PSA Decline Research Articles

Baseline Plasma Tumor DNA (ctDNA) Correlates with PSA Kinetics in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide.

Simple SummaryProstate cancer is a very common disease in men. Nowadays several life-prolonging therapies are available, also efficient in the metastatic setting. However, it is important to choose the best approach for each patient, and in this context molecular biomarkers are fundamental. Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain correlates with worse outcomes. This study investigates correlation between PSA response endpoints, plasma DNA analysis and progression free/overall survival, underling the importance of a multimodal approach to early predict outcome.Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate ctDNA fraction and AR CN from plasma samples. We divided patients into high and low ctDNA level and in AR gain and AR normal. Results: 220 baseline samples were collected from mCRPC treated with abiraterone (n = 140) or enzalutamide (n = 80). A lower rate of PSA decline ≥ 50% was observed in patients with high ctDNA (p = 0.017) and AR gain (p = 0.0003). Combining ctDNA fraction and AR CN, we found a different median PSA progression-free survival (PFS) among four groups: (1) low ctDNA/AR normal, (2) high ctDNA/AR normal, (3) low ctDNA/AR gain, and (4) high ctDNA/AR gain (11.4 vs. 5.0 vs. 4.8 vs. 3.7 months, p < 0.0001). In a multivariable analysis, high ctDNA, AR gain, PSA DT, PSA DT velocity remained independent predictors of PSA PFS. Conclusions: Elevated ctDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abiraterone or enzalutamide.

The prognostic potential of alkaline phosphatase and lactic acid dehydrogenase in bmCRPC patients without significant PSA response under enzalutamide

BackgroundIn patients with bone metastatic castration-resistant prostate cancer (bmCRPC) on systemic treatment, it is difficult to differentiate between continuous rise of prostate specific antigen (PSA) representing progression, and PSA-surge, which is followed by clinical response or stable disease. The purpose of this study was to evaluate the prognostic value of dynamic changes of alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels as a predictor of clinical efficacy or therapeutic resistance of patients who do not show a sufficient initial PSA decline of ≥50% from baseline during early therapy with Enzalutamide.MethodsForty-eight men with bmCRPC on Enzalutamide 07/2010-09/2019 with initially rising PSA were analyzed. We monitored PSA, LDH and ALP at week 0, 2, 4, and every 4 weeks thereafter and analyzed the correlation between ALP rising at 12 weeks with or without LDH-normalization and the association with survival. For this we used Kaplan Meier analysis and uni- and multivariate cox-regression models.ResultsIn Kaplan-Meier analysis, ALP rising at 12 weeks with or without LDH-normalization was associated with significantly worse median progression-free survival (PFS) of 3 months vs. 5 months (Log rank P = 0.02) and 3 months vs. 5 months (P = 0.01), respectively and overall survival (OS) with 8 months vs. 15 months (P = 0.02) and 8 months vs. 17 months (P < 0.01). In univariate analysis of PFS, ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization and application of Enzalutamide after chemotherapy showed a statistically significant association towards shorter PFS (hazard ratio (HR): 0.51, P = 0.04; HR: 0.48, P = 0.03; HR: 0.48, P = 0.03). Worse OS was significantly associated with ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization, and application of Enzalutamide after chemotherapy (HR: 0.47, P = 0.02; HR: 0.36, P < 0.01; HR: 0.31, P < 0.01). In multivariate analysis only the application of Enzalutamide after chemotherapy remained an independent prognostic factor for worse OS (HR: 0.36, P = 0.01).ConclusionsDynamic changes of ALP (non-rise) and LDH (normalization) under therapy with Enzalutamide may be associated with clinical benefit, better PFS, and OS in patients with bmCRPC who do not show a PSA decline.

A preliminary study on the diagnostic value of PSADR, DPC and TSRP in the distinction of prostatitis and prostate cancer

BackgroundThe purpose of this study was to investigate the ability of differential diagnosis of prostate specific antigen decline rate (PSADR) per week, degree of prostatic collapse (DPC) and tissue signal rate of prostate (TSRP) between prostatitis and prostate cancer.MethodsThe clinical data of 92 patients [prostate specific antigen (PSA) > 10 ng/mL] who underwent prostate biopsy in the Department of Urology, the Second Affiliated Hospital of Xi ’an Jiaotong University from May 2017 to April 2020 were reviewed retrospectively. They were divided into two groups, prostatitis group (n = 42) and prostate cancer (PCa) group (n = 50), according to pathological results. Parameters, like patient characteristics, PSADR, DPC, TSRP and infectious indicators, were compared and analyzed by t test or non-parametric test to identify if there were significant differences. The thresholds of parameters were determined by the receiver operating characteristic curve (ROC), and the data were analyzed to investigate the diagnostic value in distinguishing of prostatitis and prostate cancer.ResultsThere were statistical differences in age, PSADR, DPC, TSRP, neutrophil percentage in serum, white blood cell (WBC) in urine and prostate volume between prostatitis group and PCa group (P < 0.001, < 0.001, = 0.001, 0.001, 0.024, 0.014, < 0.001 respectively). There was no statistical difference in serum WBC count, serum neutrophil count, monocyte percentage and urine bacterial count between two groups (P = 0.089, 0.087, 0.248, 0.119, respectively). Determined by ROC curve, when the thresholds of PSADR per week as 3.175 ng/mL/week, DPC as 1.113, TSRP as 2.708 were cutoffs of distinguishing prostatitis and prostate cancer. When combining these three indexes to diagnose, the accuracy rate of diagnosis of prostatitis was 78.85%, the accuracy rate of diagnosis of prostate cancer was 97.50%. Univariate analysis suggested that PSADR, DPC and TSRP played an important role in differentiating prostate cancer from prostatitis (P < 0.05), multivariate analysis suggested PSADR > 3.175 might be good indicators when distinguishing prostate disease with prostatitis (OR = 14.305, 95%CI = 3.779 ~ 54.147), while DPC > 1.113 and TSRP > 2.708 might be associated with a higher risk of prostate cancer (OR = 0.151, 95%CI = 0.039 ~ 0.588; OR = 0.012, 95%CI = 0.005 ~ 0.524, respectively).ConclusionThe combination of PSADR per week, DPC, and TSRP might be helpful to distinguish prostate cancer and prostatitis, and can reduce unnecessary invasive and histological procedure.

177Lu-PSMA-I&amp;T Radioligand Therapy for Treating Metastatic Castration-Resistant Prostate Cancer: A Single-Centre Study in East Asians

PurposeThere is increasing evidence for convincing efficacy and safety of 177Lu-labled prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) for metastatic castration-resistant prostate cancer (mCRPC). However, data are not available regarding the feasibility of 177Lu-labled PSMA-targeted RLT in East Asians. The present study summarized the first experience with 177Lu-PSMA-I&T therapy for mCRPC in China.MethodsForty consecutive patients with mCRPC were enrolled from December 2019 to September 2021. Eligible patients received 177Lu-PSMA-I&T RLT at intervals of 8-12 weeks. Toxicity was assessed based on standardized physicians’ reports and the Common Toxicity Criteria for Adverse Events criteria. Response to PRLT was evaluated according to the changes of prostate specific antigen (PSA) response and imaging response. Quality of life (QOL), Karnofsky performance status (KPS) and pain (visual analogue scale, VAS) were also evaluated. The impacts of baseline parameters on the therapeutic effects were explored by univariate and multivariate logistic regression analyses.ResultsAll patients underwent a total of 86 cycles of 177Lu-PSMA-I&T (range: 1-5 cycles) with dosages of 3.70-14.43GBq per cycle, with a median of 8 months followed up. Six patients (15%) developed mild reversible xerostomia during follow-up, and 28 patients (70%) experienced grade 1-4 bone marrow dysfunction. Changes in PSA were assessed after therapy, accompanied by the partial response (PR) in 25 patients (62.5%), the stable disease (SD) in 5 patients (12.5%), and the progressive disease (PD) in 10 patients (25%), respectively. QOL, KPS (%) and VAS scores were improved significantly due to treatment (P<0.05). Overweight and elevated AST, ALP, and LDH were associated with poor outcomes.Conclusions 177Lu-PSMA-I&T achieves the favourable response and well tolerance in mCRPC, which associates with not only PSA decline but also with tumor remission including lymphadenopathy and bone metastasis. We also find that patients with overweight and high AST, ALP, and LDH should be cautious to undergo the PRLT. Large-cohort studies are warranted to confirm the initial findings and elucidate the survival benefit of the treatment.

177 Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis.

BackgroundAn updated systematic review and meta‐analysis of relevant studies to evaluate the effectiveness of prostate‐specific membrane antigen (PSMA)‐targeted endoradiotherapy/radioligand therapy (PRLT) in castration resistant prostate cancer (CRPC).MethodsA systematic search was performed in July 2020 using PubMed/Medline database to update our prior systematic review. The search was limited to papers published from 2019 to June 2020. A total of 472 papers were reviewed. The studied parameters included pooled proportion of patients showing any or ≥50% prostate‐specific antigen (PSA) decline after PRLT. Survival effects of PRLT were assessed based on pooled hazard ratios (HRs) of the overall survival (OS) according to any PSA as well as ≥50% PSA decline after PRLT. Response to therapy based on ≥50% PSA decrease after PRLT versus controls was evaluated using Mantel‐Haenszel random effect meta‐analysis. All p values < 0.05 were considered as statistically significant.ResultsA total of 45 publications were added to the prior 24 studies. 69 papers with total of 4157 patients were included for meta‐analysis. Meta‐analysis of the two recent randomized controlled trials showed that patients treated with 177Lu‐PSMA 617 had a significantly higher response to therapy compared to controls based on ≥50% PSA decrease. Meta‐analysis of the HRs of OS according to any PSA decline and ≥50% PSA decline showed survival prolongation after PRLT.ConclusionsPRLT results in higher proportion of patients responding to therapy based on ≥50% PSA decline compared to controls. Any PSA decline and ≥50% PSA decline showed survival prolongation after PRLT.Advances in knowledge: This is the first meta‐analysis to aggregate the recent randomized controlled trials of PRLT which shows CRPC patients had a higher response to therapy after PRLT compared to controls.

Outcome of Patients with PSMA PET/CT Screen Failure by VISION Criteria and Treated with 177Lu-PSMA Therapy: A Multicenter Retrospective Analysis.

The aim of the study was to assess the outcome of patients with metastatic castration-resistant prostate cancer treated with 177Lu-prostate-specific membrane antigen (PSMA) who would have been a screen failure (SF) in the VISION trial based on PSMA PET/CT criteria. Methods: We conducted a retrospective multicenter cohort study on 301 patients with metastatic castration-resistant prostate cancer treated with 177Lu-PSMA. The patients were classified into eligible (VISION-PET-E) and SF (VISION-PET-SF) groups on the basis of the baseline PSMA PET/CT results. Prostate-specific antigen (PSA) response rates, PSA progression-free survival, and overall survival were compared. Results: Of 301 patients, 272 (90.4%) and 29 (9.6%) were VISION-PET-E and VISION-PET-SF, respectively. The VISION-PET-SF patients had a worse rate of ≥50% PSA decline (21% vs. 50%, P = 0.005) and PSA progression-free survival (2.1 vs. 4.1 mo, P = 0.023) and tended to have a shorter overall survival (9.6 vs. 14.2 mo. P = 0.16) than the VISION-PET-E patients. Conclusion: The VISION-PET-SF patients had worse outcomes than the VISION-PET-E patients. Our cohort did not include preexcluded patients (10%-15%) by local site assessments. Thus, 20%-25% of the patients may be SFs in unselected populations. Refinements in patient selection for 177Lu-PSMA are needed to optimize outcomes.

Current Status of Monoclonal Antibodies-Based Therapies in Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis of Clinical Trials.

BackgroundMultiple patients with prostate cancer become resistant to castration therapies, which is termed castration-resistant prostate cancer (CRPC).PurposeThe purpose of this review is to assess the status of efficacy (≥50% decline in prostate-specific antigen (PSA), progression-free survival (PFS), and overall survival (OS)) and safety (grade 3-4 adverse effects) of monoclonal antibodies in CRPC.Data sourceWe searched databases including PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov.ResultsHazard ratios of PFS and OS were 0.77 (95% CI = 0.69-0.87, I2 = 53%) and 0.98 (95% CI = 0.86-1.11, I2 = 40%), respectively, in the favor of monoclonal antibodies as compared to placebo. Risk ratio (RR) of >50% decline in PSA was 1.99 (95% CI = 0.97-4.08, I2 = 53%) in favor of monoclonal antibodies. Pooled incidence of >50% decline in PSA levels was 15% (95% CI = 0.1-0.23, I2 = 83%), 29% (95% CI = 0.14-0.51, I2 = 93%), 63% (95% CI = 0.49-0.76, I2 = 77%), and 88% (95% CI = 0.81-0.93, I2 = 0%) in single, two, three, and four-drug regimens, respectively.ConclusionMonoclonal antibodies are well tolerated and showed better PFS as compared to placebo. However, OS was only improved with ipilimumab. Denosumab delayed skeletal-related adverse events as compared to zoledronic acid. More multicenter double-blind clinical trials may be needed to confirm these results.

Magnetic Resonance Imaging-Guided Transurethral Ultrasound Ablation of Prostate Cancer: A Systematic Review.

Purpose:MRI-guided transurethral ultrasound ablation (TULSA) uses real-time MR thermometry feedback to target prostate disease. We systematically review the literature to synthesize efficacy, functional, and safety outcomes and assess the influence of planned ablation fraction on outcome.Materials and Methods:PubMed, Embase, and the Cochrane Library were searched from inception to June 2021 following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies reporting at least one efficacy, functional, or safety outcome after a single TULSA treatment were included. The relationship of freedom from salvage treatment and potency preservation with planned ablation volume was modeled.Results:Two hundred twenty-four patients were treated in 10 studies with up to a 5-year follow-up, mainly for primary localized prostate cancer (PCa) plus smaller cohorts with recurrent PCa, and locally advanced PCa (LAPC). The prostate-specific antigen decline from baseline up to 2 years, including focal to whole-gland ablation plans, was 54% to 97%. The rate of salvage treatment after one TULSA treatment for primary PCa was 7% to 17%. Continence and potency preservation were from 92% to 100% and from 75% to 98%. Urinary symptoms were stable in men with good voiding function at baseline, and 85% of men with concurrent PCa and lower urinary tract symptoms met the criteria for improvement. Symptom relief in a small cohort of men with LAPC was observed. Grade III adverse events were incurred by 13/224 men (6%), with no rectal injury/fistula or Grade IV complication. The planned ablation fraction was linearly related to salvage-free survival. The relationship between potency preservation and planned ablation fraction followed a sigmoid curve.Conclusions:As an alternative to conventional treatments, TULSA is safe and effective for prostate tissue ablation in men with primary PCa. There is also evidence that TULSA delivers effective relief of urinary symptoms while treating PCa in a single, low-morbidity procedure. The likelihood of freedom from additional treatment or potency preservation is associated with the planned ablation fraction.

Phase 2 trial of T-cell activation using MVI-816 and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC)

BackgroundWe previously reported a trial using a DNA vaccine encoding prostatic acid phosphatase (MVI-816, pTVG-HP), given over 12 weeks concurrently or sequentially with pembrolizumab, in patients with mCRPC. We report...

A review of clinical evidence to assess differences in efficacy and safety of luteinizing hormone-releasing hormone (LHRH) agonist (goserelin) and LHRH antagonist (degarelix).

Luteinizing hormone-releasing hormone agonist (LHRH-A), goserelin, and antagonist, degarelix, are both indicated for the treatment of advanced prostate cancer (PCa); however, large comparative trials evaluating their efficacy and safety are lacking. In this review, we assessed the available evidence for both the drugs. Although degarelix achieves an early rapid decline in testosterone (T) and prostate-specific antigen (PSA) levels, median T and PSA levels, in addition to prostate volume and International Prostate Symptom Scores, become comparable with goserelin over the remaining treatment period. Degarelix causes no initial flare, therefore it is recommended in patients with spinal metastases or ureteric obstruction. Goserelin achieves lower PSA, improved time to progression, and better survival outcomes when administered adjunctively to radiotherapy compared with radiotherapy alone, with significant results even over long-term follow-up. The evidence supporting adjuvant degarelix use is limited. Goserelin has better injection site safety, single-step delivery, and an efficient administration schedule compared with degarelix, which has significantly higher injection site reactions and less efficient administration mechanism. There is conflicting evidence about the risk of cardiovascular disease (CVD), and caution is required when using LHRH-A in patients with preexisting CVD. There is considerable long-term evidence for goserelin in patients with advanced PCa, with degarelix being a more recent option. The available comparative evidence of goserelin versus degarelix has several inherent limitations related to study design, sample size, conduct, and statistical analyses, and hence warrants robust prospective trials and long-term follow-up.

Serial stereotactic body radiation therapy for oligometastatic prostate cancer (PCa) detected by positron emission tomography (PET) imaging.

109 Background: Radiopharmaceuticals, including Ga-68-prostate specific membrane antigen (PSMA)-11, F-18-fluciclovine, and choline C-11, are increasingly used to stage and inform therapies for PCa. Stereotactic body radiation therapy (SBRT) to PET-detected oligometastatic PCa has been shown to improve progression free survival (PFS) compared to observation. However, for men who subsequently develop oligorecurrent disease, outcomes following second SBRT are unknown. Methods: A retrospective, single-center, cohort study was conducted. Pts were identified through electronic health records. Inclusion criteria included pts with oligometastatic (1-5 lesions) PCa detected on PSMA, fluciclovine, or choline C-11 PET who underwent 2 consecutive courses of SBRT to tracer-avid oligometastatic disease between 7/2013 and 7/2021. Exclusion criteria included presence of visceral metastases and pure small cell neuroendocrine PCa. Data on stage, tracer type, concurrent systemic therapy, and prostate-specific antigen (PSA) responses for first SBRT (SBRT1) and second SBRT (SBRT2) were collected. Outcomes included PSA decline of ≥50% (PSA50), ≥90% (PSA90), and PSA-PFS. SBRT2 outcomes were compared based on change of concurrent systemic therapy with SBRT2 (e.g., addition of abiraterone or anti-androgen withdrawal) and PSA50 to SBRT1 using Fisher’s exact text and Wilcoxon rank sum test, respectively. Results: A total of 12 pts met eligibility criteria. At SBRT1, 10 (83%) pts had hormone-sensitive PCa (HSPC) and 2 (17%) had castration-resistant PCa (CRPC). For PET tracers, 7 (58%) used PSMA, 4 (33%) fluciclovine, and 1 (8%) choline. After SBRT1, 12 pts (100%) had a PSA decline, 8 (67%) had a PSA50 response, and 6 (50%) a PSA90 response. Median PSA PFS after SBRT1 was 30mo (95%CI 9-65mo). Six (50%) SBRT1 pts had a concurrent change in systemic therapy. At SBRT2, 8 (67%) pts had HSPC and 4 (33%) had CRPC; 7 (58%) used PSMA and 5 (42%) fluciclovine. After SBRT2, 12 (100%) pts had a PSA decline, 8 (67%) had a PSA50 response, and 8 (67%) a PSA90 response. After SBRT2, median PSA PFS was 23mo (95%CI 12-35mo). Among 7 pts who had a concurrent change in systemic therapy with SBRT2, all (100%) had a PSA50 response; among 5 who did not (4 of whom did not receive any systemic therapy), 1 (20%) had a PSA50 response (P=0.01). Among 8 pts who had a PSA50 response to SBRT1, 7 (88%) had one to SBRT2; among 4 who did not have a PSA50 response to SBRT1, 1 (25%) had one to SBRT2 (P=0.01). No complications related to SBRT were documented. Conclusions: Serial SBRT for oligometastatic PCa detected on fluciclovine, PSMA, or choline PET is feasible and can achieve PSA declines independent of systemic therapy. PSA responses were greater when systemic therapy was changed. This preliminary evidence of benefit, based on PSA responses and PSA PFS, provides rationale for larger, prospective studies of serial SBRT for oligometastatic PCa.

Prostate-specific antigen (PSA) outcomes in black (B) and white (W) chemotherapy-naïve (CN) prostate cancer (PC) patients (pts) treated with enzalutamide (ENZA).

20 Background: Population-level data suggest that B men are more likely to be diagnosed and die from PC. In juxtaposition, across multiple treatments for advanced PC, studies suggest B men have better survival than W men, including with novel hormone therapies (NHTs) such as ENZA. Whether improved survival is driven by better clinical response is unknown as data on racial differences in treatment response for ENZA are limited. This study assessed real-world PSA outcomes (response and progression) of ENZA-treated B vs W CN PC pts in the US. Methods: This retrospective cohort study included PC pts who initiated ENZA in the IntrinsiQ Specialty Solutions urology electronic medical records database from Sept 1, 2014 to Feb 28, 2018. The index date was the first prescription for ENZA. Patients with evidence of prior chemotherapy and/or abiraterone were excluded. Baseline characteristics, PSA response (PSA decline ≥50% or ≥90%), and clinical progression-free survival (cPFS) were assessed by race. Kaplan-Meier and Cox models adjusting for baseline characteristics were used to estimate PSA response and cPFS. Results: The study included 214 B and 1,332 W CN PC pts. Black pts were younger and had a higher baseline median PSA than W pts. Charlson Comorbidity Index (CCI), median duration of therapy, follow-up time, and number of post-index PSA tests were similar between races. In adjusted analyses, the chances of pts achieving ≥50% PSA decline was similar, whereas a numerically higher trend was observed for ≥90% PSA decline in B pts (Table). In addition, B men had significantly better cPFS (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.68, 0.98; p=0.03) [Table]. Conclusions: This real-world study found similar PSA response in B and W CN PC pts treated with ENZA but suggests that B pts may have better cPFS than W pts. Further research is warranted to validate these findings.[Table: see text]

Attainment of early, deep prostate-specific antigen response in metastatic castration-sensitive prostate cancer: A comparison of patients initiated on apalutamide or enzalutamide.

43 Background: Deep prostate-specific antigen (PSA) response, defined as a ≥90% decline in PSA (PSA90), is an important early prognostic factor for achieving radiographic progression free survival and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with a next generation androgen receptor inhibitor (ARI) or androgen biosynthesis inhibitor. This study compared PSA90 responses among patients with mCSPC at first use of a next generation ARI. Methods: Clinical data from 69 community urology practices in the United States were evaluated. Patients with mCSPC were classified into treatment cohorts based on their first filled prescription (index date) for apalutamide (APA) or enzalutamide (ENZ) after 12/16/2019. Patients were followed from index date until the earliest of index regimen discontinuation, treatment switch, end of clinical activity or end of data availability (03/05/2021). Included patients had ≥12 months of clinical activity to assess baseline characteristics. Inverse probability of treatment weighting (IPTW) was used to reduce baseline confounding by controlling for age, race, index year, androgen deprivation therapy (ADT) use ≥6 months, first-generation antiandrogen use, most recent PSA level, most recent testosterone level, Gleason score, and time between metastasis and the index date. PSA90 was defined as the earliest attainment of ≥90% decline in PSA relative to baseline PSA (most recent value within 13 weeks pre-index). The proportion of patients achieving a PSA90 and the time to PSA90 was compared using a weighted Kaplan-Meier (KM) analysis and weighted Cox proportional hazards models. Results: A total of 186 APA patients and 165 ENZ patients met the study criteria. Patients’ characteristics were generally well balanced after IPTW (Table). By 6 months, 73.6% of APA and 69.5% of ENZ patients had a post index PSA measurement. At 6 months, significantly more mCSPC patients initiated on APA attained PSA90 response than patients initiated on ENZ (p=0.014; Table). This result continued to remain significant at 9 months and at the end of the follow-up (Table). The median time to PSA90 was 3.1 months for APA patients and 5.2 months for ENZ patients. Conclusions: This real-world study of mCSPC cohorts demonstrates that initiation of APA leads to significantly more patients achieving a deep PSA response more rapidly than patients initiating ENZ. [Table: see text]

Tumor mutational burden as a predictive biomarker for immune checkpoint inhibitor versus taxane chemotherapy benefit in metastatic castration-resistant prostate cancer: A real-world biomarker study.

162 Background: The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes on one treatment vs. another. To date, no study has compared the treatment class-specific outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) on Immune Checkpoint Inhibitor (ICPI) vs. taxane chemotherapy by tumor mutational burden (TMB, mutations/megabase). Methods: Association of genomic data with clinical variables and outcomes in cohort of patients with mCRPC treated January 2011- April 2021. Longitudinal de-identified clinical data from ̃280 U.S. academic or community-based cancer clinics were derived from electronic health records, curated via technology-enabled abstraction by Flatiron Health and linked to genomic testing by Foundation Medicine (FoundationOne or FoundationOne CDx assays). 45 patients (14 with TMB ≥ 10, 31 TMB &lt; 10) received single-agent anti-PD1 axis ICPI, 696 (30 with TMB ≥ 10, 666 TMB &lt; 10) received single-agent taxanes, at discretion of physician without randomization. For time to next therapy (TTNT) and overall survival (OS) assessments, imbalances between treatment groups were adjusted with propensity weighting. Results: Overall cohort: Median age: 70 (IQR: 64 – 76), median PSA: 79.4 (IQR: 19.0 – 254), 108 (18.8%) were ECOG 2+, 644 (86.9%) had received prior systemic treatments for mCRPC. Patients receiving ICPI vs. taxanes had comparable pre-therapy age, PSA, hemoglobin, alkaline phosphatase, prior second generation novel hormonal therapy use, and prior opioid use, but higher TMB (median 3.5, IQR: 1.7 – 15 vs. median 2.5, IQR 1.3 – 3.8, p &lt; 0.001), higher ECOG scores (0, 1, 2+ respectively 13.9%, 55.6%, 30.6% vs. 29.4%, 52.6%, 18.8%, p = 0.057), and greater prior taxane use (73.3% vs. 53.7%, p = 0.01). Among patients with evaluable PSA response, no difference was observed on taxanes by TMB level. No patients had PSA decline ≥ 50% on ICPI if TMB &lt; 10, 4 of 9 with TMB ≥ 10 had PSA decline ≥ 50%. TMB &lt; 10 receiving ICPI vs. taxanes had worse TTNT (median 2.4 vs. 4.1 months; HR: 2.7, 95%CI: 1.7 – 4.0, p &lt; 0.001) and numerically worse OS (median 4.2 vs. 6.0 months, HR: 1.08; 95%CI: 0.68– 1.7, p = 0.73). In contrast, for TMB ≥ 10 ICPI vs. taxane use was associated with more favorable TTNT (median 8.0 vs. 2.4 months; HR: 0.37, 95%CI: 0.15 – 0.87, p = 0.022) and OS (median 19.9 vs. 4.2 months; HR: 0.23, 95%CI: 0.10 – 0.57, p = 0.0085). Among all 741 patients, 44 had TMB ≥ 10, 22 had high microsatellite instability (MSI-H), 20 had both. Treatment interactions with TMB ≥ 10 (TTNT: p &lt; 0.001, OS: p = 0.021) were stronger than MSI-H (TTNT: p = 0.0038, OS: p = 0.080). Conclusions: The results suggest ICPI may be a viable alternative to taxane chemotherapy for patients with mCRPC with TMB ≥ 10, adding validity to existing FDA approved platform and pan-tumor TMB score cutoff of 10.

Phase 2 trial of immunotherapy in tumors with CDK12 inactivation (IMPACT): Results from cohort A of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) receiving dual immune checkpoint inhibition (ICI).

103 Background: Prostate cancer with CDK12 inactivation represents a distinct subtype in mCRPC, tumors are characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens and increased tumor T cell infiltration. Retrospective experiences with ICI in CDK12 inactivation CRPC pts reported PSA and radiographic responses. We conducted a prospective multi-site clinical trial of ipilimumab and nivolumab in CDK12 inactivation or mutated cancers. Herein, we report our findings in the completed cohort A of men with mCPRC. Methods: Eligible pts had mCRPC (ongoing androgen deprivation therapy with serum testosterone £ 50 ng/dL) and putative CDK12 inactivation of function aberrations on any commercial or institutional CLIA/CAP approved next generation sequencing assay. Archival tumor tissue was requested for correlative biomarker analysis. Pts received nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was PSA response, defined as a greater than or equal to 50% decline in PSA from baseline. Secondary endpoints included safety/toxicity, secondary efficacy measures including QoL and overall survival. Exploratory objectives included baseline tumor whole exome analysis and changes in circulating immune profiles with therapy. Results: As of data cut-off in Aug 2021, 28 mCRPC pts enrolled in Cohort A; median ECOG PS was 1 (0-2 range), 22/28 had Gleason 8-10 cancer, mean baseline PSA at study entry was 231 ng/dL, all pts had received ≥1 prior oral androgen signaling inhibitor and ≥1 cytotoxic chemotherapy. Unconfirmed PSA ≥30% decline was seen in 6/28 pts (21.4%) and PSA ≥50% decline in 4/28 pts (14.2%). Grade ≥3 possible/probable/definite adverse events were noted in 7/28 (25%) and SAEs in 10/28 pts (35.7%). Six pts (21.4%) experienced a rapid PSA increase by ≥ 10-fold over baseline. Conclusions: Combination immunotherapy was reasonably tolerated in this heavily pre-treated population and was associated with unconfirmed PSA responses in a subset of pts. Ongoing correlative analyses could explain responses mechanistically. Enrollment in Cohort B of non-prostate cancers and Cohort C of nivolumab monotherapy in prostate cancer are still ongoing. Clinical trial information: NCT03570619.

Trial in progress: Durvalumab and olaparib for the treatment of prostate cancer in men predicted to have a high neoantigen load.

TPS202 Background: Approximately 30% of patients (pts) treated with definitive surgical and/or radiation therapy for localized prostate adenocarcinoma develop biochemical recurrence (BCR). The optimal time to initiate androgen deprivation therapy (ADT) for such patients is controversial and depends on patient and provider preference, absolute PSA value, and PSA doubling time (PSADT), which has been associated with time to metastasis. Because the time from BCR to metastasis can be long in many cases, strategies allowing pts to avoid ADT while extending metastasis-free survival are desirable. Prior studies have shown that a high tumor neoantigen load correlates with response to anti-PD(L)1. We hypothesized that PARP inhibitor-induced genomic instability may sensitize tumors to anti-PD(L)1 through: i) increasing mutational burden and subsequent tumor neoantigen formation, and/or ii) through activation of other immunogenic pathways (e.g. the STING pathway). This trial investigates an ADT-sparing approach for men predicted to have high neoantigen load and who have BCR prostate cancer. Methods: This is a phase 2 clinical trial testing durvalumab (1500 mg IV every 4 weeks) and olaparib (300 mg PO twice a day) (one cycle = 4 weeks) in men with BCR (PSADT≤10 months) whose tumors are predicted to have high neoantigen load based on: biallelic CDK12 mutations (Cohort A), mismatch repair deficiency (MMRd)/high microsatellite instability (MSI-H) (Cohort B), or loss of function mutations in homologous recombination repair (HRR) genes (Cohort C). Cohorts A and B will receive 3 cycles of durvalumab followed by 3 cycles of the combination of durvalumab and olaparib. Given the proven efficacy of olaparib in prostate cancer patient whose tumors posses an HRR gene mutation, Cohort C will receive 6 full cycles of the combination. Ten patients will be enrolled in each cohort (total n = 30) at two collaborating sites. This study was designed to provide preliminary efficacy data across eligible cohorts, with a primary objective of estimating the proportion of pts with an undetectable PSA at 12 months within each cohort. Secondary objectives include safety, proportion of patients with ≥50% decline in PSA from baseline and quality of life measures. Correlative studies will assess blood and tissue molecular biomarkers for association with outcomes. The study is open with two patients enrolled at the time of abstract submission. Clinical trial information: NCT04336943.

HSD3B1 polymorphism in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate and prednisone (AAP): Pharmacodynamics and therapeutic implications.

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

Novel framework for treatment response evaluation using PSMA-PET/CT in patients with metastatic castration-resistant prostate cancer (RECIP): An international multicenter study.

42 Background: We aimed to develop a novel framework for Response Evaluation Criteria In PSMA-PET/CT (RECIP) 1.0 and a composite response classification which combines responses by PSA measurements and by RECIP 1.0 (PSA+RECIP). Methods: This was an international, multicenter, retrospective study. 124 men with mCRPC who underwent 177Lu-PSMA therapy and received PSMA-PET/CT at baseline (bPET) and at interim at 12 weeks (iPET) were included. Pairs of bPET and iPET were interpreted by consensus among three blinded readers for appearance of new lesions. Tumor lesions were segmented and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP 1.0, which was defined as: complete response (RECIP-CR: absence of any PSMA-ligand uptake on iPET), partial response (PSMA-PR: decline ≥30% in PSMA-VOL and no appearance of new lesions), progressive disease (RECIP-PD: increase ≥20% in PSMA-VOL and appearance of new lesions), stable disease (RECIP-SD: any condition but RECIP-PR or RECIP-PD). Changes in PSA levels at 12 weeks by PCWG3 were recorded. Responses by PSA+RECIP were defined as: response (PSA decline ≥50% or RECIP-PR/CR) and progression (PSA increase ≥25% or RECIP-PD). Study's primary outcome measure was the prognostic value of RECIP 1.0 for overall survival (OS). Secondary outcome measure was the prognostic accuracy (C-index) of PSA+RECIP vs PSA responses. Results: Patients with progressive disease (RECIP-PD; n=39; 8.3 mo) had shorter OS compared to patients with stable disease (RECIP-SD; n=47; 13.1 mo; p&lt;0.001) and to those with partial response (RECIP-PR; n=38; 21.7 mo; p&lt;0.001). PSA+RECIP had superior C-indices in identifying responders and progressors compared to PSA only: 0.65 vs 0.62 (p=0.028) and 0.66 vs 0.63 (p=0.044), respectively. Conclusions: PSMA-PET/CT by RECIP 1.0 is prognostic for OS and can be used as a response biomarker to monitor efficacy of 177Lu-PSMA in men with mCRPC. PSA+RECIP may be used as a novel composite endpoint in mCRPC clinical trial design.

Implications of androgen receptor (AR) alterations identified by genomic testing of tissue and blood from advanced prostate cancer (aPC) patients (pts).

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

Targeting resistant prostate cancer, with or without DNA repair defects, using the combination of ceralasertib (ATR inhibitor) and olaparib (the TRAP trial).

88 Background: Men with metastatic, castration resistant prostate cancer (mCRPC) harboring DNA repair defects (̃20%) achieve a radiographic progression free survival of 7.4 months with PARP inhibitors (PARPi). Preclinical studies combining a PARPi (olaparib) and DNA damage checkpoint inhibitor (ATR inhibitor, ceralasertib) show synergy, providing the rationale to test this combination in men with mCRPC, including where single agent olaparib has been shown to be active. Methods: Two cohorts were accrued to a trial combining ceralasertib with olaparib in men a) with or b) without DNA repair defects. All patients progressed on ≥1 prior mCRPC therapy with no prior PARPi or platinum chemotherapy. The primary endpoint was disease response (confirmed PSA decline ≥50% and/or RECIST response), while disease progression was defined per Prostate Cancer Working Group 3 definition. Each cohort is analyzed independently for disease endpoints, while both groups were combined for toxicity assessments. Results: The 12 person DNA repair-deficient (DRDef) cohort allowed patients with germline BRCA2 loss (n = 4), somatic BRCA2 loss (n = 1) and ATM loss (n = 1 germline, n = 5 somatic and n = 1 somatic with unknown germline). 35 men without BRCA2/BRCA1 or ATM genomic loss were accrued to the DNA repair-proficient (DRPro) cohort. These men had next-generation sequencing (NGS) on contemporary biopsies (prior to enrolment without intervening therapy, 12), prior NGS on metastatic tissue (10), prior NGS on primary prostatic tissue (n = 3), or cell-free analyses (5). Five patients have incomplete cell-free analyses. At data cutoff (October 2021), in the DRDef cohort, the response rate by confirmed ≥50% PSA decline was 4/10 (40%) including 3 of 4 BRCA2 patients, and another is awaiting sufficient follow up; 1 of 6 ATM-deficient patients responded and another is awaiting sufficient follow up. All 4 DRDef responders remain on therapy (median of 8 months). For patients in the DRPro cohort who have completed therapy and response assessment (n = 21), 3 responded, one with a duration of 12 months, two with 6 months. An updated analysis will be presented. Conclusions: This analysis suggests potential activity of the doublet for DRDef (BRCA2 mainly) and DRPro mCRPC. Ongoing biomarker analysis (e.g. ATM IHC, contemporaneous cell-free DNA analysis rather than archived tissue) may help guide selection of patients most likely to benefit. Clinical trial information: NCT03787680.