Prostate Cancer Clinical Trials Consortium

5002 Background: Phase III post-hoc analyses show poor prognosis of PSA >0.2 in mHSPC treated by androgen deprivation therapy (ADT) and ARPI, but it remains unclear 1) when PSA cutoffs should be interpreted for prognostic significance, and 2) how PSA cutoffs may differ in real-world multinational data. IRONMAN (International Registry for Men with Advanced Prostate Cancer) prospectively enrolled mHSPC patients from 16 countries and is a unique large data set to investigate these questions. Methods: Patients with mHSPC who received ADT, ARPI +/- docetaxel with PSA data enrolled in the IRONMAN registry were included. 3 PSA strata (>0.2, 0.02 to 0.2, and <0.02ng/ml) were defined at 6- and 12-months (primary analysis) after treatment start. Multivariable Cox proportional hazard regression models were constructed for overall survival (OS) and progression-free survival (PFS, as defined by any of biochemical, radiographic or clinically progression) with adjustment for disease characteristics. A 12-month landmark population was constructed to determine conditional OS and PFS in each PSA stratum. Results: 1288 patients received ADT and ARPI within 90 days of IRONMAN enrolment and met inclusion. Key characteristics were median age 70 years, 69.5% de-novo metastatic, 59% Gleason 8-10, 73% Caucasian, 8.2% Black, 1.5% Asian, 7.3% lung metastases, 3.4% liver metastases, and 53.2% enrolment from centers outside US/Canada. Intensification agents were: abiraterone acetate (576, 44.7%), apalutamide (283, 22.0%), darolutamide (135, 10.5%), or enzalutamide (294, 22.8%), and 122 (8.7%) received docetaxel in addition to ADT-ARPI. PSA at 6, 12 month landmarks respectively were: <0.02 (10%, 21%); 0.02-0.2 (41%, 45%); >0.2 (49%, 34%), with 70% of patients with 6-month PSA >0.2 retained at 12-months. Outcome data in the 12-month landmark cohort are detailed in Table 1, with 3-year OS for the PSA >0.2 stratum significantly worse than the PSA<0.02 stratum (45.3 vs 92.7%, p<0.001), representing a 7-fold mortality risk in the Cox model adjusted hazard ratio (aHR) and 8-fold risk of progression. Conclusions: IRONMAN provides large real-world data validating the poor prognosis of mHSPC with PSA>0.2 after 6-12 months ADT-ARPI treatment and these patients could be targeted for intensification in future trials. Conversely, PSA<0.02 at 6-12 months defines the best prognosis and may be of interest for de-intensification strategies. OS and PFS outcomes by 12-month PSA strata. 12-mo PSA (ng/ml) n 3-yr OS [95%CI] 3-yr PFS [95% CI] OS Cox model mortality risk [95% CI] >0.2 264 45.3% [36.7-55.9] 36.7% [28.6-47.1] aHR 7.34 [3.66-14.71] 0.02-0.2 585 80.0% [74.5-85.9] 72.9% [66.9-79.1] aHR 2.16 [1.06-4.41] <0.02 439 92.7% [87.9-97.8] 93.0% [88.6-97.5] reference

In 2020, BLOODPAC recommended 11 pre-analytical minimal technical data elements for collection and submission of liquid biopsy data to public databases. This article expands on that work by recommending 22 clinical context and 10 patient context data elements. These elements, essential for liquid biopsy data submitted to repositories like the BLOODPAC Data Commons, cover tumor characteristics, disease progression, and patient demographics, supporting biomarker validation, research, and clinical trials.

Studies have shown improved survival among individuals with cancer with higher levels of social support. Few studies have investigated social support and overall survival (OS) in individuals with advanced prostate cancer in an international cohort. We investigated the associations of marital status and living arrangements with OS among individuals with advanced prostate cancer in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). IRONMAN is enrolling participants diagnosed with advanced prostate cancer (metastatic hormone-sensitive prostate cancer, mHSPC; castration-resistant prostate cancer, CRPC) from 16 countries. Participants in this analysis were recruited between July 2017 and January 2023. Adjusting for demographics and tumor characteristics, the associations were estimated using Cox regression and stratified by disease state (mHSPC, CRPC), age (<70, ≥70 years), and continent of enrollment (North America, Europe, Other). We included 2,119 participants with advanced prostate cancer, of whom 427 died during up to 5 years of follow-up (median 6 months). Two-thirds had mHSPC. Most were married/in a civil partnership (79%) and 6% were widowed. Very few married participants were living alone (1%), while most unmarried participants were living alone (70%). Married participants had better OS than unmarried participants [adjusted HR: 1.44; 95% confidence interval (CI): 1.02-2.02]. Widowed participants had the worst survival compared with married individuals (adjusted HR: 1.89; 95% CI: 1.22-2.94). Among those with advanced prostate cancer, unmarried and widowed participants had worse OS compared with married participants. This research highlighted the importance of social support in OS within this vulnerable population.

275 Background: Docetaxel prednisone (DP) is a standard of care for men with metastatic castrate resistant prostate cancer (mCRPC) with median progression-free survival (PFS) of 4-6 months and overall survival (OS) of 19 months, supporting a need for further treatment options. Pazopanib (PAZO) is a multi-targeted kinase inhibitor of VEGF receptors approved for treatment of kidney cancer and sarcoma. We performed a two center, Phase Ib study of DP + PAZO to evaluate the safety and early efficacy in mCRPC. Methods: This is a 2 site phase 1 DOD Prostate Cancer Clinical Trials Consortium trial of DP + PAZO once daily with ongoing ADT in men with mCRPC. The primary endpoint was safety; secondary endpoints included evaluation of a maximum tolerated dose (MTD) through a dose escalation and expansion design, pharmacokinetic assessments, PSA and radiographic responses, and toxicity. Results: Twenty-five men were treated over 6 dose levels using a 3+3 design. Pegfilgrastim (Neu) was added to the regimen after myelosuppression limited dose escalation. With Neu, our target MTD of D 75 mg/m2; P 10 mg QD and PAZO 800 mg QD was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. 17 patients had received prior Abi and/or Enza. The most common AEs were alopecia (86%), fatigue (69%), diarrhea (58%), and nausea (53%), and the most common Grade 3-5 SAEs were neutropenia (33%) and leukopenia (19%). Three deaths attributed to study treatment occurred: one from pneumonitis, one from respiratory failure, and one from intracranial hemorrhage. The proportion of 30%, 50% and 90 % PSA declines were 69%, 58% and 25%, respectively. The objective response rate was 31% (11/36). Median PFS was 18.6 months (95% CI: 6.5, 27.7) and OS was 22.2 months (95% CI: 14.7, -). Predicted median OS using the Halabi nomogram was 20.9 months (95% CI: 19.2, 23.0) with 23%, 34% and 43% of patients in low, intermediate and high risk groups, respectively. Conclusions: DP + PAZO (with Neu) were tolerable at full doses and demonstrated a surprisingly long PFS and high objective response rate in a relatively poor risk group of mCRPC patients. These data support further randomized studies of DP + Pazo in Abi/Enza refractory patients. Clinical trial information: NCT01385228.

190 Background: Cabazitaxel resistance develops within a few months of treatment initiation in most men with mCRPC in post-docetaxel, and thus combination therapy with other active agents may improve outcomes. Tasquinimod is an oral immunomodulatory agent with anti-angiogenic and anti-tumor in preclinical models of PC and clinical activity in phase II and III trials. Methods: We conducted a phase I dose escalation trial of cabazitaxel plus tasquinimod in men with mCRPC. Cabazitaxel was dosed at 25 mg/m2 every 3 weeks with low dose prednisone and PEG-filgrastim support, and tasquinimod dose levels included 0.25, 0.5, and 1.0 mg, using a 3 week within-patient dose escalation for dose levels 2 and 3, starting all patients at 0.25 mg once daily. The primary objective was to define the recommended phase II dose (RP2D) based on safety and dose limiting toxicity. Preliminary efficacy (PSA decline, PFS) and pharmacokinetic interactions were key secondary objectives. Results: We enrolled 25 men with mCRPC who had failed docetaxel across 3 dose levels. Median PSA at entry was 220 ng/dl. The RP2D was 0.5 mg tasquinimod based on excess DLTs (2 of 3 men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation). Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function test abnormalities. The proportion of men with a &gt; 30% PSA decline was 63% (95% CI: 41%, 81%). The median composite PFS was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with 6 men receiving &gt; 10 cycles. Best overall RECIST responses (CR+PR) were observed in 3 men (12%), stable disease in 12 (48%). No unexpected adverse events were observed and no pharmacokinetic interactions were observed. Conclusions: The RP2D was cabazitaxel 25 mg/m2 with prednisone and PEG-filgrastim every 3 weeks with tasquinimod 0.25 mg once daily for 3 weeks followed by 0.5 mg. Preliminary evidence of efficacy over cabazitaxel alone is based on observed PSA response and PFS data, and a substantial number of men were progression free beyond 10 cycles with good tolerability. Clinical trial information: NCT01513733.