Trials In Prostate Cancer Research Articles

Elective pelvic nodal irradiation in the setting of ultrahypofractionated versus moderately hypofractionated and conventionally fractionated radiotherapy for prostate cancer: Outcomes from 3 prospective clinical trials

Background and purposeData is needed regarding the use of ultrahypofractionated radiotherapy (UHRT) in the context of prostate cancer elective nodal irradiation (ENI), and how this compares to conventionally fractionated radiotherapy (CFRT) ENI with CFRT or moderately hypofractionated radiotherapy (MHRT) to the prostate. Materials and methodsBetween 2011–2019, 3 prospective clinical trials of unfavourable intermediate or high-risk prostate cancer receiving CFRT (78 Gy in 39 fractions to prostate; 46 Gy in 23 fractions to pelvis), MHRT (68 Gy in 25 fractions to prostate; 48 Gy to pelvis), or UHRT (35–40 Gy in 5 fractions to prostate +/- boost to 50 Gy to intraprostatic lesion; 25 Gy to pelvis) were conducted. Primary endpoints included biochemical failure (Phoenix definition), and acute and late toxicities (CTCAE v3.0/4.0). ResultsTwo-hundred-forty patients were enrolled: 90 (37.5 %) had CFRT, 90 (37.5 %) MHRT, and 60 (25 %) UHRT. Median follow-up time was 71.6 months (IQR 53.6–94.8). Cumulative incidence of biochemical failure (95 % CI) at 5-years was 11.7 % (3.5–19.8 %) for CFRT, 6.5 % (0.8–12.2 %) MHRT, and 1.8 % (0–5.2 %) UHRT, which was not significantly different between treatments (p = 0.38). Acute grade ≥ 2 genitourinary toxicity was significantly worse for UHRT versus CFRT and MHRT, but not for acute grade ≥ 3 genitourinary, or acute gastrointestinal toxicities. UHRT was not associated with worse late toxicities. ConclusionENI with UHRT resulted in similar oncologic outcomes to CFRT ENI with prostate CFRT/MHRT, with worse acute grade ≥ 2 GU toxicity but no differences in late toxicity. Randomized phase 3 trials of ENI using UHRT techniques are much anticipated.

Development of a new radical cystectomy surveillance protocol and nurse-led cystectomy follow-up clinic in Australia.

This study determined, implemented, and assessed a nurse-led radical cystectomy follow-up protocol. In 2021, an evidence-based risk-stratified protocol (non-urological cancers and benign [N-UC&B], low, or high risk) was developed from current guidelines, local and national expert opinion, and after formal discussion with the Urological Society of Australia and New Zealand (USANZ) Western Australia (WA) and Australia and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. Retrospective and prospective assessment of cystectomy follow-up occurred between 2015 and 2023. Patients received 'surgeon-led' follow-up March 2015 to August 2021, and 'nurse-led' follow-up August 2021 to April 2023. Adherence to follow-up, cost-analysis, and healthcare efficiency calculations were performed. Of 176 cystectomy patients, 159 (90.3%) were eligible for inclusion. Overall adherence to nurse-led follow-up was 78.6% compared to 43.4% in surgeon-led (P < 0.001). Adherence to nurse-led follow-up was higher in all risk categories (high-risk 79.1% vs. 43%, P < 0.001; low risk 75% vs. 52.3%, P = 0.110; N-UC&B 71% vs. 30%, P = 0.153). Nurse-led consultation saved $59.50 per consultation with overall cost savings of $179.50, $416.50, and $595 for the entire follow-up period for N-UC&B, low, and high-risk groups based on consultation alone. A total of 1072 appointments (536 h, $62 390.40) would have been saved if the surgeon-led cohort of patients were seen in nurse-led clinics. Protocol driven nurse-led cystectomy follow-up demonstrates excellent adherence and may be more cost-effective than surgeon-led follow-up.

Optimising Aerobic And Resistance Emphasis In Exercise Trials In Prostate Cancer: A Feasibility Trial

Optimising Aerobic And Resistance Emphasis In Exercise Trials In Prostate Cancer: A Feasibility Trial

Does insulin resistance predict prostate cancer? Results from the Reduction by Dutasteride of Prostate Cancer (REDUCE) Trial.

Prior studies testing the association between insulin resistance (IR) and prostate cancer (PC) risk are inconsistent. We examined the association between Homeostatic Assessment of Insulin Resistance (HOMA-IR; calculated from fasting baseline insulin and glucose) and PC in REDUCE, a 4-year randomized trial of dutasteride vs. placebo for PC prevention. All patients had prestudy negative biopsies and underwent study mandated biopsies at 2 and 4 years regardless of prostate-specific antigen. Multivariable logistic regression models were used to investigate the associations between log-transformed or categorized HOMA-IR scores and PC risk. Multinominal regression was used to assess associations between HOMA-IR scores and tumor grade (low grade [grade group 1]; high-grade [grade groups 2-5]). Among 5430 REDUCE participants (1212 with PC; 856 low- and 356 high-grade), higher HOMA-IR was associated with lower PC risk (log-HOMA-IR: OR,0.89; 95% CI,0.80-0.99; p=.03; categorized HOMA-IR: p-trend=.04). When stratified by grade, HOMA-IR was significantly associated with reduced low-grade PC risk (log-HOMA-IR: OR,0.84; 95% CI,0.74-0.94; p=.003; categorized HOMA-IR: p-trend=.002) but was unrelated to high-grade PC (log-HOMA-IR: OR,1.02; 95% CI,0.86-1.21; p=.81; categorized HOMA-IR: p-trend=.26). Results were similar in placebo and treatment arms. In summary, higher HOMA-IR was associated with a reduced risk of low-grade PC but was not associated with high-grade disease. The mechanisms to explain these findings are unclear.

Abstract B001: Engaging patient advocates in the battle against cancer directly in their communities in culturally and language specific ways

Abstract Background: Patient advocates from diverse communities are at the forefront of informing on the latest scientific findings to different audiences; and connecting to resources to help battle cancer. However, disparities exists that exacerbate barriers to the delivery of cancer information. These disparities are the result of impactful socio-determinants of health that range from language barriers to food insecurity, mental health challenges and a lack of connection to support services and clinical trials. Lazarex Cancer Foundation has established Pop-up Hubs that go directly into the community to alleviate barriers while empowering patient advocates from varied cultural and racial/ethnic groups to deliver cancer information that account for culture, race/ethnicity literacy and numeracy levels, and delivered in multiple languages. Patient advocates are cancer-care ambassadors that help reduce the cancer burden, provide referrals, follow-up with needed information or care, and enroll patients into clinical trials. Methods: With community participation, patient advocates have helped develop culturally and language specific educational materials, approach communities in their own neighborhoods, and help connect to support services, such as free food distribution, mental health services, and raise awareness on environmental and lifestyle factors that can influence a cancer trajectory. Our patient advocates follow up with community members seeking resolution to their cancer concerns. Patient advocates promote screenings and help link individuals and their families. Patient advocates also work with community coalitions, testify before local decision-makers, and promote early detection, screening, tobacco cessation, weight management, nutritious culturally specific meals, and advise on exercise. Results: Working with patient advocates in a participatory manner, we have developed and disseminated educational materials on prostate cancer, breast cancer, colorectal cancer, cervical cancer, and clinical trials. Patient advocates have provided cancer information to 5,000 individuals of Latino/a (Spanish speaking), Black/African American, and Asian (Korean and Mandarin speaking) heritage). 3,773 have received cancer information, have connected 260 individuals to support groups; provided 112 community members with individualized follow-up increasing knowledge and access to services. Reached over 3 million people via various media and between 2018-2024 supported the passing with our partners of 31 tobacco laws in California. Conclusion: Patient advocates have created knowledgeable inviting environments for community members directly in the diverse communities of Los Angeles. The information provided includes screening guidelines, the importance of diversity participation in clinical trials, self or patient advocacy, and accessing trustworthy, reliable sources. Patient advocates are opening new ways to reach communities in a participatory manner in their own backyard; enhancing our ongoing effort to reduce cancer disparities. Citation Format: Lourdes Baezconde-Garbanati, Elena Nieves, Carolina Aristizabal1, Yaneth L. Rodriguez, Rosa Barahona, Marya Shego, Dana Dornsife. Engaging patient advocates in the battle against cancer directly in their communities in culturally and language specific ways [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B001.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Association between low total serum testosterone and body mass index in Australian survivors of testicular cancer: a retrospective analysis

BackgroundPrimary hypogonadism is a recognised complication in survivors of testicular cancer. However, secondary hypogonadism can result from other causes that suppress the hypothalamic-pituitary axis, including obesity, high dose glucocorticoids, chronic end organ failure, and diabetes. The aim of this study was to explore low total serum testosterone in Australian survivors of testicular cancer and examine associations with body mass index, age, and prior chemotherapy use.MethodsClinical data including height, weight, diagnosis, treatment, and hormonal evaluations during follow-up were extracted from the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Chemocog study (2007-2012), accompanied by data from two Australian, high-volume testicular cancer centres included in the iTestis testicular cancer registry (2012-2019). Low testosterone was defined by a serum concentration of testosterone (T) < 10 nmol/L, and was classified as primary by a serum concentration of luteinising hormone (LH) > 8 IU/L, otherwise as secondary.ResultsTwo hundred eighty-five individuals with either stage 1 or advanced testicular cancer were included. Of these, 105 (37%) were treated with orchidectomy and chemotherapy. Forty-nine (17%) met criteria for low testosterone during follow-up: 21 (43%) had primary and 27 (55%) had secondary low testosterone. Survivors of testicular cancer with higher body mass index were more likely to display low testosterone, both primary (p = 0.032) and secondary (p = 0.028). Our data did not show evidence of an association between older age or chemotherapy use and low testosterone in our cohort.ConclusionsLow total serum testosterone was common in survivors of testicular cancer, and associated with a higher body mass index prior to orchidectomy, suggesting that elevated body mass index may contribute to low testosterone in this population, and that body weight, diet, and exercise should be addressed in testicular cancer follow-up.

1616P Circulating tumour DNA (ctDNA) measurements and PET-imaging to evaluate response in a phase Ib trial of metastatic castration-resistant prostate cancer (mCRPC) treated with Lutetium-177-PSMA-617 (LuPSMA) plus pembrolizumab (PRINCE)

1616P Circulating tumour DNA (ctDNA) measurements and PET-imaging to evaluate response in a phase Ib trial of metastatic castration-resistant prostate cancer (mCRPC) treated with Lutetium-177-PSMA-617 (LuPSMA) plus pembrolizumab (PRINCE)

How Can Participant Experience of Quality-of-Life Research Be Improved in Cancer Research: Views of the Patient and Public Involvement Representatives from the STAMPEDE2 Prostate Cancer Trial

Enhancement of the participant experience in quality of life (QOL) research is imperative to improve recruitment and ongoing engagement in QOL studies. Implementation of recommendations made by the patient and public involvement representatives for STAMPEDE2 could optimise the impact of QOL studies, with a benefit for participants and collection of invaluable data for cancer care research.

Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician's choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician's choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or 'all' patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician's choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2-ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53-altered patients. In summary, ARPIs outperform taxanes and physician's choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 .

A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk.

Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T<0.5ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360mg SC and 180mg IM with a maintenance dose of 360mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

Effects of high-intensity interval training on cardiometabolic biomarkers in patients with prostate cancer undergoing active surveillance: a randomized controlled trial.

To report the effects of a 12-week high-intensity interval training (HIIT) program on cardiometabolic biomarkers in patients with prostate cancer on active surveillance (AS) from the Exercise During Active Surveillance for Prostate Cancer (ERASE) Trial. Fifty-two men with prostate cancer on AS were randomized to either an exercise (HIIT; n = 26) or usual care (UC; n = 26) group. The HIIT intervention consisted of progressive, supervised, aerobic HIIT at an intensity of 85 to 95% VO2peak for 28 to 40 min per session performed three times/week for 12 weeks. Blood samples were collected at baseline and postintervention to analyze cardiometabolic biomarkers. Analysis of covariance was used to examine between-group mean differences. Blood data were obtained from 49/52 (94%) participants at postintervention. Participants were aged 63.4 ± 7.1 years and 40% were obese. The HIIT group attended 96% of the planned exercise sessions. No significant between-group changes in weight were observed after the intervention. Compared to UC, HIIT significantly improved total cholesterol (-0.40 mmol/L; 95% confidence interval[CI], -0.70 to -0.10; p = 0.011), non-high-density lipoprotein-c (-0.35 mmol/L; 95% CI, -0.60 to -0.11; p = 0.006), insulin (-13.6 pmol/L; 95% CI, -25.3 to -1.8; p = 0.025), insulin-like growth factor (IGF)-1 (-15.0 ng/mL; 95% CI, -29.9 to -0.1; p = 0.048), and IGF binding protein (IGFBP)-3 (152.3 ng/mL; 95% CI, 12.6 to 292.1; p = 0.033). No significant differences were observed for fasting glucose, HbA1c, other lipid markers, IGFBP-1, adiponectin, and leptin. The ERASE Trial showed that a 12-week aerobic HIIT program improved several cardiometabolic biomarkers in patients with prostate cancer on AS that may contribute to cardiovascular health benefits and potentially influence signaling pathways in the progression of prostate cancer. Further research is needed to confirm the effects of exercise on cardiometabolic markers in men with prostate cancer on AS and determine if these effects are associated with improved long-term clinical outcomes.

Use of Placebo in Urologic Oncology Randomized Controlled Trials.

Use of placebo in oncology randomized controlled trials (RCT) is ethically controversial. Placebo may introduce bias, as toxicity profiles of treatment arms can inadvertently unblind subjects and investigators. We investigated the use of placebo in urologic oncology RCTs, hypothesizing that most placebo-controlled trials are effectively unblinded, either explicitly with open-label design or implicitly due to large differences in adverse events (AE) or oncologic outcomes. Urologic oncology RCTs utilizing placebo were identified via ClinicalTrials.gov. Interventional prostate, bladder/urothelial, and renal cancer trials from 2014 to 2024 were included. Subject incompletion, all-cause mortality, AE rates, and serious AE (SAE) rates were identified and compared between placebo and active arms using χ2 and Fisher's exact tests. Sixty studies met inclusion criteria and included 66 placebo arms with 12,918 subjects and 81 active arms with 16,098 subjects. There was no significant difference in incompletion rates between placebo and active arms. Subjects enrolled in active arms reported statistically significant higher SAE and AE rates compared to those in placebo arms across the majority of physiological domains, including 18/24 domains for SAEs and 13/24 for AEs. This relationship persisted in sensitivity analyses where unblinded trials were excluded. In urologic oncology placebo-controlled RCTs, active arms are associated with significantly higher rates of AEs and SAEs compared with placebo arms. These findings indicate a strong possibility that true blinding is not possible in oncology RCTs, even with optimal study design, and serve to better inform future clinical trial design and implementation challenges in employing placebo control.

Scaling and interpreting treatment effects in clinical trials using restricted mean survival time.

Restricted mean survival time is the expected duration of survival up to a chosen time of restriction . For comparison studies, the difference in restricted mean survival times between two groups provides a summary measure of the treatment effect that is free of assumptions regarding the relative shape of the two survival curves, such as proportional hazards. However, it can be difficult to judge the magnitude of the effect from a comparison of restricted means due to the truncation of observation at time . In this article, we describe additional ways of expressing the treatment effect based on restricted means that can be helpful in this regard. These include the ratio of restricted means, the ratio of life-years (or time) lost, and the average integrated difference between the survival curves, equal to the difference in restricted means divided by These alternative metrics are straightforward to calculate and provide a means for scaling the effect size as an aid to interpretation. Examples from two randomized, multicenter clinical trials in prostate cancer, NRG/RTOG 0521 and NRG/RTOG 0534, with primary endpoints of overall survival and biochemical/radiological progression-free survival, respectively, are presented to illustrate the ideas. The four effect measures (restricted mean survival time difference, restricted mean survival time ratio, time lost ratio, and average survival rate difference) were 0.45 years, 1.05, 0.81, and 0.038 for RTOG 0521 and 1.36 years, 1.17, 0.56, and 0.12 for RTOG 0534 with = 12 and 11 years, respectively. Thus, for example, the 0.45-year difference in the first trial translates into a 19% reduction in time lost and a 3.8% average absolute difference between the survival curves over the 12-year horizon, a modest effect size, whereas the 1.36-year difference in the second trial corresponds to a 44% reduction in time lost and a 12% absolute survival difference, a rather large effect. In addition to the difference in restricted mean survival times, these alternative measures can be helpful in determining whether the magnitude of the treatment effect is clinically meaningful.

Uncertainty estimation using a 3D probabilistic U-Net for segmentation with small radiotherapy clinical trial datasets

Background and objectivesBio-medical image segmentation models typically attempt to predict one segmentation that resembles a ground-truth structure as closely as possible. However, as medical images are not perfect representations of anatomy, obtaining this ground truth is not possible. A surrogate commonly used is to have multiple expert observers define the same structure for a dataset. When multiple observers define the same structure on the same image there can be significant differences depending on the structure, image quality/modality and the region being defined. It is often desirable to estimate this type of aleatoric uncertainty in a segmentation model to help understand the region in which the true structure is likely to be positioned. Furthermore, obtaining these datasets is resource intensive so training such models using limited data may be required. With a small dataset size, differing patient anatomy is likely not well represented causing epistemic uncertainty which should also be estimated so it can be determined for which cases the model is effective or not. MethodsWe use a 3D probabilistic U-Net to train a model from which several segmentations can be sampled to estimate the range of uncertainty seen between multiple observers. To ensure that regions where observers disagree most are emphasised in model training, we expand the Generalised Evidence Lower Bound (ELBO) with a Constrained Optimisation (GECO) loss function with an additional contour loss term to give attention to this region. Ensemble and Monte-Carlo dropout (MCDO) uncertainty quantification methods are used during inference to estimate model confidence on an unseen case. We apply our methodology to two radiotherapy clinical trial datasets, a gastric cancer trial (TOPGEAR, TROG 08.08) and a post-prostatectomy prostate cancer trial (RAVES, TROG 08.03). Each dataset contains only 10 cases each for model development to segment the clinical target volume (CTV) which was defined by multiple observers on each case. An additional 50 cases are available as a hold-out dataset for each trial which had only one observer define the CTV structure on each case. Up to 50 samples were generated using the probabilistic model for each case in the hold-out dataset. To assess performance, each manually defined structure was matched to the closest matching sampled segmentation based on commonly used metrics. ResultsThe TOPGEAR CTV model achieved a Dice Similarity Coefficient (DSC) and Surface DSC (sDSC) of 0.7 and 0.43 respectively with the RAVES model achieving 0.75 and 0.71 respectively. Segmentation quality across cases in the hold-out datasets was variable however both the ensemble and MCDO uncertainty estimation approaches were able to accurately estimate model confidence with a p-value < 0.001 for both TOPGEAR and RAVES when comparing the DSC using the Pearson correlation coefficient. ConclusionsWe demonstrated that training auto-segmentation models which can estimate aleatoric and epistemic uncertainty using limited datasets is possible. Having the model estimate prediction confidence is important to understand for which unseen cases a model is likely to be useful.

Quality of life and testosterone recovery after androgen deprivation therapy in patients with high-risk prostate cancer: Long-term data from a phase III trial.

11098 Background: No prospectively collected data exist assessing the impact a hypogonadal status has on quality of life (QoL). Using data from a randomized Phase III trial in high-risk prostate cancer (HRPC) and based on Patient Reported Outcomes (PRO), we compared QoL between patients (pts) with or without testosterone (T) recovery after ADT. Methods: From 10/2000 to 01/2008, 630 pts with HRPC were randomised to 36 (310 pts) vs. 18 months (320 pts) of ADT. We assessed QoL by the validated EORTC 30 items regrouped into 9 scales and the PR 25 items into 5 scales. All items and scales scores were linearly transformed to a 0 to100 points scale. T measured at baseline and during follow-ups. T recovery was defined as a return to normal level. PRO measured up to 5 years. We estimated means and standard deviation of items and scales for each group at each time point. We analyzed all items and scales scores with general linear model with repeated measures to evaluate changes between patients who did versus those who did not recover T to a normal level, over time, in both ADT groups. P-value &lt;0.01 was considered statistically significant to account for multiple comparisons and a difference in mean scores of ≥10 points was considered clinically relevant. Results: 494/630 patients were retained for the analysis. 515 had proper T data available (baseline and follow-up) from whom 21 were excluded (no QoL data). With a median follow-up of 13.1 years, the two groups were well-balanced. Over a period of 21 years, 5 982 T measurements were available: 3590 in 314 pts in the and 2392 in the 18- and 36-month cohort, respectively. A total of 256 (51.8%) recovered T to, at least, a pre-castrate level. A significantly higher percentage of pts recovered a normal T level in the 18-month cohort as compared to the 36-month (56.4% vs. 43.9%, p=0.008). Among pts regaining T to a normal level, the median time to recovery was significantly faster for the 18 compared to the 36-month cohort, 3.0 (95% CI: 2.55 to 3.65) vs. 5.00 (4.50 to 5.96) years, p&lt;0.001. Considering the unified 55 items, overall adherence to QoL questionnaires (QoLQ) was 83.1% (4554/5480), 88.2% vs. 93.3% at baseline and 61.5% vs 58.3% at 5 years, for 18 vs. 36-month, respectively. Patients recovering T had a significantly better QoL. In 32 out of 55 items and in 10 out of 21 scales (p&lt;0.01) in the 18-month and 30 out of 55 items and 10 out of 21 scales the 36-month cohort. Also 9 items and one scale reached clinical relevance in the 18-month cohort and 10 items and one scale in the 36-month cohort. Conclusions: In HRPC treated with RT and long-term ADT, T recovery to normal level is associated with major improvements in QoL in several domains. Since a higher proportion of pts recover a normal T level in a much shorter time without apparent detriment in long term outcomes, our results suggest that 18-month may be the most appropriate ADT duration for these pts.

Racial/ethnic distribution of participants in NRG oncology clinical trials: 2014-2023.

e13706 Background: External validity and applicability of clinical research relies upon characteristics of trial participants matching those of the respective disease groups in the general population. Understanding the racial/ethnic distribution of patients enrolled in recent US-based, federally sponsored Phase II and III clinical trials could inform strategies to further align characteristics of trial participants with those of disease group populations. As such, we report the racial/ethnic distribution of participants in NRG Oncology studies during 2014-2023 and compare the distribution to that from the Surveillance, Epidemiology, and End Results (SEER) program data during 2014-2020 (most recent data available). Methods: Proportions of self-reported race/ethnicity were summarized for the 33,370 trial participants enrolled since Mar 1, 2014 (NRG Oncology inception) to therapeutic, symptoms management, and other interventional trials. SEER proportions were used to benchmark NRG trials for representativeness of disease burden in the population. Results: Among NRG trial participants, 71.5% were non-Hispanic (NH) White, 9.7% NH Black, 4.9% Hispanic, and 7.8% N-H Asian (Table). Examining distributions within selected cancer sites relative to cancer proportional incidence in 2014-2020 SEER data, NRG accrual to prostate, lung, cervix, and breast cancer trials is commensurate with observed disease burden for NH Blacks and modestly lower for Asians. For other sites shown, representation was 2 to 5 percentage points lower than SEER frequencies for Blacks and Asians. For all sites, accrual of individuals of Hispanic background was lower than that reported in SEER. As the NRG trials do not reflect sampling across stages and other features of a given cancer in the population, further analysis to be presented will consist of more detailed breakdowns of trial participant disease-specific cancer stage and tumor subtype and comparison to relevant observations from the 2014-2020 SEER database. Conclusions: This high-level comparison of the racial/ethnic distribution of NRG trial participants provides supportive information for population representative enrollment in several cancer sites, but also identifies opportunities to improve enrollment diversity to represent more closely the respective affected population. Areas of success identified merit further investigation to understand if there are best practices which may be applied more broadly towards expanding access to federally funded clinical trials. [Table: see text]

Underrepresentation of Asian Americans, Native Hawaiians, and other Pacific Islanders (AA &amp; NHPI) in cancer clinical trials that led to FDA approvals in 2010-2022.

11026 Background: About 6% and 0.3% of the total United States (US) population identify as Asian or NHPI alone, respectively. The most commonly diagnosed cancers among AA &amp; NHPI in the US are breast, prostate, lung, thyroid, and colorectal. Liver, gastric, and head and neck cancers occur in higher rates in AA &amp; NHPI vs. non-Hispanic White. Enrollment of Asian &amp; NHPI patients in multiregional cancer clinical trials may provide additional data regarding intrinsic and extrinsic factors (e.g., diet, infections, environmental exposures) impacting the etiology of cancer. We investigated enrollment trends of NHPI and Asian (within and outside of US) patients in cancer clinical trials that led to an FDA approval from 2010-2022. Methods: We analyzed data from ~98,000 patients in 171 cancer therapeutic clinical trials that led to FDA approvals for breast, prostate, lung, thyroid, colorectal, liver, gastric, and head and neck cancer indications from 2010-2022. Separate race categories of Asian and Native Hawaiian and other Pacific Islander were used. Results: Descriptive statistics of NHPI and Asians within and outside of US enrollment in breast, prostate, lung, thyroid, colorectal, liver, gastric, and head and neck cancer trials that led to an FDA approval from 2010-2022 are summarized in the table. Enrollment of Asian patients in the US was &lt;1% (except for liver cancer) and NHPI patients was &lt;0.2%. Conclusions: Although cancer is the leading cause of death for AA &amp; NHPI, AA &amp; NHPI are under-represented in cancer clinical trials, especially when data are further disaggregated into enrollment of NHPI and Asians within and outside of the US. Cancer etiology may vary in Asians in the US vs. Asia due to different intrinsic/extrinsic risk factors, underscoring the importance of enrolling more AA &amp; NHPI into clinical trials to expand the evidence supporting drug approvals in the US and to advance health equity through clinical trial diversity. [Table: see text]

Abstract PO3-06-13: A novel stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor targeting microtubules (60c) is effective against taxane-resistant, metastatic breast cancer

Abstract Background: Improving survival for patients diagnosed with metastatic disease and treating spontaneous chemoresistance remain major clinical challenges in treating breast cancer. Triple negative breast cancer (TNBC), characterized by a lack of therapeutically targetable receptors (ER/PR/HER2), is an aggressive subtype of breast cancer. TNBC therapy relies on a combination of systemically administered chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA approved MTAs that bind to the colchicine-binding site. Approximately 70% of patients who initially respond to paclitaxel, a first-line MTA, will develop taxane resistance (TxR) within 6 months. We have previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), sabizabulin (formerly known as Veru-111), not only inhibits TNBC tumor progression but also treats pre-established metastatic disease in a taxane-refractory PDX model, HCI-10-Luc2. Sabizabulin is currently in phase II/III trials for advanced prostate cancer. To further improve potency and metabolic stability, we created next-generation derivatives of the sabizabulin scaffold, including 60c. Results: 60c shows improved potency compared to sabizabulin against taxane-sensitive and TxR TNBC models, inhibiting proliferation and clonogenicity at low nanomolar concentrations, and inducing apoptosis in a dose-dependent manner. In vivo, 60c therapy significantly suppressed primary tumor growth and lung metastasis in an orthotopic MDA-MB-231-TxR xenograft model without gross toxicity, and with equivalent efficacy to combrestatin A4 phosphate (CA-4P), another CBSI in clinical trials. In the taxane-refractory HCI-10-Luc2 PDX model, 60c significantly suppressed both the growth of the primary tumor (by ~3.5 fold) and the expansion of pre-established axillary metastases (by ~26 fold) whereas paclitaxel had no effect. Analysis of total photon flux of organs excised at study endpoint showed that 60c had distinct anti-metastatic tropism as compared to sabizabulin. Whereas 60c completely suppressed metastases to the spleen (0/9 mice had signal), and significantly reduced metastatic burden in the leg bones (only 3/9 mice had signal) and in the kidney (only 2/9 mice had signal), 60c had no statistically significant effect on liver metastases. In contrast, we had previously reported that sabizabulin strongly repressed liver metastases in the same PDX model (0 mice with detectable liver metastases), with less potent effects on bone. Unlike 60c, sabizabulin showed no improvement relative to the vehicle control for spleen and kidney metastases. Together, our data positions 60c as a promising candidate for TNBC therapy, particularly for patients with TxR disease. Our results also suggest that different CBSI scaffolds may preferentially inhibit metastasis to specific organs, which requires further investigation. Citation Format: Damilola Oluwalana, Kelli Hartman, Raisa Krutilina, Hao Chen, Hilaire Playa, Shanshan Deng, Deanna Parke, Duane Miller, Tiffany Seagroves, Wei Li. A novel stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor targeting microtubules (60c) is effective against taxane-resistant, metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-13.

2404: Proton therapy robustness in a pilot study prior to a randomised trial for high-risk prostate cancer

2404: Proton therapy robustness in a pilot study prior to a randomised trial for high-risk prostate cancer