Dorff, Tanya B.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel’s discussions on select 2026 updates to the guidelines regarding nonmetastatic disease: the elimination of the very-low-risk group, updates to the Principles of Active Surveillance, and caution in the use of focal therapy in newly diagnosed patients.

PURPOSE Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC). METHODS Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response. RESULTS Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP -mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (≥8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP- mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02). CONCLUSION SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP -mutated PC support its consideration as a unique molecular subtype with prognostic implications.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

AbstractCurrent US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high‐level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day‐to‐day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US‐focused expert clinical decision‐making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration‐sensitive prostate cancer; poly [ADP‐ribose] polymerase inhibitors; prostate‐specific membrane antigen radioligand therapy; and metastatic, castration‐resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.

5006 Background: The PRESTO trial (NCT03009981) showed that in patients with biochemically relapsed prostate cancer following radical prostatectomy with a PSA doubling time of ≤ 9 months and without evidence of metastatic disease by conventional imaging, intensified androgen receptor blockade for 52 weeks (androgen deprivation therapy [ADT] plus apalutamide [Apa], or ADT plus Apa and abiraterone acetate [Abi] plus prednisone) prolonged PSA progression-free survival compared to ADT alone (Aggarwal et al, JCO 2024). Here we report the HRQOL results. Methods: HRQOL measures included the Hot Flash Related Daily Interference Scale (HFRDIS), Expanded Prostate Cancer Index Composite (EPIC)-26 Sexual domain, PROMIS Fatigue Short Form and EQ-5D-5L, which assesses overall HRQOL in the 504 randomized patients. Published minimally important difference thresholds for these HRQOL measures are: HFRDIS 1.66 points, EPIC Sexual 10-12, PROMIS Fatigue 3-5, and EQ-5D-5L 0.06. General linear mixed modeling was used to estimate between-arm mean differences in HRQOL according to an intent-to-treat approach. Results: Mean changes from baseline to end of treatment (EOT) for each arm and for each HRQOL measure are summarized in Table. No statistically significant mean difference was reported between intensified androgen receptor blockade (Arm B, Arm C) vs ADT alone (Arm A) in any HRQOL measure. Further, numerical differences across arms for all HRQOL measures are below published minimally clinically important difference thresholds. Conclusions: Intensified androgen receptor blockade with Apa or Apa/Abi added to 52 weeks of ADT improves PSA progression-free survival without negatively affecting HRQOL. These HRQOL results add further support to intensification of androgen blockade in patients with high-risk biochemically recurrent prostate cancer. Clinical trial information: NCT03009981 . [Table: see text]

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)–positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

TPS354 Background: Carriers of germline pathogenic variants or mutations in BRCA2 and BRCA1 (referred to here as gBRCA1/2m) are enriched in metastatic prostate cancer (PrCa), and now have FDA-approved options for PARP inhibitors in late-stage disease. The NCCN guidelines recommends germline genetic testing for PrCa patients with metastatic, node positive and high risk localized prostate cancer. Prior studies have shown that gBRCA1/2m carriers with PrCa are more likely to have high-risk disease (6,7) and to develop lethal disease even after curative intent treatment (8,9). In other gBRCA1/2m-related cancers (breast, ovarian and pancreas), platinum-based regimens are part of neoadjuvant and front-line metastatic therapy options. Carboplatin is a well-tolerated, widely available and inexpensive DNA-damaging alkylating agent that is familiar to oncologists. The study hypothesis is that 4 cycles of neoadjuvant carboplatin, followed by radical prostatectomy for patients with localized high/very high risk PrCa and g BRCA1/2m will result in a meaningful pathologic complete response (pCR) rate. Methods: S2210 is a single-arm, open label study of 12 wks neoadjuvant carboplatin (4 cycles of AUC 5 every 21 days), followed by radical prostatectomy. Key eligibility criteria include people with high/very high-risk disease: cT3a or Grade Group 4-5 PrCa and/or PSA>20 ng/mL, have no evidence of distant metastases by conventional imaging (PSMA-PET-detected mets permitted if conventional imaging is negative and surgeon deems PSMA-detected sites resectable), who are candidates for radical prostatectomy and carboplatin, and have documented evidence of gBRCA1/2m through testing in a CLIA-certified lab. ADT prior to registration is permitted but must be discontinued on study. The study hypothesis is that the study treatment will result in ³30% rate of pathologic complete response (pCR, primary endpoint). A two-stage design will be used such that if ³1 of first 20 eligible patients achieves pCR, 20 further evaluable patients will be enrolled. This design has a significance level of 4.7%, and a power of 99%. Secondary endpoints include biochemical recurrence-free (at 2-, 3-, 5-yrs), metastasis-free and overall survival. Translational/correlative studies include analysis of 2nd allele inactivation in tumor, HRD signature, and ctDNA signature for monitoring of recurrence. S2210 was activated in August 2023. Clinical trial information: NCT05806515 .