bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal variability in symptom burden for patients with prostate cancer (PC).
Authors: Wong Risa Liang , Cheng Heather H. , Fann Jesse R. , Hnida James , Chakoian Marty , Jannat Samia , Schenker Yael , Yu Evan Y. , Gore John L.
Published: June 2023

e17019

Background: Patients with PC often live for many years and can experience burdensome symptoms associated with PC and its treatment. The longitudinal fluctuations in symptom burden for a given individual with PC, or for groups with different PC disease states, are not well-described. We assessed self-rated performance status (PS), pain interference with daily activities, bother from sexual dysfunction, depression, and anxiety symptoms longitudinally for a cohort of patients with PC. Methods: For one year, patients with PC and ≥1 Urology or Medical Oncology clinic visit in the prior 6 months were emailed surveys every 60 days containing the ECOG PS instrument (range 0-4, higher scores = worse PS), PROMIS Pain Interference Short Form 4a (normalized range 1-5, higher scores = greater pain interference), PROMIS Sexual Bother (Male) items SFBOT 204, 205, and 206 (normalized range 1-5, higher scores = greater bother), PHQ-9 depression scale (range 0-27, score ≥10 considered positive for moderate symptoms), and GAD-7 anxiety scale (range 0-21, score ≥10 considered positive for moderate symptoms). We used chart review to obtain baseline characteristics and one-way ANOVA for comparisons. Results: For 201 enrolled patients, mean (SD) number of surveys completed was 5.8 (1.8) over a mean (SD) of 10.6 (3.1) months. At baseline, 50.7% had localized PC (LPC), 18.9% biochemically recurrent PC (BCR-PC), and 30.3% metastatic PC (MPC). 40.8% of patients were on androgen deprivation therapy, which was not associated with greater sexual bother (p = 0.17). Mean (SD) values for ECOG PS, pain interference, sexual bother, the PHQ-9, and the GAD-7 are shown by PC disease state (Table). For patients who completed ≥2 surveys (N = 192), mean (SD) ranges for these scales were 0.4 (0.6), 0.8 (0.9), 1.2 (0.8), 3.7 (3.3), and 2.6 (2.6), respectively. Mean range differed by PC disease state for ECOG PS (0.31 LPC vs 0.63 BCR-PC vs 0.59 MPC, p = 0.003) and pain interference (0.63 LPC vs 1.02 BCR-PC vs 0.95 MPC, p = 0.03). For patients with ≥1 positive PHQ-9 (N = 36) or GAD-7 (N = 11) screen over ≥2 surveys, a mean (SD) of 41% (30%) and 39% (33%), respectively, of their total screens were positive. Mean (SD) ranges for these patients were 8.4 (3.6) for the PHQ-9 and 8.5 (3.4) for the GAD-7 (both p < 0.001 compared with those who never screened positive). Conclusions: Patients with more advanced PC had worse PS, pain, and depression, but those with BCR-PC reported greater longitudinal fluctuations in PS and pain. Patients who screened positive for depression or anxiety only did so in ~40% of their surveys, and had greater longitudinal variability in their PHQ-9/GAD-7 scores than those who never screened positive. [Table: see text]
Testicular GERM cell tumors treatment outcome in a national cancer institution in Peru.
Authors: Rioja Patricia , Valencia Guillermo , Morante Zaida , Fuentes Hugo , Mantilla Raul , Salinas Agramonte Luis André , Sanchez Alarcon Jorge Luis , Vidaurre Tatiana , Neciosup Silvia P.
Published: June 2023

e17031

Background: Testicular germ cell tumor (TGCT) is the most common neoplasm in young men and the incidence has been increasing over the last few decades, especially among Hispanic men. Multidisciplinary management is associated with excellent oncological outcomes. Here, we describe the treatment outcome of TGCT patients treated in single institution in Peru. Methods: We conducted a retrospective study of TGCT treated at Instituto Nacional de Enfermedades Neoplasicas from 2016 to 2019. Clinical and pathological data were collected from medical records. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method and compared with long-rank test. A level of p < 0.05 was considered significant. The statistical package SPSS v19 was used for the data analysis. Results: 221 patients were identified, 56% were non-seminomatous (NS) and 44% were seminomatous (S). Orchiectomy was performed in 94% of patients, only 6% underwent orchiectomy after chemotherapy. In both groups, the treatment regimens were: BEP (Bleomycin/Etoposide/cisplatin) 90%, Carboplatin 8.1% and EP (Etoposide/Cisplatin) 1.8%. 42 (21%) of patients receive rescue therapy, being the most frequent TIP (paclitaxel/ifosfamide/cisplatin). In NS patients, 5-year PFS was superior in good risk compared with poor risk (100% vs. 86%, p = 0.028) and for tumor markers level, S0 was superior to S3 (100% vs. 82%, p = 0.008). In S, 5-year PFS was no significant in any of groups of analysis. With a median follow-up of 57 months, OS in NS was 91%, 83% and 81% in 12, 36 and 60 months, respectively and OS in S was 96%, 87% and 87% in 12, 36 and 60 months, respectively. The analysis of 5-year OS according to clinical stage and risk stratification are shown in the Table 1. Only 2 patients received high-dose chemotherapy and still in complete response. Conclusions: Despite the high incidence of advanced TGCT, our patients had excellent survival results; being lower in those with CS III (both NS and S groups), poor risk and S3 for NS, and intermediate risk for S. Multidisciplinary management in a high volume institution is important for better outcomes in our patients. [Table: see text]
Retrospective review of 250 gallium-68 PSMA scans in prostate cancer patients in Health Canada Special Access Program.
Authors: Cohen Philip Frank , Tarzwell Robert , Leong Jason
Published: June 2023

e17035

Background: Prostate Cancer is the most common malignancy in men, and until recently has been staged using standard imaging tests, such as ultrasound, CT, bone scan, and MRI. A novel imaging test targeting the membrane receptor, Prostate Specific Membrane Antigen (PSMA) using the PET tracer Ga-68 PSMA-11 has recently been approved in several countries for staging and assessing potential for radionuclide therapy. This agent was only recently approved in Canada, but has been available through the Health Canada Special Access (SA) Program for over a year, until it was approved (Illuccix, Telix Pharmaceuticals). Methods: In the past year, 275 prostate cancer patients were scanned at our facility (INITIO Medical Imaging, Burnaby BC) through Health Canada SA. All patients were required to have positive prostate cancer biopsies, with negative or indeterminate CT and bone scan, and rising PSA (prostate specific antigen) blood test in order to qualify for SA, or high risk Gleason Score prostate cancer. Results: Of the 275 patients, 71 had high risk cancers and 28/71 had positive PSMA studies (39%). 185 of the patients had biochemical evidence of recurrence and negative /indeterminate conventional imaging tests, and 101/185 or 55% had positive PSMA scans. All other patients were scanned for metastatic castrate resistant prostate cancer (MCRPC). Conclusions: Ga-68 PSMA scans are highly sensitive for upstaging patients at high risk of prostate cancer metastasis or recurrence, even with negative conventional imaging studies.
Therapy with metronomic cyclophosphamide (mCyc) in metastatic castrate resistant prostate cancer (mCRPC) and genomic correlates.
Authors: Mar Nataliya , Dwabe Sami , Zarrabi Kevin Kayvan , Eturi Aditya , Kelly William Kevin , Rezazadeh Arash
Published: June 2023

e17041

Background: Multiple historic studies demonstrated activity of mCyc in various solid tumors, including mCRPC. Low doses of oral mCyc can lead to enhanced immune stimulation by depleting regulatory T-cells. Its adverse effect profile is well established, with grade 3 and 4 toxicities being rare. In recent years, use of mCyc in mCRPC has fallen out of favor with development of novel therapies. Methods: We conducted a retrospective study of all patients with mCRPC, who received therapy with mCyc for at least 4 weeks at the University of California Irvine and Thomas Jefferson University between 6/1/17 and 1/31/23. Different oral mCyc regimens were included - 50 mg daily continuously, 50 mg daily on days 1 to 14 out of a 28-day cycle, and 250 mg daily on days 1 to 14 out of a 28-day cycle. Results: A total of 20 patients were included, from 62 to 92 years in age. At prostate cancer (PCa) diagnosis, 60.0% (12/20) had de novo metastatic disease. Duration of mCyc therapy was 4 to 41 weeks. Median number of unique PCa therapies received prior to mCyc was 4 [range: 1 to 9], with 75.0% (15/20) pretreated with taxane-based chemotherapy. 25.0% (5/20) of patients achieved a 50% drop in PSA (PSA50), while 30.0% (6/20) achieved PSA reduction but less than PSA50. 10.0% (2/20) had PSA stability without reduction, but experienced improvement in cancer-related symptoms. In those with PSA50, median duration of therapy was 16.3 weeks [range: 14 to 41]. In PSA responders, median time to PSA nadir was 7.2 weeks [range: 1 to 28]. After starting mCyc, 38.5% (5/13) of patients with any PSA or clinical response (i.e. responders) had a transient PSA rise followed by PSA decline, which is suggestive of tumor flare. In responders, 15.4% (2/13) had liver metastasis and 7.7% (1/13) had bone marrow involvement with associated cytopenias. In responders with previous prostate biopsies, 66.6% (6/9) had Gleason 9 or 10 disease. 53.8% (7/13) of responders had genomic data available with a liquid biopsy or tissue sequencing, revealing 3 patients with TP53 mutations and 1 patient with BRCA2 and RB1 co-mutations. 15.0% (3/20) of patients required dose reduction and 20.0% (4/20) dose interruption due to toxicity, with no treatment discontinuations observed. Adverse reactions leading to dose modifications included cytopenias, anorexia, fatigue, nausea, and diarrhea. Conclusions: Despite availability of novel therapeutics for mCRPC, treatment options remain limited. Recognizing the small sample size of this retrospective dataset, oral mCyc showed promising activity with a quick onset of action and a tolerable toxicity profile in heavily pretreated mCRPC patients with aggressive disease features. Given its unique mechanism of action, this provides rationale for future clinical trials, including combining mCyc with other immunomodulating agents such as PD1/PD-L1 inhibitors.
Clonal hematopoiesis of indeterminate potential (CHIP) and association with response to bipolar androgen therapy (BAT).
Authors: Holler Albert E , Gondek Lukasz , Tsai Hua-Ling , Markowski Mark Christopher , Paller Channing Judith , Carducci Michael Anthony , Denmeade Samuel R. , Antonarakis Emmanuel S. , Luo Jun , Marshall Catherine Handy
Published: June 2023

e17048

Background: CHIP, the expansion of hematopoietic cells carrying acquired somatic alterations associated with hematologic malignancies, is associated with increased inflammation, risk of heart disease, and poor outcomes. BAT, where testosterone levels are therapeutically manipulated between castrate levels to supraphysiologic levels, has been shown to be an effective therapy for some men with castration resistant prostate cancer. Clinical predictors of response are not established. We hypothesized that CHIP, would be negatively associated with clinical outcomes. Methods: Baseline peripheral blood from participants on the RESTORE Cohort C (NCT02090114) were analyzed for the presence of CHIP. Patients in this cohort had castration resistant prostate cancer with progressive disease after treatment with ADT alone. All participants were treated with 400mg of intramuscular testosterone cypionate every 28 days. Peripheral blood mononuclear cells were analyzed for the presence of CHIP using targeted next generation sequencing focused on 49 genes most commonly mutated in CHIP and myeloid malignancies. Given patients had metastatic and non-metastatic CRPC, progression free survival was determined based on the time to the start of the next therapy. Results: CHIP was present in 6 of 29 patients at baseline (21%) with one patient having 2 clones (Table). Median age of patients CHIP+ was 73 compared to age of 68 in the CHIP- group (p = 0.16). Median PSA was higher in the CHIP+ group (median 15, IQR 1-56) compared to the CHIP- group (median 3.5, IQR 1-57). 67% of the CHIP+ group and 57% of the CHIP- group had baseline Gleason scores of > = 8. The CHIP+ group had a median PFS of 8.8 months compared to 13.3 months in the CHIP- group (HR 3.3 95%CI 1.2, 9.1; p = 0.02). This remained significant after adjusting for age. There was no difference in overall survival (HR = 2.5 95% CI 0.5,2.9; p = 0.3). Conclusions: Among men treated with BAT as first line treatment for CRPC after ADT alone, CHIP was associated with a decreased progression free survival. Larger studies are needed to understand the impact of CHIP in larger cohorts of men treated with BAT and other therapies for prostate cancer.[Table: see text]
Castration-resistant prostate cancer (CRPC) on PSMA-PET: Imaging features, disease distribution, and a comparison to castration-sensitive prostate cancer (CSPC).
Authors: Hsu Miles , Shan Xinhe , Zhang Rebecca , Pantel Austin , Takvorian Samuel U , Narayan Vivek , Vaughn David J. , Vapiwala Neha , Haas Naomi B.
Published: June 2023

e17062

Background: 18F-DCFPyL PET/CT is increasingly used in the staging and response assessment of patients (pts) with prostate cancer. Recent studies suggest that short-term ADT increases prostate-specific membrane antigen (PSMA) expression, whereas long-term ADT suppresses PSMA. Changes in PSMA expression after the development of CRPC are uncertain. We described 18F-DCFPyL PET findings in pts with CRPC and compared them to findings in CSPC. Methods: We analyzed 538 18F-DCFPyL scans performed at our large academic center. CRPC was defined as rising PSA w/ testosterone < 50 ng/dL on ADT. M0 CRPC was defined as absence of extra-pelvic disease (dz) and oligometastatic CRPC (oCRPC) was defined as ≤ 5 LN + osseous lesions and absence of visceral dz. Highest SUV max (hSUVmax) was abstracted from radiologist impression. Means between groups were compared using two-tailed t-tests; undetectable PSA levels were scored as “0”. Logistic regression was used to compare dz distribution between castrate states. Significance was defined as p < 0.05. Results: There were 81 pts with CRPC, 72 pts with metastatic CRPC (mCRPC) and 123 pts with mCSPC. The median ages of pts with mCRPC (74.5 years) and mCSPC (71) were similar. The mean PSAs of mCSPC (20.2 ng/mL) and mCRPC (69.4) were significantly different. hSUVmax was higher in mCRPC (mean 40.3, 95% CI 32.7 – 47.8) than in mHSPC (22.6, 18.4 – 26.9), p < 0.001. Distribution of mCRPC lesions was as follows: prostate bed (26.4%), local pelvic LN (25%), distant LN (M1a, 41.7%), osseous (M1b, 16.7%), and visceral (M1c, 16.7%). In a multivariate analysis mCRPC pts had lower rates of pelvic LN dz and higher rates of M1c, with a trend toward increased M1b (p < 0.10), compared to mCSPC pts. ADT and androgen pathway inhibition did not affect hSUVmax in CRPC. Within CRPC, there were 9 pts with M0 dz, 24 pts with oCRPC, and 48 pts with polymetastatic dz (pmCRPC). The ages (Table) of pmCRPC and oCRPC pts were similar. The mean PSA of pmCRPC (100.9) was higher than that of oCRPC (8.8) and M0 CRPC (5.7). hSUVmax between oCRPC (40.3) and pmCRPC (40.3) was similar. Conclusions: The greater hSUVmax in mCRPC may implicate the effect of ADT on PSMA expression or may describe differing tumor biology. mCRPC pts had less local dz and more frequent distant metastases, likely reflecting more advanced disease. These findings will help inform detection of developing castrate resistance on PSMA-PET. More data are needed on the classification of oligometastatic dz on PSMA-PET and the impact of hormone therapy on PSMA in CRPC. [Table: see text]
Impact of pre-treatment hemoglobin (Hgb) on outcomes in metastatic castration resistant prostate cancer (mCRPC) with lutetium-177-PSMA-617 (Lu-177).
Authors: Nelson Ariel Ann , Riemersma Kristin , Bylow Kathryn A. , Holt Michael , Kilari Deepak
Published: June 2023

e17065

Background: The Phase 3 VISION and TheraP trials excluded men with Hgb≤ 9 g/dL or blood transfusion within 30 days of Lu-177. Patients (pts) with mCRPC who are eligible for Lu-177 are often pancytopenic due to marrow infiltration and previous cytotoxic therapy. Clinicians are often faced with the dilemma of packed red blood cell (RBC) transfusion (Tx) to meet “eligibility requirements" of Lu-177. The impact of low Hgb levels on treatment (trt) outcomes is unclear. Methods: We retrospectively identified pts with mCRPC who received at least one cycle of Lu-177 between July 2022 and January 2023 at a single institution. Demographic, disease, laboratory and trt characteristics were recorded. Pts with Hgb level ≤10 g/dL or who received RBC Tx up to 14 days prior to the first Lu-177 dose were compared to pts with a pre-trt Hgb level ≥10 g/dL and no prior PRBC Tx. Data were summarized using descriptive statistics. Time to trt discontinuation was defined as the time from the first Lu-177 cycle until progressive disease per treating physician (clinical, radiographic, PSA progression) or adverse effect necessitating cessation and compared using the Kaplan Meier method. Cox proportional hazard regression analysis were utilized to assess the association of Hgb ≤ or ≥ 10 g/dL on the risk of trt discontinuation. Results: 51 pts were included, median follow up was 5.75 months, median age 70 years, 90% Caucasian. 49% (n = 25) had Gleason 9 /10 disease. Median number of prior trt was 4. 94% (n = 48), received prior docetaxel and 39% (n = 20) received prior cabazitaxel. 27% (n = 14) of pts had either Hgb≤10 or received a RBC Tx prior to trt. Of these, 50% of pts (n = 7) had stopped Lu-177 prior to completion of 6 cycles. Median number of cycles was 3. Reasons for trt cessation included clinical decline (n = 4), PSA or radiographic disease progression (n = 2), cytopenia (n = 1). Of pts who had Hgb ≥10 (n = 37), most (86%) are in ongoing trt, 11% (n = 4) have stopped trt due to progressive disease, 1 pt died. Pts with Hgb≤10 had a shorter time to trt discontinuation, 4.5 months (95% CI: 4.43- NA) vs not reached for those with Hgb≥10, p = 0.004 and an increased risk of trt discontinuation HR = 1.65 (95% CI: 1.53-18.09, p = 0.009). Conclusions: Pre-trt Hgb≤10 g/dL may be associated with worse outcomes in pts with mCRPC undergoing trt with Lu-177 and caution should be exercised. A larger data set and longer follow up is needed to further investigate outcomes in this pt population. Multivariable analysis is planned. [Table: see text]
Androgen receptor inhibitors and anti-NKG2A checkpoint inhibitor to enhance NK cell–mediated killing of prostate cancer cell lines in vitro.
Authors: Schwermann Maximilian , Tajiknia Vida , Zhou Lanlan , George Andrew , Srinivasan Praveen , De Souza Andre , Mega Anthony E. , Safran Howard , Carneiro Benedito A. , El-Deiry Wafik S.
Published: June 2023

e17066

Background: The blockade of the androgen receptor (AR) pathway is essential for the treatment of prostate cancer (PC). Checkpoint inhibitors have limited activity in immunologically cold prostate tumors. Emerging results suggest that AR signaling modulates CD8+ T cells and modifies its cytotoxic function, but the therapeutic role of NK cells in anti-tumor immune response in PC remains unknown. We investigated the mechanisms of AR inhibitors (ARi) enzalutamide (Enza) and darolutamide (Daro) on the antitumor function of NK cells and their enhancement when combined with NKG2A inhibitor. Methods: We performed co-culture assays with PC cell lines (LNCap, 22Rv1 [ARv7 mutation], DU145, PC3 [AR-]) and NK-92 cells, in a 1:1 ratio, in the presence of ARi and in combination with the anti-NKG2A mAb monalizumab and analyzed immune cell-mediated tumor cell killing (ImageXpress Confocal HT). NK cells expression of NKG2A and PD-1 receptors and PC cell lines expression of HLA-E and PD-L1 were investigated after treatment with Enza and Daro by flow cytometry. Results: ARi significantly increased immune-mediated NK-92 cell killing of PC cell lines at 24hrs (control[C]: 15.8%±3.9; Enza: 40%±4.3; Daro: 36%±3.72, p < 0.0001). This immune enhancement effect was increased by NKG2A blockade with monalizumab ([C]: 31.2%±3.1, [T]: 43.92%±4.52, p = 0.0045). Treatment of the LNCaP cell line (AR+) with ARi increased HLA-E ([MFI values x10³] control[C]: 28.57±2.9; [T]: 37.38 ±1.2 p = 0.0046) and PD-L1 expression ([MFI values x10³] control[C]: 163.1±8.1; [T]: 202.5±11.2 p = 0.003). No significant difference was observed in the surface expression of these markers in the AR- cell lines. NKG2A surface expression on NK cells was also upregulated upon treatment with ARi ([MFI values x10³] control[C]: 52.42±2.9; [T]: 61.4 ±2.2 p = 0.008). Conclusions: Enza and Daro enhance NK cell killing of PC cell lines, and the combination of ARi with checkpoint inhibitor monalizumab promotes NK cell activation. Blockade of AR signaling modulates PC cells' expression of HLA-E and PD-L1 and NK cell expression of NKG2A. These results describe a novel modulatory effect of androgen on NK cell function and provide insights for future NK-cell-based therapeutic approaches for treating PC. Experiments validating these results in patient samples are ongoing.
Development of BLX-3030, a potent and selective inhibitor of CDK9 for the treatment of NMYC-driven NEPCS.
Authors: Medley Kyle , Li Zhaoliang , Lin Chenyu , Bearss David J , Vankayalapati Hariprasad
Published: June 2023

e17067

Background: Cell lineage reprogramming in cancer cells is a major mechanism for cancers to develop drug resistance and escape targeted therapy. The use of new potent targeted therapies in prostate cancers has led to the development of highly aggressive cancers, including neuroendocrine prostate cancer (NEPC).Gene amplification of N-MYC and C-MYC oncogenes leads to its overexpression in NEPC and mCRPC patients. This overexpression is highly prevalent in these lethal subtypes of cancers, detected in 2% of all Prostate Cancers (PCa) and over 10-17% of mCRPC patients. N-MYC is a transcriptional target of CDK9, which acts as an oncogenic driver, sufficient to transform human-derived prostate cancer cells to take on NEPC phenotypic changes. This results in a more aggressive disease identified in late-stage human PCa patients. Additionally, N-MYC and C-MYC are required for tumor drug resistance and its downregulation, through CDK9 inhibition, lowers tumor growth. Our efforts have demonstrated that targeting both N-MYC and C-MYC as a driver of NEPC and mCRPC with a highly selective CDK9 inhibitor (BLX-3030) is a viable approach for therapeutic intervention of mCRPC and NEPC. Methods: We employed our AI/ML driven FIELDS fragment-based design strategies, in vitro including FACS/apoptosis, cell migration, live cell imaging, immunofluorescent and in vivo tumor models, 7-day tox, PK, selectivity, and ADME-Tox and in vitro safety and secondary pharmacological assays. Results: We discovered and synthesized a series of novel small molecule CDK9 agents that reversibly bind to CDK9, competitively block the ATP site with an IC50 of < 5 nM, and elicit pharmacological responses in N-MYC, C-MYC, and other prostate cancer cells in vitro and in vivo. We detected the expression of CDK9 and N-MYC in PC-3, DU-145, LNCaP, LASCPC-01, NCI-H660, and 22RV1 cell lines. BLX-3030 exhibited potent cellular efficacy in PC cells (IC50 of 22 to 590 nM) and in N-MYC expressed cells (IC50 of 76, 470, and 132 nM), respectively. BLX-3030 reduced pCDK9, C-MYC, Mcl-1, N-MYC and its downstream RNA Pol II (Ser-2) and pAR (Ser-81) in a dose dependent manner. Additionally, we performed FACS/apoptosis, cell migration, and live cell imaging, including immunofluorescence. We also conducted three separate in vivo efficacy mouse models (LASCPC-01, 22RV1, and C4-2) which demonstrated > 70% TGI. Several in vitro ADME-Tox, hERG, P450, safety panel screen, in vivo MTD and dose range finding experiments in SD rats and beagle dogs will also be presented. Conclusions: In summary, a series of BLX-3030 and its analogs display a potency in MYC-driven PCa, with ideal PK properties in rodent, canine species ranging 28-82 % F, with low clearance, and > 3.0 hr half-life. Within this profile, BLX-3030 was selected as a candidate that had the appropriate developable properties. Our plans for IND enabling studies and future clinical trials will also be discussed.
Efficacy and safety of darolutamide in Chinese patients with metastatic hormone-sensitive prostate cancer (mHSPC): A subpopulation analysis of the phase 3 ARASENS study.
Authors: Wang Shanshan , Fu Cheng , Zou Qing , Li Youyuan , He Dalin , Wang Shaogang , Wang Hongkai , Smith Matthew Raymond , Tombal Bertrand F. , Hussain Maha H. A. , Niu Yi , Cai Ling , Hu Nan , Huang Shiyun , Kapur Shivani , Li Rui , Kuss Iris , Ye Dingwei
Published: June 2023

e17076

Background: Darolutamide (DARO) is an androgen receptor inhibitor approved in China for the treatment of nonmetastatic castration-resistant prostate cancer (CRPC). In the global ARASENS trial, DARO significantly increased overall survival (OS) vs placebo (PBO) in patients (pts) with mHSPC. The efficacy and safety of DARO in the Chinese subpopulation of ARASENS are reported here. Methods: In this randomized, double-blind phase 3 trial, 1305 pts with mHSPC were randomized 1:1 to receive DARO 600 mg orally twice daily or PBO, in combination with androgen-deprivation therapy (ADT) and docetaxel. The primary endpoint was OS. Results: In mainland China, 202 pts were randomized to the DARO group (n = 104) or the PBO group (n = 98). Demographics and baseline characteristics were well balanced between treatment groups and comparable to the overall ARASENS population, except for a slightly higher proportion of pts with Gleason score ≥8, higher proportion with metastatic disease at diagnosis, and higher median baseline prostate-specific antigen (PSA) in Chinese pts vs the overall population. The risk of death was reduced by 36% (HR 0.64, 95% CI 0.41–0.99) with DARO vs PBO in Chinese pts (Table). The key secondary endpoint time to CRPC (HR 0.32, 95% CI 0.20–0.50) and the exploratory endpoint time to PSA progression (HR 0.22, 95% CI 0.13–0.37) also favored DARO. In the DARO group, 81% of pts had a maximum PSA decline of ≥90% from baseline (PSA90) at week 12, while 88% had PSA90 and 71% reached PSA < 0.2 ng/mL at any time. Incidences of treatment-emergent adverse events (TEAEs) in Chinese pts were similar between treatment groups and comparable to the overall population. The most common grade 3/4 TEAE in Chinese pts was neutropenia (DARO 64%, PBO 62%), a known toxicity of docetaxel; grade 3/4 febrile neutropenia occurred in 4.0% of Chinese pts compared with 7.6% in the overall population. Conclusions: In the ARASENS subpopulation of Chinese pts with mHSPC, DARO + ADT + docetaxel showed favorable efficacy and safety vs PBO + ADT + docetaxel: OS and clinically relevant secondary endpoints favored DARO vs PBO, and the incidences of TEAEs were similar in the two treatment groups. These results are consistent with the findings reported for the overall population in ARASENS. Clinical trial information: NCT02799602 . [Table: see text]
Outcomes of patients (pts) with de novo metastatic hormone-sensitive prostate cancer (mHSPC) who progressed to metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TRUMPET registry.
Authors: Shevrin Daniel H. , Symanowski James Thomas , Shore Neal D. , Lin Daniel W. , Russell David , Kral Pavol , Song Yi , El-Chaar Nader N. , Karsh Lawrence Ivan
Published: June 2023

e17085

Background: Significant lack of treatment (Tx) intensification is seen in clinical practice for pts with mHSPC until progression to mCRPC. The TRUMPET registry enabled a post-hoc analysis of clinical outcomes in pts with mCRPC, initially diagnosed with de novo mHSPC vs nmHSPC. Methods: TRUMPET, a prospective, observational study of US pts with CRPC, enrolled male adults (03/2015-09/2018) who began first or second-line Tx for M0/M1 CRPC. For this post hoc, pts with M1 CRPC at enrollment initially diagnosed with de novo mHSPC (clinical TNM1 stage) were compared to M1 CRPC pts initially diagnosed with nmHSPC (clinical TNM0 stage). Clinical outcomes (radiographic progression-free survival [rPFS], prostate specific antigen [PSA] progression, time to opiate initiation [OI], mortality) were analysed with Kaplan–Meier and Cox proportional hazards models. An exploratory subanalysis investigated outcomes in de novo mHSPC pts who received Tx intensification (docetaxel or abiraterone) with androgen-deprivation therapy (ADT) as primary Tx prior to mCRPC vs pts who did not. Results: M1 CRPC pts initially diagnosed with de novo mHSPC (n = 199) or nmHSPC (n = 254) were included; median age: 70.0 vs 73.0 years, duration from initial PC diagnosis to baseline mCRPC visit: 1.62 vs 6.72 years, PSA at PC diagnosis: 113.1 vs 10.1 ng/mL, Gleason score: 9.0 vs 8.0, respectively. In the de novo mHSPC and nmHSPC groups, initial CRPC Tx was chemotherapy in 9.0% vs 5.9% of pts, novel hormonal therapy (enzalutamide or abiraterone) in 55.3% vs 59.1%, immunotherapy in 35.2% vs 42.9%, respectively. No differences were seen in rPFS or PSA progression (table). The de novo mHSPC group showed a trend toward shorter time to OI and significantly increased risk of mortality (37%) with 6.6 months shorter median survival vs nmHSPC. The subanalysis included 44 (22.1%) de novo mHSPC pts who received Tx intensification with ADT at initial diagnosis. A trend towards improved survival was seen in the Tx-intensified vs nonintensified subgroup (median time to death [95%CI]; 47.7 months [22.18, NE] vs 37.3 months [28.35, 43.01]). Conclusions: At mCRPC diagnosis, pts with de novo mHSPC have significantly higher mortality risk than pts with nmHSPC, indicating a need to delay progression of de novo mHSPC to mCRPC. The trend for improved survival benefit in pts with Tx-intensified de novo mHSPC further underlines the need for early Tx intensification. [Table: see text]
Biochemical recurrence after salvage prostate bed radiotherapy captured on PSMA-PET: Patient characteristics and distribution of recurrent disease.
Authors: Hsu Miles , Shan Xinhe , Vapiwala Neha , Zhang Rebecca , Pantel Austin , Berlin Eva , Narayan Vivek , Takvorian Samuel U , Vaughn David J. , Haas Naomi B.
Published: June 2023

e17088

Background: The SPPORT trial demonstrated that salvage whole pelvic radiotherapy (sWPRT) after radical prostatectomy (RP) reduced prostate cancer progression compared to salvage prostate bed radiotherapy (sPBRT), at the expense of greater toxicity. To identify pts most appropriate for sWPRT, we studied the incidence of and risk factors associated with radiologic relapse after sPBRT on 18F-DCFPyL PET, a sensitive new imaging modality. Methods: We analyzed 538 18F-DCFPyL PET/CTs performed at our large academic institution and screened for pts who had biochemical recurrence (BCR), defined as PSA > 0.2 ng/mL, after receiving sPBRT for persistent or recurrent PSA. Risk factors including pathologic T stage (pT), pathologic Gleason score (pGS), seminal vesicle invasion (SVI), positive margins, perineural invasion (PNI), PSA at RP (PSA1), prior to RT (PSA2), and at time of scan (PSA3), and PSA doubling time after sPBRT (PSADT) were obtained. Associations between risk factors and radiographic relapse were quantified with logistic regression, with a p < 0.05 defined as significant. Results: 38 pts with BCR after sPBRT were identified. Median values were: pt age = 69.5 years (interquartile range 64 – 74), PSA1 = 7.83 ng/mL (4.7 – 11.5), PSA2 = 0.26 (0.1 – 0.8), PSA3 = 0.71 (0.5 – 2.2), PSA DT = 9.8 (5.3 – 18.2). Pt characteristics were: pT (pT2, 46% of pts; pT3a/b, 54%), pGS ( < 7, 11%; 3+4, 32%; 4+3, 39%; > 7, 18%), 19% w/ SVI, 68% w/ positive margins, 93% w/ PNI and 80% (of evaluable pts) w/ high-risk decipher score. 42% of pts received salvage ADT with sPBRT. 68% of pts had detectable disease on 18F-DCFPyL PET. Radiologic relapse in pelvic LNs was present in 47% of all pts, and 32% of pts had relapse only in the pelvic nodes. 26% of pts had distant metastases (DM) on imaging. Only 13% of pts had DM without pelvic LN involvement. Between pts with pelvic LN only relapse (n = 12) and pts without radiographic disease (n = 12), age, pT, pGS, SVI, margins, ADT, PSA1-3 and PSADT did not differ on univariate or multivariate analyses. On the univariate analysis between pts with DM (n = 10) and without DM (n = 28), only PSA3 (p < 0.05) was associated with radiographic relapse, and pT trended toward a negative association (p< 0.10) with DM. Only PSA3 (p < 0.10) trended toward association with DM in a multivariate analysis using age, pT, margins, ADT, and PSA2-3. Conclusions: Pts with biochemical relapse after sPBRT had frequent high-risk pathology. Aside from PSA3, no risk factors were predictive of detectable pelvic nodal or DM disease. However, most pts with detectable disease had pelvic LN involvement, suggesting that a substantial portion of these high-risk pts may have benefited from whole-pelvic RT. Further data on risk factors will help inform selection of pts appropriate for salvage whole pelvic RT.
Results of digital patient-reported outcomes measures (PROMs) data collection for patients with localized prostate cancer at diagnosis.
Authors: Knipper Sophie , Dewulf Karel , Branger Nicolas , Rybikowski Stanislas , Maubon Thomas , Salem Naji , Guerin Mathilde , Vicier Cecile , Gravis Gwenaelle , Walz Jochen , Pignot Geraldine
Published: June 2023

e17103

Background: Patient-reported outcomes measures (PROMs) allow optimal evaluation of side effects of treatments and their impact on quality of life. Therefore, the objective of our study was to analyze the functional outcomes at different timepoints for urinary continence and erectile function in patients treated with active surveillance (AS), brachytherapy (BT), radiotherapy (RT, +/- hormonal treatment (HT)) and radical prostatectomy (RP). Methods: Since May 2019, all patients treated for localized prostate cancer in our center have been offered inclusion in a digital prospective program, with automated sending of PROMs questionnaires via a dedicated digital application, before treatment (baseline), at 1 (M1), 3 (M3), 6 (M6) and 12 months (M12). Data were analyzed for urinary continence and erectile function (EPIC-26 HRQOL Domain Summary Score of Urinary Incontinence (UI) and Sexuality) according to treatment strategy. Results: Overall, 552 patients answered questionnaires (05/2019-12/2022), including 97 AS patients, 23 patients treated by BT, 9 patients treated by RT, 37 patients treated by RT with HT and 386 patients treated by RP. Regarding continence, the median UI score at M12 (compared to baseline) was 88 (vs. 100) for AS, 100 (vs. 100) for BT, 100 (vs. 100) for RT, 93 (vs. 100) for RT with HT and 100 (vs. 100) for RP. Regarding erectile function, the median sexuality score at M12 (compared to baseline) was 100 (vs. 73) for AS, 40 (vs. 61) for BT, 40 (vs. 47) for RT, 17 (vs. 54) for RT with HT, 32 (vs. 67) for RP. Conclusions: Surgical treatment transiently affects continence but with almost complete recovery at one year in the majority of cases. However, erectile dysfunction remains a critical issue with an important deterioration for surgery as well as radiotherapy with combined HT. [Table: see text]
3D open-top light-sheet microscopy and 3D microdissection of neuoadjuvant-treated primary prostate cancer reveals latent subclonal mutations.
Authors: Reder Nicholas , Pritchard Colin C. , Konnick Eric Q , Huang Hongyi , Lerma Angelica , Glaser Adam K , True Lawrence D , Liu Jonathan T.C. , Schweizer Michael Thomas
Published: June 2023

e17109

Background: Intratumoral molecular heterogeneity is a well described phenomenon in primary prostate cancer. Increased genomic heterogeneity is associated with more aggressive clinical behavior, including recurrence and metastasis. However, current methods to characterize heterogeneity suffer from tradeoffs between generating high quality morphologic information, correlating morphology with genomic alterations, and workflow considerations. We describe a technology to image prostate samples in 3D, perform 3D microdissection of regions of interest (ROIs), and preserve nucleic acids for DNA sequencing. Methods: Samples (N = 18) were obtained from patients (N = 12) enrolled in an open-label, single-site, Phase II neoadjuvant trial in men with NCCN high to very-high risk PC. Patients received 12 weeks of apalutamide, abiraterone acetate plus prednisone, degarelix, and indomethacin followed by radical prostatectomy (RP). Fresh frozen prostate samples (~2x2x0.4cm) were obtained from RP specimens. Frozen samples were fixed in an ethanol-based fixative, stained with nuclear (TOPRO-3) and general protein (eosin) fluorescent dyes, cleared with ethyl cinnamate, and imaged using 3D open-top light-sheet (OTLS) fluorescence microscopy. Image-guided 3D microdissection was performed on ROIs with distinct morphologies. Microdissected ROIs measured 0.5x0.5x2mm. Microdissected samples were sent for DNA extraction and sequencing using the comprehensive clinically-validated UW-OncoPlex NGS assay. Results: The tissue from neoadjuvant-treated patients contained sparse carcinoma, with cancer volumes ranging from 0.01-0.3 cm2 and cellularity ranging from 2%-30%. Molecular alterations were detected in a sample with only 0.07 cm2 volume of carcinoma with 5% cellularity. The read depth of 3D microdissected samples was 3.9 times greater than the read depth of FFPE samples from the same patients. At least two morphologically distinct ROIs were 3D microdissected from 11 of 12 patients. Four of the 18 samples had molecular alterations that differed between ROIs, i.e. intra-sample molecular heterogeneity. For example, one sample with three microdissected ROIs had a PTEN alteration exclusive to a single ROI. Conclusions: The findings show the potential for 3D microdissection of morphologically distinct subclones in samples from neoadjuvant-treated patient, to enable sequencing of specific cellular populations. The sparsity of carcinoma necessitated a spatially targeted approach for extracting material for sequencing. The increased yield from avoiding FFPE processing and carcinoma enrichment from targeted 3D microdissection of carcinoma ROIs enabled the detection of spatially distinct molecular subclones. Future work will include the analysis of additional samples and implementation of AI-guided ROI detection to streamline workflows.
Socioeconomic and demographic patterns associated with treatment delay in prostate cancer: An analysis of the National Cancer Database.
Authors: Abodunrin Faith , Adeoye Oluwatayo , Nelson Nick , Amadi Nwonuwkuru I , Silberstein Peter T. , Tupper Connor
Published: June 2023

e17122

Background: Prostate cancer is the second leading cause of cancer related deaths in men. In 2023, about 288,300 new cases of prostate cancer are expected . Delays in cancer treatment can impact patients’ outcomes. In our study, we sought to describe socioeconomic and demographic factors influencing time to treatment in prostate cancer. We also studied the trend in time to treatment through the years. Methods: Using the National Cancer Database, we identified 1,605,396 patients diagnosed with prostate cancer between 2004 and 2019. Variables used for assessment include age at diagnosis, race, Charlson-Deyo score, stage at diagnosis, insurance status, median household income in patient’s zip code and year of treatment. We separated patients into two groups: those who started treatment < 60 days and patients who started treatment > 60 days using statistical analyses. We used Chi-square test to assess for differences within these groups and multivariable analysis to determine relationships between time to treatment and the socioeconomic and demographic variables. All tests were performed with a significance level of a = 0.05. Results: Out of 1,605,396 patients included in this study, 806,576 patients began treatment 60 days or less after diagnosis and 798,820 began treatment over 60 days after diagnosis. Older patients (age > 71) were less likely to be treated later than younger patients aged < 60 years (OR 0.530). Black and Hispanic patients were significantly more likely to start treatment later than white patients (OR 1.231; OR 1.086 p < 0.001). Compared to uninsured patients, those with private and other government coverage were more significantly likely to begin treatment later (OR 1.144; OR 1.469 p < 0.001). Patients with advanced stage prostate cancer were at lower risk for delayed treatment compared to those with localized disease (OR 0.218 P < 0.001). Compared to community programs, patients at academic/research programs were significantly more likely to begin treatment later (OR 2.097 p < 0.0001). In 2004, 40.5% patients began treatment over 60 days from diagnosis compared to 55.1% in 2019 (p < 0.001). We found that patients diagnosed between 2016 and 2019 were more likely to be treated later than those diagnosed between 2004-2007 (OR 1.717 p < 0.001). Conclusions: Increased rate of later time to treatment were seen in younger patients, minority groups, staging at diagnosis less than stage IV, patients treated at academic or research programs, and patients diagnosed between 2016-2019. This is likely due to the rise of active surveillance rather than immediate treatment as a management strategy in prostate cancer. Black men are at increased risk for advanced disease, hence, treatment delays should be avoided in these patients. Institution-level studies should be done to determine the pattern of treatment and address treatment delays.
Treatment patterns and outcomes among locally advanced cervical cancer patients receiving concurrent chemoradiotherapy.
Authors: Coutinho Francesca , Gokhale Mugdha , Doran Charlotte , Monberg Matthew , Yamada Karin Sayuri , Chen Lei
Published: June 2023

e17511

Background: Concurrent chemoradiotherapy (CCRT) is standard treatment for patients with locally advanced cervical cancer (LACC). However, little is known on the real-world treatment patterns and outcomes among LACC patients. This study evaluated patient characteristics and treatment patterns of LACC patients, and real-world outcomes among patients receiving CCRT as the first treatment after diagnosis (CCRT-first) in US academic and community settings. Methods: Data were drawn from the ConcertAI Oncology Dataset, a US-based electronic medical record dataset. We included adult patients diagnosed between 2010-2018 with LACC, defined as stage IB2-IIB with node involvement or stage III-IVA cervical cancer, with squamous cell carcinoma (excl. verrucous), adenocarcinoma (excl. clear cell and endometroid), or adenosquamous carcinoma. Patients with prior immunotherapy or a second primary cancer (other than in situ or non-melanoma skin cancer) were excluded. Patients were followed from initial diagnosis through end of the second regimen of systemic anti-cancer therapy, end of record, or death, whichever occurred first. Patient characteristics and treatments were reported overall and in CCRT-first patients. Among CCRT-first patients, real-world time on CCRT treatment (rwTOT), recurrence-free survival (rwRFS), and progression-free survival (rwPFS) among patients with persistent disease were estimated using Kaplan-Meier methods. Results: Overall, 300 patients with LACC were included. At LACC diagnosis, median age of patients was 51 years, 53.7% were White, 30.0% were Black, 48.0% were peri/postmenopausal, 89.3% had squamous cell histology, 75.3% had stage III disease, 92.7% had no evidence of performance status impairment, 50.3% were treated in community settings, and 21.7% had only public insurance (11.0% Medicaid, 10.7% Medicare; 56.3% had no documentation of insurance). Distributions were similar among CCRT-first patients. First treatment after diagnosis included CCRT (N=229), surgery (N=28), systemic therapy (N=11), and radiation therapy alone (N=5). 27 were untreated, and 29 patients received CCRT after another therapy. Of the 229 CCRT-first patients, median (95% CI) rwTOT was 1.6 (1.4-1.7) months; 78.2% received cisplatin within CCRT, and median duration of cisplatin treatment was 35 days; 28.4% received a systemic therapy after CCRT, and 11.8% further initiated a second systemic therapy. 27 patients had recurrent disease after complete response (median rwRFS not reached). 179 patients had persistent disease after CCRT, among whom median (95% CI) rwPFS was 29.7 (16.9-59.3) months from CCRT start. Conclusions: In US clinical practice during 2010-2018, most LACC patients received CCRT as the first treatment after diagnosis. The high proportion of patients who develop persistent disease after CCRT indicates a need for improved first treatment options.
Response and re-treatment response to immune checkpoint inhibitor treatment in advanced cervical cancer: A follow up study.
Authors: Wolf Jennifer , Xu Yiqing
Published: June 2023

e17516

Background: Single agent checkpoint inhibitor immunotherapy (CII) was approved in June 2018 for second line treatment for metastatic cervical cancer after failure of platinum-based chemotherapy. Clinical trials recommended 2 years of treatment, however the optimal duration of treatment, outcome after stopping treatment and response after re-initiation of immunotherapy is still largely unclear. Methods: A cohort of 10 patients who were started on CII before September 31, 2019, with an initial analysis published in July 2021 were eligible. We performed an updated review of the duration of response, outcome off treatment after 2 years, and outcome after re-initiation of CII. Results: The current median follow up is 40 months (range, 2.0-50.8 months), 4 patients did not respond to treatment and have passed away, while six patients remain alive. The previous report showed 7 responders, with 3 complete responses (CR) at a median follow up of 20.7 m. With prolonged treatment, 6 patients achieved CR or stable minimal disease. After more than 2 years of treatment, 2 continued treatment for 39m and 50 m. Among the 4 patients who stopped treatment, 2 of them are 18 m and 20 m off treatment and remain no evidence of disease. Another 2 patients developed asymptomatic recurrence detected on surveillance CT (at 9 m and 12 m respectively), both with small volume of disease in the retroperitoneal and pelvic lymph nodes. They were both re-initiated on CII, and showed a CR and partial response (PR) respectively, on 3-6 month follow up CT scans, now 11.7 m and 3.5 m on treatment. A median PD-L1 combined expression score (CPS) was similar between responders (n=6) (20) and non-responders (26) (n=4) in the entire cohort overall, and was 83 in the group of patients who discontinued treatment after 2 years and have been without evidence of disease since (n=2). Conclusions: Patients who respond to immune checkpoint inhibitors may have durable response off treatment and may respond again to re-treatment in the event of recurrent disease. Our limited data suggest that providers can use CPS to aid in decision making. [Table: see text]