PSA Response Research Articles

Experience of rescue therapy with [177Lu]Lu-rhPSMA-10.1 in patients with primary or acquired resistance to [177Lu]Lu-PSMA-I&T.

Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T. Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4-8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application. Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients. Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.

P127 PSA response in high-risk/high-volume metastatic hormone-sensitive prostate cancer treated with the novel androgen receptor-targeting agents: Real-world data

P127 PSA response in high-risk/high-volume metastatic hormone-sensitive prostate cancer treated with the novel androgen receptor-targeting agents: Real-world data

Assessing the predictive value of intraductal carcinoma of the prostate (IDC-P) in determining abiraterone efficacy for metastatic hormone-sensitive prostate cancer (mHSPC) patients.

This study explored the value of intraductal carcinoma of the prostate (IDC-P) in predicting the efficacy of abiraterone treatment in metastatic hormone-sensitive prostate cancer (mHSPC) patients. A retrospective study of 925 patients who underwent prostate biopsies to detect IDC-P was conducted, with participants divided into two cohorts. The first cohort of 165 mHSPC patients receiving abiraterone treatment was analyzed to compare therapeutic effectiveness between IDC-P positive and negative cases. Utilizing propensity score matching (PSM) to reduce bias, outcomes such as PSA response, progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival were assessed. Additionally, the second cohort of 760 mHSPC patients compared the efficacy of abiraterone with conventional hormone therapy, focusing on differences between IDC-P positive and negative individuals. After PSM, our first cohort included 108 patients with similar baseline characteristics. Among them, 50% (54/108) were diagnosed with IDC-P, with 22.2% (12/54) having IDC-P pattern 1 and 77.8% (42/54) with IDC-P pattern 2. While no notable difference was seen in PSA responses between IDC-P positive and negative patients, IDC-P presence linked to worse clinical outcomes (PSA-PFS: 18.6 months vs. not reached [NR], p = 0.009; rPFS: 23.6 months vs. NR, p = 0.020). Further analysis showed comparable outcomes for IDC-P pattern 1 but significantly worse prognosis for IDC-P pattern 2 (PSA-PFS: 18.6 months vs. NR, p = 0.002; rPFS: 22.4 months vs. NR, p = 0.010). Subgroup analysis revealed IDC-P pattern 2 consistently predicted poorer outcomes across patient subgroups. Remarkably, both IDC-P positive and negative patients gained more from androgen deprivation therapy with abiraterone than conventional treatment, with IDC-P negative patients showing a more significant survival advantage, supported by better hazard ratios (0.47 and 0.66). This study found that IDC-P, especially pattern 2, predicts poor prognosis in mHSPC patients on abiraterone therapy. Also, abiraterone's advantage over hormone therapy is reduced in cases with IDC-P compared to those without.

Nutritional Supplement with Fermented Soy in Patients Under Active Surveillance for Low-Risk or Intermediate-Risk Prostate Cancer: Results from the PRAEMUNE Trial.

Background/Objectives: To investigate the effect of a fermented soy supplement during 18 months in patients under active surveillance (AS) for low-risk and selected favorable intermediate-risk prostate cancer (PCa), with an emphasis on PSA modulation. Methods: Low-risk patients with ISUP grade 1, clinical stage cT1 or cT2a, PSA < 10 ng/mL and favorable intermediate-risk patients with ISUP grade 2 (<10% pattern 4), clinical stage T2b-c, PSA 10-20 ng/mL. The primary outcome was PSA response defined as maximum PSA rise less than or equal to 0.87 ng/mL after 1 year, based on the weighted average of PSA velocity (PSAV) in previous studies in similar populations. Secondary outcomes were disease progression, adverse histology on repeat biopsy or switch to active therapy. In addition, primary and secondary outcomes with imputed data were also determined as sensitivity analyses, using Mann-Whitney U or Chi-squared tests. Results: Overall, 92 (61.3%) of 150 patients showed a PSA level response. This was more evident in ISUP 1 patients and resulted in fewer follow-up MRIs and fewer control biopsies, as well as a fewer number of positive control biopsies with statistical significance in the imputed dataset. Obtaining a PSA response was numerically associated with less initiated therapy. Conclusions: a fermented soy supplement in patients under AS for low-risk and selected favorable intermediate-risk PCa could be useful in selecting patients who may remain under AS or who may need to switch to active therapy.

Assessment of the therapeutic efficacy of [177Lu]Lu-PSMA-X compared to taxane chemotherapy in taxane-chemo-naïve patients with metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

Radioligand therapy (RLT) with 177Lu-labelled prostate specific membrane antigen ([177Lu]Lu-PSMA-X, referring with "PSMA-X" to a generic PSMA chemical compound) inhibitors has emerged as a viable treatment option in metastatic castration resistant prostate cancer patients having previously progressed on taxane and androgen receptor inhibitors. The aim of this study was to perform a systematic review and meta-analysis to assess the therapeutic efficacy of [177Lu]Lu-PSMA-X compared to taxane chemotherapy in taxane-chemo-naïve patients with metastatic castration-resistant prostate cancer. Searches in several bibliographic databases were made using relevant key words, and articles published up to March 2024 were included. The endpoints included prostate specific antigen (PSA) response rate (RR), progression-free survival, and overall survival. Individual patient data were pooled when feasible. PSA50 was defined as the median proportion of patients achieving at least a 50% decline in serum PSA from baseline. A meta-analysis of the PSA50 response rate (proportion meta-analysis) was performed, generating pooled estimates and 95% confidence intervals (95% CI). From the initially selected 8,414 studies published between 2019 and 2023, 24 were included in the [177Lu]Lu-PSMA-X treated group and 17 in the taxane treated group. Our findings show that [177Lu]Lu-PSMA-X RLT yielded comparable PSA50 responses in taxane-naïve patients versus those receiving taxane chemotherapy, despite considerable study heterogeneity. Notably, the taxane-naïve group had more extensive pretreatment. This meta-analysis combines the largest cohorts of taxane-naïve mCRPC patients treated with [177Lu]Lu-PSMA-X RLT and taxane-treated mCRPC. It underscores similar PSA50 response rates in both groups, suggesting a potential role for [177Lu]Lu-PSMA-X RLT in taxane-naïve patients who cannot or choose not to undergo chemotherapy.

Matched-pair analysis of mCRPC patients receiving 177Lu-labeled PSMA-targeted radioligand therapy in a 4-week versus 6-week treatment interval

BackgroundThe optimal regimen for 177Lu-labeled prostate-specific membrane antigen-targeted radioligand therapy, including treatment intervals, remains under study, with evidence suggesting shorter intervals could benefit patients with high disease volume and rapid progression. This retrospective analysis evaluated treatment toxicity, PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) in matched cohorts of mCRPC patients receiving 177Lu-PSMA-RLT at 4-week versus 6-week intervals.ResultsA PSA response (PSA decline ≥ 50%) was achieved in 47.8% and 21.7% of patients in the 4-week and 6-week treatment interval groups, respectively (p = 0.12). There was a trend towards longer PSA-PFS in the 4-week group compared to the 6-week group (median PSA-PFS, 26.0 weeks vs. 18.0 weeks; HR 0.6; p = 0.2). Although not statistically significant, there was a trend towards shorter OS in the 4-week group compared to the 6-week group (median OS, 15.1 months vs. 18.4 months; HR 1.3; p = 0.5). The 4-week group had a significantly greater decrease in leucocyte and platelet counts compared to the 6-week group (38.5% vs. 18.2% and 26.7% vs. 10.7%; p = 0.047 and p = 0.02). Severe adverse events were modest in both groups.ConclusionsIntensifying treatment intervals from 6 weeks to 4 weeks showed some improvements in PSA response and PSA-PFS for mCRPC patients, but did not significantly affect OS. Additionally, bone marrow reserve was significantly reduced with the intensified regimen. Therefore, the overall benefit remains uncertain, and further prospective studies are needed to compare 4-week and 6-week intervals regarding toxicity, treatment response, and outcome.

Immunotherapy Vaccines for Prostate Cancer Treatment.

Therapeutic tumor vaccines have emerged as a compelling avenue for treating patients afflicted with advanced prostate cancer (PCa), particularly those experiencing biochemical relapse or ineligible for surgical intervention. This study serves to consolidate recent research findings on therapeutic vaccines targeting prostate tumors while delineating prevalent challenges within vaccine research and development. We searched electronic databases, including PubMed, Web of Science, Embase, and Scopus, up to August 31, 2024, using keywords such as 'vaccine', 'prostate cancer', 'immunotherapy', and others. We reviewed studies on various therapeutic vaccines, including dendritic cell-based, antigen, nucleic acid, and tumor cell vaccines. Studies consistently showed that therapeutic vaccines, notably DC vaccines, had favorable safety profiles with few adverse effects. These vaccines, with varied antigenic formulations, demonstrated strong clinical outcomes, as indicated by metrics such as PSA response rates (9.5%-58%), extended PSA doubling times (52.9%-89.7%), overall survival durations (17.7-33.8 months), two-year mortality rates (0%-12.5%), biochemical relapse rates (42%-73%), and antigen-specific immune responses (33.3%-71.4% in responsive groups). While clinical data for tumor vaccines have illuminated robust evidence of tumoricidal activity, the processes of their formulation and deployment are riddled with complexities. Combining vaccines with other therapies may enhance outcomes, and future research should focus on early interventions and deciphering the immune system's role in oncogenesis.

Nivolumab in patients with metastatic castration-resistant prostate cancer with and without DNA repair defects.

Despite the success of immune checkpoint inhibitors (ICIs) across various cancers, their efficacy in metastatic castration-resistant prostate cancer (mCRPC) is modest, except for a subset of patients who experience significant, yet unpredictable, benefits. DNA repair defects (DRD) are associated with higher neoantigen load, which may predict response. Our study explored the potential of DRD for enhanced responsiveness to the ICI nivolumab. We conducted a phase II, multi-center, single-arm trial evaluating nivolumab in post-docetaxel mCRPC patients. DRD was assessed using circulating tumor DNA (ctDNA). The primary endpoint was PSA50 response. Secondary endpoints included objective response rate (ORR), radiographic progression-free survival (rPFS), and overall survival (OS). Also, exploratory comprehensive genomic profiling was performed via whole-exome sequencing (WES) of tumor samples and matched normal tissue, alongside PD-L1 expression evaluation. Among the 38 enrolled patients, DRD was identifiable in 30.5% (11/36) through ctDNA and/or WES analysis. The overall PSA50 response rate was 10.5% (4/38). PSA50 response and ORR did not significantly differ between patients with and without DRD (18.2% vs. 8%; p = 0.57 and 50% vs. 17.6%, p= 0.27, respectively). Median PSA-PFS (1.9 vs. 2.8 months, p=0.52) and rPFS (3.4 vs. 5.5 months, p=0.7) were not statistically different between patients with and without DRD. Grade ≥ 3 adverse events were reported in 47.3% of participants. Nivolumab has clinical activity in a subset of mCRPC patients, however, DRD do not predicted response.These results highlight the necessity of identifying new biomarkers to more accurately determine mCRPC patients who might respond to ICIs.

Bipolar androgen therapy for treatment of metastatic castration‐resistant prostate cancer: A case series

AbstractIntroductionAdvanced prostate cancer treatment has improved with androgen receptor signaling inhibitors (ARPI), yet many patients develop metastatic castration‐resistant prostate cancer (mCRPC), characterized by sustained androgen receptor (AR) signaling. Bipolar androgen therapy (BAT) introduces supraphysiologic testosterone levels to inhibit tumor growth, offering novel treatment for mCRPC by exploiting AR‐dependent mechanisms.Case PresentationsCase 1: A 53‐year‐old man with mCRPC, post multiple systemic therapies, initiated BAT and pembrolizumab, achieving PSA reduction and improved quality of life before progression. The patient exhibited AR amplification, which may have contributed to favorable response to BAT.Case 2: A 73‐year‐old man with recurrent prostate cancer, stable on ADT and abiraterone, experienced PSA decline with BAT to an undetectable level, maintaining stability post‐therapy discontinuation.Case 3: A 73‐year‐old man with metastatic prostate cancer, initially resistant to enzalutamide, achieved clinical benefit and disease control with BAT, although he did not meet PSA response criteria, patient had remarkable response upon enzalutamide rechallenge.Case 4: A 90‐year‐old man with localized prostate cancer, refractory to multiple treatments, experienced symptom relief and PSA reduction with BAT before progression.ConclusionBAT represents a promising treatment strategy for mCRPC. This case series underscores BAT's potential to induce significant clinical and biochemical responses, resensitize tumors to ARPIs, and improve patients' quality of life. Despite eventual progression in some cases, BAT offers a period of disease control. Further research is needed to optimize patient selection and understand the molecular determinants of BAT responsiveness.

Deep PSA response and extended time‐to‐nadir as robust predictors of survival in Asian patients with de novo metastatic hormone‐sensitive prostate cancer receiving upfront intensified treatment

AbstractIntroductionIn de novo metastatic hormone‐sensitive prostate cancer (mHSPC) treated with upfront intensification using androgen receptor signaling inhibitor or chemotherapy (Docetaxel), achieving a PSA nadir less than 0.2 ng/mL, indicative of superior survival in trials, may often be unattainable in real‐world settings. We explored the predictive value of the degree of PSA decline and time to PSA nadir (TTPN) on oncological outcomes.MethodsA prospectively maintained database of consecutive prostate cancer cases in Hong Kong was accessed. Patients diagnosed with de novo mHSPC from 2016 to 2022 and treated with upfront intensification were included in this analysis. Landmark analysis on PSA kinetics at 6‐months following treatment intensification was performed. They were classified based on 1) TTPN (≥6 months vs. &lt;6 months), and 2) a combined response (deep responders achieving both ≥95% PSA decline and TTPN ≥ 6 months vs. shallow responders). Multivariable regression analysis was employed to identify the effects of confounders.FindingsA total of 131 patients were included in this analysis. Classifying patients by combined response best predicted survival outcomes. Deep responders had better progression‐free survival (HR = 0.56; 95%CI = 0.34–0.91; p = 0.019), overall survival (HR = 0.50; 95%CI = 0.26–0.97; p = 0.036), and cancer‐specific survival (HR = 0.43; 95%CI = 0.19–0.99; p = 0.042). Difference in overall survival remained significant after adjustment in multivariable regression analysis.ConclusionOur analysis demonstrates that alternative PSA targets can predict treatment response and survival outcomes in de novo mHSPC patients in a real‐world setting, providing valuable information for patient counselling and potentially guiding future trial design.

Prognostic Significance of Baseline Clinical and [68Ga]Ga-PSMA PET Derived Parameters on Biochemical Response, Overall Survival, and PSA Progression-Free Survival in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Undergoing [177Lu]Lu-PSMA Therapy.

In this study, we sought to identify the clinical baseline characteristics and pre-therapy 68Ga-PSMA PET derived parameters that can have impact on PSA (biochemical) response, OS and PSA PFS in patients with metastatic castration-resistant prostate cancer (mCRPC) who undergo RLT with [177Lu]Lu-PSMA-617. Various pre-treatment clinical and PSMA PET derived parameters were gathered and computed. We used PSA response as the criteria for more than a 50% decrease in PSA level, and OS and PSA PFS as endpoints. We assessed the collected parameters in relation to PSA response. Additionally, we employed univariable Cox regression and Kaplan-Meier analysis with log rank to evaluate the influence of the parameters on OS and PFS. A total of 125 mCRPC patients were included in this study. The median age was 68 years (range: 49-89). Among the cases, 77 patients (62%) showed PSARS, while 48 patients (38%) did not show PSA response. The median OS was 14 months (range: 1-60), and the median PSA-PFS was 10 months (range: 1-56). Age, prior history of chemotherapy, and SUVmax had a significant impact on PSA response (p<0.05). PSA response, RBC count, hemoglobin, hematocrit, neutrophil to lymphocyte ratio (NLR), alkaline phosphatase (ALP), number of metastases, wbPSMA-TV, and wbTL-PSMA significantly affected OS. GS, platelet count, NLR, and number of metastases were found to have a significant impact on PSA PFS. We have identified several baseline clinical and PSMA PET derived parameters that can serve as prognostic factors for predicting PSA response, OS, and PSA PFS after RLT. Based on the findings, we believe that these clinical baseline characteristics can assist nuclear medicine specialists in identifying RLT responders who have long-term survival and PFS.

Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer.

ESK981 is a potent tyrosine kinase and PIKfyve lipid kinase inhibitor. This phase II trial evaluated the efficacy of ESK981 as a single agent in patients with androgen receptor-positive (AR +) metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had mCRPC with progression on AR-targeted agents and without prior chemotherapy treatment. Each patient received 160mg ESK981 once daily for 5days per week for 4weeks per cycle (except for an adverse event (AE) occurrence). The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included the time and the duration of PSA response, PSA progression rates, PSA progression free survival (PFS) and overall survival (OS). Exploratory investigations included whole exome sequencing in patients before treatment, and morphological evaluation of biopsy samples pre- and post-treatment. PSA was evaluated in 13 patients. Only one patient (7.7% two-sided 95% Wilson CI (0.4%, 33.3%)) experienced a reduction in their PSA levels by 50% or more. The most common grade 3 treatment-related AEs were cardiac disorders, diarrhea, hypertension, alanine transaminase and aspartate transaminase elevations. No grade 4-5 events occurred. Median PFS was 1.8months, and median OS was 12.1months. Peripheral immune cells showed increased T cell activation and cytokine production in two patients who received 12-weeks of ESK981. Although relatively well tolerated, ESK981 alone showed no anti-tumor activity in patients with AR + mCRPC and its further evaluation as a single agent in AR + mCRPC is not warranted. (Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018).

1614P PSA responses and PSMA scan changes after immunotherapy for biochemically recurrent prostate cancer (BCR) without androgen deprivation therapy (ADT)

1614P PSA responses and PSMA scan changes after immunotherapy for biochemically recurrent prostate cancer (BCR) without androgen deprivation therapy (ADT)

Olaparib Without Androgen Deprivation for High-Risk Biochemically Recurrent Prostate Cancer Following Prostatectomy

Olaparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that provides benefit in combination with hormonal therapies in patients with metastatic prostate cancer who harbor homologous recombination repair (HRR) alterations. Its efficacy in the absence of androgen deprivation therapy has not been tested. To determine the activity of olaparib monotherapy among patients with high-risk biochemically recurrent (BCR) prostate cancer after radical prostatectomy. This phase 2, single-arm nonrandomized controlled trial enrolled genetically unselected patients across 4 sites in the US from May 2017 to November 2022. Eligible patients had BCR disease following radical prostatectomy, a prostate-specific antigen (PSA) doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher, and a testosterone level of 150 ng/dL or higher. Treatment was with olaparib, 300 mg, by mouth twice daily until doubling of the baseline PSA, clinical or radiographic progression, or unacceptable toxic effects. The primary end point was a confirmed 50% or higher decline in PSA from baseline (PSA50). Key secondary end points were outcomes by HRR alteration status, as well as safety and tolerability. Of the 51 male patients enrolled (mean [SD] age, 63.8 [6.8] years), 13 participants (26%) had a PSA50 response, all within the HRR-positive group (13 of 27 participants [48%]). All 11 participants with BRCA2 alterations experienced a PSA50 response. Common adverse events were fatigue in 32 participants (63%), nausea in 28 (55%), and leukopenia in 22 (43%), and were consistent with known adverse effects of olaparib. In this nonrandomized controlled trial, olaparib monotherapy led to high and durable PSA50 response rates in patients with BRCA2 alterations. Olaparib warrants further study as a treatment strategy for some patients with BCR prostate cancer but does not have sufficient activity in those without HRR alterations and should not be considered for those patients. ClinicalTrials.gov Identifier: NCT03047135.

Impact of Neuroendocrine Differentiation (NED) on Enzalutamide and Abiraterone Efficacy in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Retrospective Analysis.

Neuroendocrine differentiation (NED) represents a possible androgen receptor pathway inhibitors (ARPI) resistance mechanism in metastatic castration resistance prostate cancer (mCRPC). As mCRPC with NED has been excluded from clinical trials evaluating ARPI efficacy, this study investigates the prognostic impact of NED in mCRPC patients treated with ARPIs. Methods: We retrospectively analyzed 327 mCRPC patient data treated with Enzalutamide or Abiraterone in the first and second or successive lines of treatment. NED was assessed using prostate biopsy samples through immunohistochemical staining. Results: NED was confirmed in 32/327 (9.8%) mCRPC patients. In the overall population, mCRPC with NED showed worse PFS (4.38 vs. 11.48 months HR 2.505 [1.71-3.68] p < 0.05), disease control rate (DCR), and PSA response. In the first line setting, mCRPC with NED demonstrated worse PFS (8.5 vs. 14.9 months HR 2.13 [1.18-3.88], p < 0.05). Similarly, in the second or successive lines, mCRPC with NED showed worse PFS (4.0 vs. 7.5 months HR 2.43 [1.45-4.05] p < 0.05), DCR, PSA response and OS (12.53 vs. 18.03 months HR 1.86 [1.12-3.10] p < 0.05). The adverse impact of NED on PFS was consistence across all subgroups; we also noted a trend of worse PFS in patients with high vs. low NED. Conclusions: In our study, mCRPC with NED treated with Enzalutamide or Abiraterone showed worse clinical outcomes. NED assessment should be considered to optimize treatment decisions in the mCRPC setting.

PSA response and cabazitaxel outcomes stratified by prior docetaxel PSA response in metastatic castrate-resistant prostate cancer (mCRPC).

119 Background: In the TheraP trial, both cabazitaxel and lutetium Lu 177 vipivotide textraxetan demonstrated similar overall survival (OS) in patients with mCRPC previously treated with docetaxel. We seek to identify predictors for cabazitaxel benefit by evaluating patients’ cabazitaxel outcomes in the context of prior docetaxel outcomes. Methods: We identified patients who started cabazitaxel after January 2010 at our institution. Patients were included if they received docetaxel for mCRPC but excluded if they received docetaxel for hormone-sensitive disease, used taxane in combination with other agents (e.g. carboplatin), or received multiple courses of same taxane (e.g. “re-challenges”). For adequate assessment of PSA response, patients were only included if pre-chemo PSA was &gt; 20 ng/mL and had received at least two cycles of both taxanes. PSA response was defined as &gt;50% decrease from baseline sustained for at least 3 weeks (PSA50). OS was calculated from time of cabazitaxel start to death from any cause. Results: Eighty patients were identified with a median age of 70 years at cabazitaxel start. Forty (50%) patients had a PSA50 with docetaxel, while only 18.8% had a PSA50 with subsequent cabazitaxel. Patients who had a PSA50 to docetaxel had a significantly higher chance of PSA50 to cabazitaxel (OR 5.29, 95% CI: 1.36, 20.53, p = 0.0162); the PSA50 rates on cabazitaxel were 30% and 7.5% between those that did and did not have a PSA50 to docetaxel, respectively. There were no significant differences in cabazitaxel median OS based on prior docetaxel PSA50. Conclusions: Patients who had PSA50 to docetaxel had a significantly higher chance to have a PSA50 to cabazitaxel. Prior docetaxel PSA50 could be considered when deciding whether to use cabazitaxel or an alternative agent for subsequent treatment. [Table: see text]

Abiraterone, Olaparib, or Abiraterone + Olaparib in First-Line Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects (BRCAAway).

Deleterious germline/somatic homologous recombination repair mutations (HRRm) are present in ∼25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinically, poly(ADP-ribose) polymerase (PARP) inhibition demonstrated synergism with androgen receptor pathway (ARP)-targeted therapy. This trial evaluated the efficacy of ARP inhibitor versus PARP inhibitor versus their combination as first-line therapy in patients with mCRPC with HRRms. BRCAAway is a biomarker preselected, randomized, phase 2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi/pred), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi/pred + Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRms received olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety. Sixty-one of 165 eligible patients had BRCA1/2 or ATM mutations: median age: 67 (IQR, 62-73) years. Mutations: BRCA1 n = 3, BRCA2 n = 46, ATM n = 11, and multiple n = 1; 33 germline and 28 somatic mutations. Median PFS [95% confidence interval (CI)]: Abi/pred, 8.6 months (m; 2.9, 17), Ola, 14 m (8.4, 20), and Abi/pred + Ola, 39 m [22, not reached (NR)]. There were no G4/5 adverse events; 8/19 patients on Abi/pred treatment crossed over to Ola, and 8/21 vice versa. Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15) and Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25) and Abi/pred-after-Ola, 16 m (11, NR). Seventeen of 165 patients with other HRRms received olaparib: median PFS (95% CI): 5.5 m (2, 11). In patients with mCRPC with BRCA1/2 or ATM HRRm, Abi/pred + Ola was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.

Comparative analysis of novel hormonal agents in non-metastatic castration-resistant prostate cancer: A Taiwanese perspective.

Non-metastatic castration-resistant prostate cancer (nmCRPC) is an asymptomatic condition with the potential to progress to metastasis. Novel hormonal agents (NHAs) are currently considered the gold standard treatment for nmCRPC, offering significant survival benefits. However, further evidence is needed to determine whether there are differences in the performance of these drugs among Asian populations. This retrospective analysis of nmCRPC patients aims to compare the efficacy and safety of three NHAs-apalutamide, darolutamide, and enzalutamide. Data were collected from two prominent prostate care centers in Taichung, Taiwan. Patient characteristics, treatment details, PSA responses, and adverse events were analyzed. Statistical comparisons were performed, and the study received Institutional Review Board approval. Total of 64 patients were recruited in this study, including 29 darolutamide, 26 apalutamide, and 9 enzalutamide patients. Baseline characteristics varied between the three patient groups, but the treatment response still revealed similar results. The apalutamide group experienced more adverse events, notably skin rash. Discontinuation rates due to adverse events differed among the groups, and patients receiving darolutamide were less likely to discontinue treatment. This real-world study provides insights into NHA utilization in nmCRPC within the Taiwanese population. Adverse event profiles varied, emphasizing the need for individualized treatment decisions. The study underscores the importance of regional considerations and contributes valuable data for optimizing treatment outcomes in nmCRPC.

Circulating Tumor DNA Assessment for Treatment Monitoring Adds Value to PSA in Metastatic Castration-Resistant Prostate Cancer.

Enzalutamide after abiraterone progression is commonly used in metastatic castration-resistant prostate cancer despite a low rate of clinical benefit. Analyzing IMbassador250, a phase III trial assessing enzalutamide with or without atezolizumab after abiraterone, we hypothesized that baseline and early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients more likely to exhibit survival benefit from enzalutamide. ctDNA was quantified from plasma samples using a tissue-agnostic assay without buffy coat sequencing. Baseline ctDNA TF, changes in ctDNA TF from baseline to cycle 3 day 1 (C3D1), and detection at C3D1 alone were compared with overall response rate, radiographic progression-free survival (rPFS), median OS (mOS), and 50% reduction in PSA. ctDNA TF detection at baseline and/or C3D1 was associated with shorter rPFS and OS in 494 evaluable patients. Detection of ctDNA TF at C3D1, with or without detection at cycle 1 day 1, was associated with worse rPFS and mOS than lack of detection. When ctDNA TF and PSA response at C3D1 were discordant, patients with (ctDNA TF undetected/PSA not reduced) had more favorable outcomes than (ctDNA TF detected/PSA reduced; mOS 22.1 vs. 16 months; P < 0.001). In a large cohort of patients with metastatic castration-resistant prostate cancer receiving enzalutamide after abiraterone, we demonstrate the utility of a new tissue-agnostic assay for monitoring molecular response based on ctDNA TF detection and dynamics. ctDNA TF provides a minimally invasive, complementary biomarker to PSA testing and may refine personalized treatment approaches.

Impact of definitive radiotherapy on metabolic response measured with 68Ga-PSMA-PET/CT in patients with intermediate-risk prostate cancer.

To assess the early metabolic response of the primary tumor using Gallium-68 (68Ga)-labeled-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-PET/CT), as well as the relationship between PSMA change in the primary tumor and PSA response after definitive radiotherapy (RT), either alone or in combination with androgen deprivation therapy (ADT) in intermediate risk prostate cancer (IR-PCa) patients. The clinical data of 71 IR-PCa patients treated with RT alone (36 patients, 50.7%) or RT and ADT (35 patients, 49.3%) were retrospectively analyzed. The difference between pre- and Posttreatment primary tumor PSMA expression and serum PSA values measured 4 months after completion of treatment were compared between treatment arms. Correlation between primary tumor metabolic response and serum PSA changes was analyzed. The median duration between pre- and Posttreatment 68Ga-PSMA-PET/CT for the entire patient population was 6.9 months (range, 5.6-8.4 months), and it was similar in both treatment arms. A decrease in primary tumor maximum standardized uptake value (SUVmax) was seen in 66 patients (93.0%), with a median value of 61.2%, which is significantly lower in patients undergoing RT alone than those undergoing RT and ADT (45.1 ± 30.6% vs. 59.1 ± 24.7%; p = 0.004). The complete metabolic response rate was significantly higher in patients undergoing RT and ADT than those treated with RT alone (40% vs. 0%; p < 0.001). Although moderate and positive correlation between pretreatment SUVmax and oosttreatment SUVmax was observed, there was no significant correlation between SUV change and PSA change. For patients treated with RT and ADT, posttreatment SUVmax was significantly lower and SUV change was significantly higher in patients with PSA nadir than in those without. Our preliminary results show that RT, with or without ADT, significantly reduces primary tumor SUVmax and serum PSA levels. Nonetheless, our findings indicate that early treatment response using 68Ga-PSMA-PET/CT is not feasible for those treated with RT alone, and it may only be useful in better distinguishing patients with and without PSA nadir for those who received both RT and ADT.