.17 (0.44, 49.27), 3.10 (0.83, 12.01), and 0.50 (0.10, 2.13), respectively. Undetectable PSA, median PFS, and 12-month PFS by Arm are listed in the table. Conclusions: In mCRPC pts with inactivating BRCA1, BRCA2 and/or ATM alterations Abi/pred + olaparib was well tolerated and resulted in longer PFS and better PSA response vs either agent alone. Clinical trial information: NCT03012321. [Table: see text]
Gene-by-gene analysis in the MAGNITUDE study of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Sandhu Shahneen , Attard Gerhardt , Olmos David , Efstathiou Eleni , Castro Elena , Rathkopf Dana E. , Smith Matthew Raymond , Roubaud Guilhem , Small Eric Jay , Gomes Andrea Juliana , Saad Marniza , Tural Deniz , Thomas Shibu , Urtishak Karen , Gormley Michael , Mason Gary , Diorio Brooke , Wang George C. , Lopez-Gitlitz Angela , Chi Kim N.
Published: June 2022

5020

Background: NIRA + AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations in the Phase 3 MAGNTUDE study. There is a paucity of data supporting use of PARP inhibitors in pts with HRR gene alterations other than BRCA1/2. We report on the efficacy of NIRA + AAP in pts with mCRPC and a qualifying single gene HRR alteration other than BRCA1/2. Methods: A pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate (ORR) across 186 pts (91 randomized to NIRA + AAP, 95 to PBO + AAP) with an alteration in the ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene (excluding cooccurring alterations) . This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity are also presented. Results: (Table). Pts with PALB2 or CHEK2 alterations had consistent improvement across all endpoints. In pts with ATM alterations benefit was observed in TCC, TSP, TPSA and ORR. There was benefit only in TPSA and ORR for pts with CDK12 alterations. When combined into functional groups, pts with an alteration in the HRR-Fanconi pathway ( BRIP1, FANCA, and PALB2) as well as pts with a HRR associated alteration ( CHEK2 or HDAC2) showed improvement in all endpoints. Conclusions: These data support the overall conclusions of the MAGNITUDE primary analysis and support benefit of NIRA + AAP in pts with HRR mutations beyond BRCA1/2. Clinical trial information: NCT03748641. [Table: see text]
The association of germline HSD3B1 genotype with outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) with or without enzalutamide (ENZA) [ARCHES].
Authors: Sharifi Nima , Azad Arun , Patel Mona , Hearn Jason W.D. , Wozniak Michele , Zohren Fabian , Sugg Jennifer , Haas Gabriel P. , Stenzl Arnulf , Armstrong Andrew J.
Published: June 2022

5022

Background: A common missense-encoding germline polymorphism in HSD3B1(1245A→C) stabilizes the 3βHSD1 enzyme and increases the rate-limiting step for metabolic flux from adrenal precursors to potent androgens. This adrenal-permissive HSD3B1(1245C) allele mechanistically drives more rapid progression after ADT in nonmetastatic and low-volume (LV) mHSPC. It is unknown whether upfront treatment with ENZA could improve these poor outcomes. We sought to determine the association between the HSD3B1 genotype and outcomes in ARCHES, a randomized, placebo (PBO)-controlled, phase 3 global study of ADT with ENZA or PBO in mHSPC. Overall, 31.3% of men on placebo crossed over to ENZA prior to progression. Methods: Germline DNA from 660 men (243 LV and 417 high volume [HV]) in ARCHES was genotyped for HSD3B1. Radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) outcomes, and overall survival (OS) were compared between men who inherited 0 (adrenal restrictive) vs. 1–2 copies of the HSD3B1(1245C) allele (adrenal permissive) using log-rank tests, Kaplan-Meier estimates, and Cox proportional hazards models for hazard ratios (HRs). Results: In ARCHES, 340 and 320 men had the adrenal-restrictive and adrenal-permissive HSD3B1 genotype, respectively. The adrenal-permissive genotype was not associated with worse rPFS, time to PSA progression (TTPP), or OS. Cox model HRs for death in the adrenal-permissive compared with adrenal-restrictive men in the ENZA + ADT and PBO + ADT arms were 1.21 (95% confidence interval [CI] 0.84, 1.74) and 1.48 (95% CI 0.98, 2.25), respectively. Three-year OS was 82% and 73% in men treated with ENZA + ADT with restrictive vs. permissive genotypes, respectively, and 68% and 70% in men treated with PBO + ADT. ENZA significantly improved rPFS, TTPP, and OS, irrespective of genotype. HRs for ENZA + ADT vs. PBO + ADT in models adjusted for genotype were: rPFS, 0.64 (p < 0.001); TTPP, 0.27 (p < 0.001), and OS, 0.62 (p < 0.001). Of OS events in the HSD3B1-genotyped men, 48 (23%) and 163 (77%) deaths occurred in the LV and HV groups, respectively. Conclusions: In men with mHSPC, ENZA improved OS, rPFS, and TTPP over PBO + ADT, irrespective of HSD3B1 genotype. Survival analysis of HSD3B1-genotyped men in this study is largely driven by men with HV disease. The analysis of men with LV disease was limited by the small number of events. Clinical trial information: NCT02677896.
Management of residual nonretroperitoneal disease in nonseminomatous germ-cell tumors (NSGCT).
Authors: King Jennifer , Kesler Kenneth , Ashkar Ryan , Althouse Sandra K. , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: June 2022

5034

Background: The management of NSGCT patients (pts) with post-chemotherapy residual non-retroperitoneal disease (RP) remains unsettled. Decisions for surveillance vs surgical resection are commonly steered by pathology from retroperitoneal lymph node dissection (RPLND). Data is limited in pts who do not require RPLND (normal or normalized RP post-chemo). Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with metastatic NSGCT who completed first-line chemotherapy and had residual extra-RP disease without residual RP disease. Pts with post-chemo non-RP surgical resection were included. Results: 134 pts met eligibility. Median age at diagnosis was 28.6 (range, 16.2-51.5). Primary tumor predominant histology was embryonal (35.1%), mixed (25.4%), seminoma (2.2%), yolk sac (9.7%), choriocarcinoma (15.7%), teratoma (11.2%). 76 pts (56.7%) had teratoma in the primary tumor. Metastatic sites at diagnosis were RP (15.7%), mediastinal LN (8.2%), lung (28.4%), liver (11.2%), bone (6.7%), brain (21.6%). Those with RP mets at diagnosis had normalization of RP nodes after chemo. IGCCCG risk was good in 57, intermediate in 21, and poor in 56 pts. Median pre-chemo AFP was 66 (0.9-467,000). hCG was 960.5 (0.5-1,300,000). First-line chemo was BEPX4 in 68, BEPx3 in 29, EPX4 in 10, VIPX4 in 9, and other in 18 pts. All pts had surgical resection of non-RP disease. None had RPLND. 84 pts had lung nodule resection, 16 had mediastinal LN, 8 had cervical LN, 5 had liver, 6 had bone, and 20 had brain met resection. Of the 76 pts with teratomatous elements in the orchiectomy, 41 (53.9%) had teratoma and 24 (31.6%) had non-teratoma GCT in post-chemo non-RP surgical specimens. Of the 58 pts without teratoma in the orchiectomy, 9 (15.5%) had teratoma and 34 (58.6%) had non-teratoma GCT in the non-RP surgical resection specimens. Teratoma in the orchiectomy was a predictor of non-RP teratoma (Fisher’s exact test P<0.0001). Conclusions: The presence of teratoma in orchiectomy predicts teratoma in residual post-chemo non-RP disease in pts who do not undergo RPLND. The absence of teratoma in orchiectomy should not preclude resection of residual non-RP disease given a subset of patients had persistent GCT. [Table: see text]
Anti-EGFR antibody plus anti-PD-1 antibody and chemotherapy as a neoadjuvant regimen for patients with locally-advanced penile squamous cell carcinoma: A prospective, single-arm, single-center, phase II clinical trial.
Authors: An Xin , Yan Ru , Guo Shengjie , Xue Ting , Ma Huali , Chen Meiting , Zhou Fangjian , Yao Kai , Dong Pei , Zhang Zhiling , Liu Zhuowei , Shi Yanxia , Han Hui
Published: June 2022

5037

Background: Advanced penile squamous cell carcinoma (PSCC) is a rare disease with a poor prognosis. We performed a monocentric, Simon’s two-stage phase II study to evaluate the efficacy and safety of PD-1 blockade plus anti-EGFR target therapy and chemotherapy as neoadjuvant therapy in patients with locally advanced PSCC. We previously reported promising results in the first stage. The enrollment of the second stage had been completed by January 2022, herein we reported the updated results. Methods: Patients with chemotherapy-naive, locally-advanced PSCC (cT4 or cTxN3M0) were enrolled. The neoadjuvant regimen consists of anti–PD-1 antibody toripalimab, anti–EGFR antibody nimotuzumab, and chemotherapy (albumin-bound paclitaxel plus cisplatin and ifosfamide). Curative surgery was performed following a maximum of four cycles of treatment. The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include overall response rate (ORR), relapse-free survival (RFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: A total of 29 patients were enrolled in two stages, with a median age of 57 (range 31-71) years. Till January 2022, 21 patients had completed the neoadjuvant treatment, 17 (81%) achieved an objective response, (CR 5, PR 12), 2 had SD, and 2 showed PD. Among 18 patients who underwent radical surgery, 11 showed no residual tumor on histopathology, with a pCR rate of 61.1% (11/18). The median follow-up time was 10.6 months. Two patients with PD died from disease, and 2 patients who experienced disease relapsed after radical surgery, in which 1 with SD, and 1 with PR. No relapse was observed among patients with pCR. The survival data are still immature. No unexpected toxicities and treatment-related death were recorded. Five out of 21 (23.8%) patients experienced grade 3 or 4 TRAEs. Grade 3 neutropenia occurred in 3 (14.3%) patients with 10 used G-CSF prophylaxis. No febrile neutropenia occurred. Other grades 3 toxicities included 1 case of peripheral sensory neuropathy and 1 anemia. The most common grade 1/2 TRAEs were alopecia (100%), decreased appetite (85.7%), nausea (71.4%), peripheral sensory neuropathy (66.7%), anemia (66.7%), neutropenia (33.3%), and infusion-related reactions (28.6%). The most common immune-related adverse events (IRAEs) were grade 1/2 hypothyroidism (19.0%), and grade 1 hyperthyroidism (4.8%). No severe IRAEs including pneumonitis, colitis, and myocarditis were observed. Conclusions: The triple combination is a provoking safe and efficacious neoadjuvant regimen for patients with advanced PSCC. Clinical trial information: NCT04475016.
Molecular correlates of high B7-H3-expressing metastatic castrate-resistant prostate cancers (mCRPC) via exome, transcriptome, and epigenome analyses.
Authors: Shi Xiaolei , Day Abderrahman , Bergom Hannah E. , Tape Sydney , Baca Sylvan , Ryan Charles J. , Zorko Nick , Antonarakis Emmanuel S. , Hwang Justin
Published: June 2022

5045

Background: mCRPC is a lethal condition with limited effective treatment options. B7-H3, a transmembrane protein of the B7 checkpoint superfamily is overexpressed in prostate cancer (PC) and is associated with poor prognosis. While several novel approaches target B7-H3 in prostate cancer, lack of knowledge about the molecular features and regulatory mechanisms of B7-H3 expression in mCRPC prevents the optimal design of these interventions. We aimed to characterize B7-H3 in mCRPC with the purpose to reveal the roles of B7-H3 in mCRPC pathogenesis, and stratify the patient population optimal for B7-H3–targeted therapies. Methods: We conducted bioinformatic interrogations at genome-scale on whole-exome and whole-transcriptome sequencing (WES, WTS) data from SU2C/PCF (n = 209, mCRPC), SUWC (n = 101, mCRPC) and GTEx (n = 246, benign prostate tissue). We developed and utilized novel machine learning (ML) algorithms to examine the association of B7-H3 with other key PC pathways. We examined the genetic and epigenetic regulation of B7-H3 by CHIP-seq. We also performed single-cell mRNA sequencing (scRNA-seq) analysis on one patient before and after treatment with the AR inhibitor, enzalutamide. We utilized both Gene Set Enrichment Analysis (GSEA) and our ML approaches to identify enriched signaling pathways in high B7-H3–expressing mCRPC. Results: Expression of B7-H3 was significantly elevated in mCRPC compared to benign prostate tissues, and was distinctive from other B7 family members. High B7-H3 expression was significantly associated with ERG fusions, AR-V7 variant, and increased FOXA1 and androgen receptor (AR) mRNA expression. At gene-level analysis, our ML algorithm suggested that B7-H3 shared similar gene networks as AR and its co-regulators, HOXB13, and FOXA1. CHIP-seq analysis revealed that the distal enhancers of B7-H3 in mCRPC were hyperactive (based on enhanced H3K27Ac marks) relative to primary tumors. Notably, these B7-H3 enhancers were bound by HOXB13, FOXA1 and AR in mCRPC samples. Our scRNA-seq analysis of one patient resistant to enzalutamide showed increased number of B7-H3-expressing cells. Based on integrated GSEA and ML analyses on WTS data, B7-H3 was positively associated with TGF-beta signaling, an enzalutamide resistance pathway. Conclusions: In mCRPC, we found B7-H3 overexpression as compared to other B7 family members. The association of B7-H3-high expression and certain genomic alterations may stratify mCRPC patients for B7-H3–targeted therapy. Further, B7-H3 exhibited regulation by AR, HOXB13 and FOXA1, at the B7-H3 enhancers. The activating epigenetic modification at the distal enhancers represents another potential marker to examine B7-H3 expression in tumors. Altogether, our study indicates that B7-H3 is a critical target in mCRPC patients, including those resistant to enzalutamide.
On-treatment plasma ctDNA fraction and treatment outcomes in metastatic castration-resistant prostate cancer.
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Ng Sarah , Kwan Edmond Michael , Annala Matti , van Oort Inge M. , Schalken Jack A. , Van Erp Nielka P. , Wyatt Alexander William , Mehra Niven
Published: June 2022

5051

Background: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naive metastatic castration-resistant prostate cancer (mCRPC), but primary or rapidly acquired resistance is common. Early identification of resistant disease is critical for improving management strategies. We investigated whether on-treatment changes in plasma ctDNA fraction (ctDNA%; the proportion of cell-free DNA that is tumor-derived) associate with ARPI treatment outcomes. Methods: We collected serial plasma cell-free DNA from 81 patients with mCRPC: at baseline and following 4 weeks of treatment during two prospective multi-center observational studies (NCT02426333; NCT02471469). CtDNA% was calculated by integrating deep targeted and shallow whole-genome sequencing. Samples were dichotomized at above and below 1%, and designated as high or low ctDNA%, respectively. Outcome measurements were radiographic and/or clinical progression-free survival (rcPFS) and overall survival (OS). Non-durable responses were defined as rcPFS < 6 months, excluding patients with PSA progression alone (n = 3) or treatment cessation for toxicity (n = 4). Results: Median follow-up was 27.4 months (IQR 17.7-34.9). CtDNA% was high in 47/81 (58%) patients at baseline and 29/81 (36%) patients at 4 weeks. The median ctDNA% for patients with high ctDNA was 15.0% (IQR 4.9-43.8%) at baseline and 5.0% (IQR 2.0-20.6%) at 4 weeks. High baseline ctDNA% was prognostic for rcPFS and OS (Table). RcPFS and OS was shortest for patients that retained high ctDNA% at 4 weeks. However, patients converting from high to low ctDNA% at 4 weeks did not experience different outcomes to patients with low ctDNA at both timepoints. ctDNA% associations with rcPFS and OS were independent of established clinical prognostic factors. 23/27 (85%) patients experiencing non-durable responses had high ctDNA% at baseline and 4 weeks. Only 3/47 patients (6%) experiencing durable responses had high ctDNA% at both timepoints. Sensitivity and specificity for predicting non-durable response was 85% and 94%, respectively. Conclusions: Early changes in ctDNA% are strongly linked to duration of first-line ARPI treatment benefit in mCRPC and may have utility for informing clinical trials testing early therapy switches in patients unlikely to experience durable disease responses. Clinical trial information: NCT02426333; NCT02471469. [Table: see text]
Health-related quality of life (HRQoL) and pain in the MAGNITUDE study of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Rathkopf Dana E. , Roubaud Guilhem , Chi Kim N. , Sandhu Shahneen , Efstathiou Eleni , Attard Gerhardt , Olmos David , Lee Ji Youl , Small Eric Jay , Gomes Andrea Juliana , Saad Marniza , Castro Elena , Tural Deniz , Mason Gary , Bevans Katherine B. , Trudeau Jeremiah , Francis Peter St. John , Wang George C. , Lopez-Gitlitz Angela , Smith Matthew Raymond
Published: June 2022

5060

Background: Results from the international, randomized, double-blind, phase 3 MAGNITUDE study demonstrated that NIRA + AAP improved radiographic progression-free survival, time to cytotoxic chemotherapy, and time to symptomatic progression, with manageable toxicity in pts with mCRPC and HRR alterations (9-gene panel). Here, we report HRQoL and pain in MAGNITUDE. Methods: Eligible pts with mCRPC and HRR alterations were randomized 1:1 to NIRA + AAP or placebo (PBO) + AAP orally daily in 28-day cycles. Pts had ECOG status ≤1 and a Brief Pain Inventory–Short Form (BPI-SF) worst pain score ≤3 in prescreening. HRQoL assessments on day 1 of specified cycles included Functional Assessment of Cancer Therapy–Prostate (FACT-P) and BPI-SF. Changes from baseline were compared between treatment arms using repeated measures analysis. Proportional hazards regression models were used to compare time to deterioration (TTD) in worst pain intensity between arms. Results: Compliance for FACT-P and BPI-SF was > 80%. Most pts maintained low pain levels over time. Repeated measures analyses showed no clinically meaningful differences in pain over time or between arms. Median TTD in pain intensity was not reached in either arm. At the 25th percentile, there was a trend toward longer TTD in pain intensity with NIRA + AAP vs PBO + AAP (11.1 vs 10.1 mo; HR, 0.87; 95% CI, 0.61-1.24). HRQoL was maintained with NIRA + AAP, with no clinically meaningful differences in FACT-P total score over time or between arms. There was a trend toward greater worsening in early cycles on FACT-P physical wellbeing with NIRA + AAP vs PBO + AAP, driven by events within the known safety profile of NIRA + AAP (worsening of side effect bother, lack of energy, and nausea); however, overall, most pts reported minimal side effect burden (Table). Conclusions: In MAGNITUDE, most pts maintained low pain levels and positive HRQoL over time, with no clinically meaningful differences between treatment arms, further supporting the use of NIRA + AAP in pts with mCRPC and HRR alterations. Side effect burden was perceived as low in both arms. Although more pts on NIRA+AAP reported worsening side effects, the symptoms were generally perceived as mild. Clinical trial information: NCT03748641. [Table: see text]
Genomic aberrations associated with overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or placebo (PBO) plus androgen deprivation therapy (ADT) in TITAN.
Authors: Agarwal Neeraj , Lucas Justin , Aguilar-Bonavides Clemente , Thomas Shibu , Gormley Michael , Chowdhury Simon , Merseburger Axel S. , Bjartell Anders , Uemura Hirotsugu , Özgüroğlu Mustafa , McCarthy Sharon , Brookman-May Sabine D. , Lefresne Florence , Mundle Suneel , Chi Kim N.
Published: June 2022

5066

Background: TITAN, a phase 3 PBO-controlled study in patients (pts) with mCSPC, showed APA + ADT improved radiographic progression-free survival and OS vs PBO + ADT. In this exploratory analysis, we report the relationships between biomarkers and OS in TITAN. Methods: Circulating tumor (ct)DNA and genomic aberrations in 17 PC-related genes, including androgen receptor (AR), were assessed at baseline (BL; 114 pts) and end of study treatment (EOST; 129 pts) using next-generation sequencing. ctDNA was assessed qualitatively; genomic aberrations were assessed within ctDNA-positive samples as inactivation (heterozygous/homozygous deletion or single nucleotide variant [SNV]) or activation (amplification or SNV). Associations of detected ctDNA/aberrations at BL or EOST with OS, and biomarkers at EOST with OS on subsequent therapies, were evaluated using univariate or multivariate analyses and Cox proportional hazards model; results were stratified by treatment arm. Results: Among pts from both treatment groups, 36% had detectable ctDNA, of which 27% had any genomic AR aberration and 24% had AR gene amplification at BL; prevalence of these biomarkers increased significantly from BL to EOST (Table). The most prevalent non-AR aberrations at BL ( TP53, homologous recombination repair [HRR] pathway, PTEN, RB1, and PIK3CA genes) increased at EOST but not significantly (Table). Among assessed aberrations, presence of ctDNA or any AR genomic aberrations at BL (HR, 1.9 or 6.7; all p < 0.05) and any AR genomic aberrations or PI3K pathway activation at EOST (1.7, p < 0.05 or 2.2, p < 0.001) was significantly associated with poor OS in multivariate analyses from both treatment groups. In univariate analyses of pts who received subsequent therapy (chemotherapy: 106; hormonal therapy: 161), worse OS was associated only with PIK3CA activation, PI3K pathway activation, or TP53 inactivation at EOST (3.7, p < 0.05; 2.4, p < 0.05; 3.0, p < 0.01, respectively) in chemo-treated pts. A small sample size in some biomarker subgroups limits interpretation. Conclusions: These hypothesis-generating data from TITAN show that presence of ctDNA or select AR and non-AR biomarkers at BL or EOST were associated with poor OS. The predictive value of these biomarkers for survival in mCSPC needs further confirmation. Clinical trial information: NCT02489318. [Table: see text]
Feasibility of a novel wrist-worn thermal device for management of vasomotor symptoms in patients with prostate cancer.
Authors: Morgans Alicia K. , Billes Sonja K , Vetter Andrew , Naghavi Nader , Le Diana , Smith Matthew , Peeke Pamela
Published: June 2022

5067

Background: Vasomotor symptoms (VMS), or hot flashes, are a common side effect of androgen deprivation therapy (ADT) for prostate cancer (PCa). VMS negatively impact sleep, fatigue, and quality of life (QOL) in PCa survivors. There are few nonpharmacological treatments for VMS. The Embr Wave is a wearable thermal device that applies cooling to thermoreceptors on the inside of the wrist and has been associated with patient reported decreases in hot flash interference in women. We performed a single-arm feasibility study evaluating the Embr Wave for management of VMS in PCa survivors. Methods: 57 PCa survivors reporting bothersome hot flashes were enrolled and instructed to use the device as needed for VMS during the 4-week study. The primary outcome was device usage recorded by the device (minutes and sessions). Additional outcomes included the change in patient reported Hot Flash Related Daily Interference Scale (HFRDIS, range 0-10) and Patient Reported Outcomes Measurement Information System Sleep Disturbance 4a (PROMIS SD, range 0-100) and Sleep Related Impairment 8a (PROMIS SRI, range 0-100). Study procedures were conducted remotely using a virtual clinical trial management platform. Results: The study was conducted from May to Dec 2021 in the US. 44 men completed the study; 39 had retrievable usage data. Median age was 66 (range 57-78) years and median 3 (1-23) years since PCa diagnosis. The most common hormonal treatments were leuprolide (n=22), abiraterone (n=13), and enzalutamide (n=6). Baseline scores indicated moderate hot flash interference and mild sleep disturbance (Table). Mean±SD (median) usage of the Embr device was 3.2±2.5 (2.3) hours and 7.6±3.6 (7.5) sessions per day. 26 (67%) participants reported using the device 7 days/nights each week. Improvements were observed in HFRDIS, PROMIS SD, and PROMIS SRI scores (Table). There were also improvements in subjective ratings of hot flash frequency, duration, interference with daily life/sleep, bothersomeness and control (all p<0.01). The majority (69%) of participants reported that the device was effective at helping them manage hot flashes. No adverse events were reported. Conclusions: Results of this study support the feasibility of use of the thermal device for management of bothersome hot flashes in PCa survivors. Future randomized controlled studies are warranted to evaluate patient reported outcomes related to frequency and severity of VMS, sleep quality, fatigue, and overall QOL, in addition to defining the potential utility of the Embr thermal device in PCa survivors experiencing VMS. Clinical trial information: NCT04892914. [Table: see text]
Clinical outcomes and safety of enzalutamide (ENZA) plus androgen-deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) in patients aged < 75 and ≥ 75 years: ARCHES post hoc analysis.
Authors: Szmulewitz Russell Zelig , Holzbeierlein Jeffrey , Azad Arun , Iguchi Taro , Villers Arnauld , Alcaraz Antonio , Alekseev Boris , Shore Neal D. , Rosbrook Brad , Zohren Fabian , Ma Jie , Haas Gabriel P. , Gomez-Veiga Francisco , Stenzl Arnulf , Armstrong Andrew J.
Published: June 2022

5069

Background: Patients with metastatic prostate cancer aged ≥75 years have a poorer prognosis compared with younger patients. In ARCHES (NCT02677896), ENZA + ADT improved radiographic progression-free survival (rPFS), overall survival (OS), and other key secondary endpoints vs. placebo (PBO) + ADT in patients with mHSPC. Final OS results confirmed a long-term survival benefit with ENZA + ADT. This post hoc analysis of ARCHES data investigated OS and other clinical outcomes in patients aged <75 and ≥75 years. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. Subgroup analysis was performed in patients aged <75 and ≥75 years. Efficacy and safety outcomes were compared across treatment arms. Results: Of the ARCHES population, 339 patients (29.5%) were aged ≥75 years (ENZA + ADT, n=170; PBO + ADT, n=169); PBO patients crossing over to ENZA were aged: <75 years, n=133; ≥75 years, n=47. Some differences in baseline characteristics were observed between age groups, such as higher prior docetaxel use in patients aged <75 years (ENZA + ADT, 21.0%; PBO + ADT, 20.4%) vs. those aged ≥75 years (ENZA + ADT, 10.6%; PBO + ADT, 11.2%). When compared to PBO + ADT, ENZA + ADT improved OS and other secondary efficacy endpoints in both age groups without evidence of statistical heterogeneity (Table); however, 95% confidence intervals for OS and rPFS hazard ratios spanned 1 in the older age group. The safety profile of treatment arms was generally similar in both age groups, with a higher incidence of falls, cognitive impairment, and cardiovascular events among elderly patients receiving ENZA + ADT vs. PBO + ADT. Conclusions: This post hoc analysis of ARCHES data demonstrated that ENZA + ADT provides clinical benefit and is generally well-tolerated in patients with mHSPC aged ≥75 years, supporting the therapeutic role of ENZA in these patients. Clinical trial information: NCT02677896. [Table: see text]
Eight-year survival rates by baseline prognostic groups in patients with metastatic hormone-sensitive prostate cancer (mHSPC): An analysis from the ECOG-ACRIN 3805 (CHAARTED) trial.
Authors: Tripathi Abhishek , Chen Yu-Hui , Jarrard David Frazier , Hahn Noah M. , Garcia Jorge A. , Dreicer Robert , Liu Glenn , Hussain Maha H. A. , Shevrin Daniel H. , Cooney Matthew M. , Eisenberger Mario A. , Kohli Manish , Plimack Elizabeth R. , Vogelzang Nicholas J. , Picus Joel , Carducci Michael Anthony , DiPaola Robert S. , Sweeney Christopher
Published: June 2022

5081

Background: To date there is no prospective survival data beyond 5 years for patients treated with ADT with or without docetaxel (D) when analyzed by well-defined baseline prognostic risk groups and treatment arms. In this updated analysis of the CHAARTED trial, we report the 8-year survival rate based on disease volume and metachronous vs. de novo metastatic disease status with ADT without or with docetaxel. Methods: An updated survival sweep was conducted in February 2022. Patients were prospectively identified by the state of metastatic disease as metachronous (prior local therapy) vs. de novo and low volume (LV) vs. high volume (HV; visceral and/or ≥4 bone metastases with one lesion beyond the vertebral bodies or pelvis) disease. Overall survival (OS) was defined as time from randomization to death or date last known alive and calculated using the Kaplan-Meier method. Results: Of the 790 patients randomized (last patient enrolled December 2012), 238 patients were still alive with a median follow up of 9.7 years for patients still alive. Median OS in the overall population was 60.4 and 47.2 mos in the ADT+ D and ADT arms respectively (Table; HR: 0.77; 95% CI: 0.65, 0.92; p=0.004). ADT+ D was associated with significantly higher 8-yr OS rate (28.5%) compared to ADT arm (15.4%; HR: 0.67; 95% CI: 0.53, 0.84; p=0.0005) in the de novo HV group (n=421). Notably, the 8-yr OS rates were almost doubled for patients with HV disease with early docetaxel (16% vs.30.2%, p<.0001) and this was seen in patients with both de novo and metachronous HV mHSPC. Conclusions: In this long-term updated analysis, ADT+D continued to demonstrate significantly improved OS in the overall population and this is still most clearly evident in patients with de novo HV mHSPC. Our findings highlight the role of baseline prognostic risk groups in predicting longer term survival and benefits from treatment intensification. Clinical trial information: NCT00309985. [Table: see text]
Recurrence, metastasis, and survival after radical prostatectomy in the era of advanced treatments.
Authors: Stensland Kristian D. , Caram Megan Veresh , Burns Jennifer A. , Sparks Jordan B. , Shin Chris , Zaslavsky Alexander , Hollenbeck Brent K. , Tsodikov Alexander , Skolarus Ted A.
Published: June 2022

5090

Background: Accurate survival estimates after prostatectomy are critical for patient counseling, treatment decisions, and trial design. Prior prostate cancer natural history studies may not reflect contemporary outcomes and often lack key endpoints (e.g. incident metastases). For these reasons, we explored population-based recurrence and survival following radical prostatectomy. Methods: We conducted a retrospective study of men with localized prostate cancer treated with radical prostatectomy from 2005-2015 with follow up through 2019 in the Veterans Health Administration. We excluded men with adjuvant radiation or hormonal therapy and defined biochemical recurrence (BCR) as a PSA ≥0.2 ng/mL. We used a validated natural language processing encoded dataset to identify incident metastatic disease. We then estimated actuarial time from surgery to BCR, BCR to metastatic disease, and metastatic disease to death using Kaplan-Meier methods. Results: Of 22,033 men post-prostatectomy, 5,963 (27%) developed BCR, with 5- and 10-year BCR estimates of 21% and 29% (Table). Of 5,963 men with BCR, 678 (11%) developed metastasis, with 5- and 10-year metastasis-free survival from time of BCR of 91% and 77%. Of these 678 men with metastases, 235 died (35%), with 5- and 10-year overall survival of 61% and 47%. Median actuarial overall survival from incident metastatic disease was 8.8 years. Conclusions: On average, we found a man undergoing radical prostatectomy for localized prostate cancer can expect about a 1 in 4 chance of biochemical recurrence. Of men with BCR, we identified a 1 in 10 chance of developing metastases, surviving nearly 9 years after incident metastasis. Both metastasis-free survival after biochemical recurrence and overall survival after developing metastasis appear to have lengthened consistent with a long natural history after prostate cancer surgery. Novel advanced prostate cancer treatments may help explain these findings, though their optimal use warrants further study especially as advanced imaging techniques to characterize recurrence increase. [Table: see text]
Clinical and biomarker results of neoadjuvant phase II study of pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer (TNBC) (NeoPACT).
Authors: Sharma Priyanka , Stecklein Shane Richard , Yoder Rachel , Staley Joshua M. , Schwensen Kelsey , O'Dea Anne , Nye Lauren Elizabeth , Elia Manana , Satelli Deepti , Crane Gregory , Madan Rashna , O'Neil Maura F. , Wagner Jamie L. , Larson Kelsey E. , Balanoff Christa , Phadnis Milind A. , Godwin Andrew K. , Salgado Roberto , Khan Qamar J. , O'Shaughnessy Joyce
Published: June 2022

513

Background: Addition of pembrolizumab to anthracycline-taxane-platinum chemotherapy improves pathologic complete response (pCR) and event free survival (EFS) in TNBC. Aim of this study was to assess the efficacy of the anthracycline free neoadjuvant regimen of pembrolizumab plus carboplatin plus docetaxel (Cb+D) in TNBC. Methods: In this multicenter study, eligible patients with stage I-III TNBC received carboplatin (AUC 6) + docetaxel (75 mg/m2) + pembrolizumab (200 mg) every 21 days x 6 cycles. The primary endpoint was pCR (no evidence of invasive tumor in breast and axilla). Secondary endpoints were residual cancer burden (RCB), EFS, toxicity, and immune response biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next generation sequencing. Samples were classified as DNA Damage Immune Response (DDIR) signature and DetermaIO signature positive/negative using predefined cutoffs. Evaluation of stromal tumor infiltrating lymphocytes (sTILs) was performed using standard criteria. Results: 117 patients were enrolled from September 2018 to January 2022. 18% were African American, 39% had node positive disease, 88% had stage II/III disease and 15% had ER/PR 1-10%. Pathologic response information is available for 105 patients. pCR and RCB 0+1 rates were 60% (95% CI 51%-70%) and 71% (95% CI 62%-80%), respectively. Treatment related adverse events led to discontinuation of any trial drug in 12% of patients. Immune adverse events were observed in 28% of patients (Grade ≥3=6%). 47% of patients had sTILs ≥30%, 48% were DetermaIO positive, and 61% DDIR positive. The table describes the impact of these biomarkers on pCR and RCB. The areas under the prediction curve (AUC) for pCR were 0.660, 0.709, and 0.719 for DDIR, sTILs, and DetermaIO respectively. At a median follow up of 21 months, 2-year EFS is 88% in all patients; 98% in pCR group and 82% in no pCR group. Conclusions: Neoadjuvant pembrolizumab plus Cb+D regimen yields pCR of 60% and 2-year EFS of 88% in the absence of adjuvant pembrolizumab. The regimen was well tolerated, and no new toxicity signals were noted. Immune enrichment identified by sTILs or DetermaIO signature was associated with high pCR rates approaching or exceeding 80%. PD-L1 and additional biomarker analyses are ongoing. Clinical trial information: NCT03639948. [Table: see text]
Effect of mevalonate pathway inhibitors on outcomes of patients (pts) with HER2-positive early breast cancer (BC) in the ALTTO trial.
Authors: De Angelis Carmine , Veeraraghavan Jamunarani , Sethunath Vidyalakshmi , Ameye Lieveke , Paesmans Marianne , El-Abed Sarra , Choudhury Anup , Napoleone Sylvia , Chumsri Saranya , Piccart-Gebhart Martine J. , Moreno-Aspitia Alvaro , Gomez Henry Leonidas , Viale Giuseppe , Hilsenbeck Susan G. , Rimawi Mothaffar F. , Osborne C. Kent , de Azambuja Evandro , Schiff Rachel
Published: June 2022

522

Background: Our preclinical findings suggest a role for the mevalonate pathway (MVA) in treatment resistance in HER2+ BC by providing alternative growth and survival signaling to bypass potent HER2 blockade, which could be overcome by the MVA inhibitors statins and nitrogen-containing bisphosphonates (NBs). Here we explored the effect of MVA inhibitors’ use on pts’ outcomes in the ALTTO trial (BIG2-06; NCT00490139). Methods: In the ALTTO trial, 8381 pts with HER2+ BC were randomized to 1 year of adjuvant lapatinib (L), trastuzumab (T), L+T, or T→L. All pts with documented treatment start with statins or NBs < 1 year after randomization were considered as MVA inhibitors users. Survival curves, with a median follow-up of 6.9 years, for disease-free survival (DFS), distant relapse-free interval (DRFI), BC-specific survival (BCSS), and overall survival (OS) according to MVA inhibitors use were estimated by the Kaplan Meier method and Log-rank test. All multivariate survival analyses employed a Cox proportional hazards regression model, adjusting for tumor size, nodal status, hormonal receptor (HoR), menopausal status, BMI, timing of chemo, and randomization arm. We considered interactions terms in Cox’s model between MVA inhibitors use and randomization arm, hormonal status, and BMI group. Results: Among the 8381 pts included in this study, 493 and 299 were statins or NBs users, respectively. Table 1 summarizes the significant differences in pts’ characteristics according to MVA inhibitors use ( P <.005). In multivariate survival analyses, only NBs use was associated independently with better BCSS (HR, 0.44; 95% CI, 0.23 - 0.84; P = 0.014). Statin use was not independently associated with prognosis but only in interaction with pts characteristics: worse DFS, BCSS and OS in pts treated with L+T, worse DRFI and OS in pts treated with HoR+ BC (respective interaction P-values <0.05 in the Cox’s model). Conclusions: NBs independently predicted improved BC-specific outcome in pts with HER2+ BC treated with adjuvant anti-HER2 therapy. Statin use was associated with an inferior outcome in pts with HoR+ disease and/or those treated with L+T. Whether this inferior association in statin users may reflect the underlying predisposition factors that can weaken the efficacy of anti-HER2 treatments and whether this effect was observed only in the L+T arm due to the more potent inhibition of the HER2 signaling pathway remain open questions. Further clinical investigations on the impact of MVA inhibitors on the outcome of pts with HER2+ BC are warranted. [Table: see text]