Morris, Michael J.

121 Background: In the Phase 3 VISION trial, treatment with the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) + protocol-permitted standard of care (SoC) significantly improved median radiographic progression-free survival (rPFS; 8.7 vs 3.4 months [mo]) and overall survival (OS; 15.3 vs 11.3 mo) in patients with metastatic castration-resistant prostate cancer (mCRPC) vs SoC alone. However, it is unclear how the addition of androgen receptor pathway inhibitors (ARPIs) affected 177 Lu-PSMA-617 treatment outcomes. Here we compared the efficacy and safety of 177 Lu-PSMA-617 in patients treated with vs without concomitant ARPIs. Methods: In VISION, adult patients with PSMA-positive mCRPC previously treated with ≥1 prior ARPI and 1–2 taxane chemotherapy regimens were randomized 2:1 to receive 177 Lu-PSMA-617 (7.4 GBq Q6W, 4–6 cycles) + SoC (which included ARPIs) vs SoC alone. In this secondary analysis, we assessed baseline characteristics, OS, rPFS, prostate-specific antigen (PSA) response rate, duration of PSA response, PSA-PFS, and safety among patients in the intervention arm who were treated with vs without concomitant ARPIs. Results: In total, 289 patients were treated with concomitant ARPIs and 262 patients were not (N=551). Imbalances between the groups were observed in some baseline characteristics: patients treated with concomitant ARPIs were younger, had lower ECOG performance scores, lower mean PSA and lactate dehydrogenase levels, and fewer prior taxane chemotherapy regimens. Baseline mean standardized [ 68 Ga]Ga-PSMA-11 uptake values and mean hemoglobin levels were well-balanced. A statistically significant difference in median OS was observed in patients treated with concomitant ARPIs vs those without (17.8 vs 12.4 mo; HR, 0.72; 95% CI, 0.58–0.89; nominal P=0.001). No statistically significant between-group differences were observed for rPFS, PSA response rate, duration of PSA response or PSA-PFS. The proportion of adverse events reported was similar in patients with or without concurrent ARPI, except for the number of adverse events leading to interruption of best supportive care/SoC, which was higher in patients treated with concurrent ARPIs. Conclusions: OS was significantly different in patients treated with concomitant ARPIs vs those without, while other efficacy endpoints were not. No new safety signals were observed for 177 Lu-PSMA-617 with concomitant ARPI. These findings may be confounded by varied exposure to ARPIs, or differing patient characteristics; patients who received concomitant ARPIs may represent a more favorable treatment population than those who did not. These findings should be considered as hypothesis-generating, and a multivariate analysis has been planned to ascertain the influence of these potential biases. Clinical trial information: NCT03511664 .

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.

Abstract Purpose: Mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion, termed clonal hematopoiesis (CH). CH in the general population is associated with hematopoietic neoplasms and reduced overall survival (OS), predominantly through cardiovascular adverse events (CVAE). Because androgen receptor pathway inhibitors (ARPI) used in metastatic castration-resistant prostate cancer (mCRPC) are also associated with CVAEs and because CH negatively impacted survival in an advanced solid tumor cohort, we hypothesized that CH in mCRPC may be associated with increased CVAEs and inferior survival. Experimental Design: A targeted DNA sequencing panel captured common CH mutations in pretreatment blood samples from 957 patients enrolled in Alliance A031201: a randomized trial of enzalutamide ± abiraterone/prednisone in the first-line mCRPC setting. The primary outcome was the impact of CH on OS; the secondary outcomes were progression-free survival (PFS) and CVAEs. Results: Baseline comorbidities were similar by CH status. No differences in OS/progression-free survival were detected regardless of treatment arm or the variant allele frequency threshold used to define CH [primary: 2% (normal-CH, N-CH); exploratory: 0.5% (low-CH) and 10% (high-CH, H-CH)]. Patients with H-CH (7.2%) and TET2-mutated N-CH (6.0%) had greater odds of any CVAE (14.5% vs. 4.0%; P = 0.0004 and 12.3% vs. 4.2%; P = 0.010, respectively). More major CVAEs were observed in patients with H-CH (5.8% vs. 1.9%; P = 0.042) and N-CH (3.4% vs. 1.8%; P = 0.147). Conclusions: CH did not affect survival in patients with mCRPC treated with ARPIs in A031201. H-CH and TET2-mutated CH were associated with more CVAEs. These findings inform the risk/benefit discussion about ARPIs in mCRPC.

AbstractBackground[177Lu]Lu–PSMA‐617 (177Lu‐PSMA‐617) plus protocol‐permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression‐free survival (rPFS) versus SOC in patients with prostate‐specific membrane antigen (PSMA)–positive metastatic castration‐resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health‐related quality of life (HRQOL).MethodsPost hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu‐PSMA‐617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy–Prostate [FACT‐P] and 5‐level EQ‐5D [EQ‐5D‐5L]). Correlation analyses used an iterative multiple imputation copula‐based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong).ResultsIn the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT‐P total score and emotional and physical well‐being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time‐to‐worsening EQ‐5D‐5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms.ConclusionsIn this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation.

TPS5118 Background: Novel androgen receptor pathway inhibitors (ARPIs) improve overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in conjunction with testosterone suppression (TS) relative to TS alone. However, the duration of treatment required to derive clinical benefit is unclear, as is whether continuous treatment is requisite for optimal cancer outcomes. Favorable PSA declines have been associated with prolonged OS in clinical trials testing TS + ARPIs. We thus designed this single-arm Phase 2 trial to test the hypothesis that pts who achieve exceptional response to upfront TS + ARPI can suspend treatment, allowing for T recovery and improvement in quality of life while maintaining favorable clinical outcomes. Methods: Eligible pts had mHSPC by conventional imaging with PSA ≥ 5 ng/ml and T ≥ 150 ng/dl (or not known to have been hypogonadal) prior to starting treatment, have been receiving TS for 540-750 days and ARPI for ≥ 360 days, and have achieved PSA < 0.2 ng/ml (stable or falling for 3 consecutive measurements) with castrate T <50 ng/dl at the time of enrollment. Intermittent ADT for biochemical recurrence prior to mHSPC diagnosis, prior local therapy, prior radiation to metastatic sites, and up to 6 cycles of docetaxel in mHSPC are permitted. Pts who underwent surgical castration, received ARPI prior to mHSPC diagnosis, or are receiving experimental treatment for mHSPC or participating in a clinical trial that does not allow for TS or ARPI interruption are excluded. After enrollment, pts discontinue both TS and ARPI and are followed with PSA and T levels every 3 months, conventional CT/MRI and bone scan at least every 6 months, and FACT-P questionnaire for patient-reported outcomes every 6 months. Treatment re-initiation triggers are PSA increase to ≥ 5 ng/ml, radiographic change (progressive disease per modified RECIST 1.1 on CT/MRI or unconfirmed progressive disease per PCWG3 on bone scan), or symptoms attributable to prostate cancer. Subsequent management is per physician discretion. The primary endpoint is remaining treatment-free with eugonadal T (> 150 mg/dl) 18 months after the start of treatment interruption, with 75 pts to be enrolled to differentiate 18-month treatment free rates of 0.30 (null hypothesis) and 0.45 (alternative hypothesis). Secondary endpoints include time to eugonadal T, duration off treatment, and changes in patient-reported outcomes. Exploratory endpoints include radiographic progression-free survival, time to next treatment, OS, and correlation of tissue- and blood-based biomarkers with clinical endpoints. The study was activated in July 2022 and accrual is ongoing throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org , Veracyte Inc. Clinical trial information: NCT05241860 .

5010 Background: hK2 (encoded by the KLK2gene) is a novel target expressed on the cell surface of prostate cancer cells with restricted expression elsewhere. JNJ-6420 is a first-in-class anti-hK2 antibody–based targeted radiotherapy delivering 225Ac, a high-energy short-range alpha-particle emitter, to prostate cancer cells. Here we report the first-in-human study evaluating JNJ-6420 in heavily pretreated biomarker-unselected participants (pts) with mCRPC who received ≥1 prior androgen receptor pathway inhibitor. Methods: Intravenous JNJ-6420 was escalated from 50 μCi to 400 μCi every 8-12 weeks in the outpatient setting with no residential radioprotective restrictions. Prior radioisotopic therapy was an exclusion criterion. Primary objectives were safety and defining a recommended phase 2 dose (RP2D). Secondary objectives included preliminary assessment of clinical activity. Results: As of January 5, 2024, 67 pts received ≥1 JNJ-6420 dose. Exposure and clinical activity for the 57 pts in the ≥150 μCi JNJ-6420 cohorts are summarized (see Table); 35/57 (61.4%) experienced grade ≥3 TEAEs, and 21 (36.8%) had a serious TEAE. TEAEs of note included thrombocytopenia (63.2%) and interstitial lung disease (ILD, 9%). All instances of ILD occurred at cumulative doses ≥500 μCi and prior to implementation of pulmonary function surveillance. Grade ≥3 TEAEs (≥10%) included anemia (26.3%), thrombocytopenia (17.5%), lymphopenia (10.5%), and leukopenia (10.5%). 9/57 (15.8%) pts discontinued treatment due to TRAEs; 4 TRAEs resulted in death. At doses ≥150 μCi, the PSA50 rate was 45.6%. To date, across all dose cohorts, 31 pts (46%) remained on treatment for ≥24 weeks. Prolonged clinical, biochemical, and radiographic responses were noted in pts receiving doses of 150 μCi and higher. Durable responses included pts on treatment for 112 weeks (96 weeks since last dose), 88 weeks (13 weeks since last dose), and 46 weeks (after a single dose). Conclusions: In this first-in-human study, key TEAEs of JNJ-6420 were thrombocytopenia and ILD, both associated with repeated dosing. At ≥150 μCi, 1-2 doses of JNJ-6420 elicited profound and durable biochemical and radiographic responses. Evaluation of the RP2D is ongoing. These data highlight hK2 as a novel target for targeted alpha-particle therapy. Clinical trial information: NCT04644770 . [Table: see text]

5008 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). In this exploratory analysis, associations between baseline circulating tumor DNA (ctDNA) and outcomes were assessed. Methods: Patients were randomized 1:1 to 177Lu-PSMA-617 (7.4 GBq Q6W; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients known to have actionable mutations (e.g. BRCA) were excluded. The primary endpoint was rPFS. Baseline plasma ctDNA was analyzed using a customized 585-gene sequencing assay. ctDNA fraction was assessed in all samples passing quality control. Alterations in key prostate cancer drivers (prevalent in >10% participants) were assessed in samples with ctDNA fraction >1%. Univariate Cox regression (reference: ARPI change) was used to assess association of ctDNA fraction or alterations with rPFS, prostate-specific antigen response (≥50% decline; PSA50) and RECIST response (RR) at the June 21, 2023 data cutoff. Results: Of 360 samples from 468 patients, 255 passed quality control and 156 had ctDNA fraction >1% (median 5.85%; range 0–85). Detection of ctDNA alterations was comparable between arms and with published data. Median rPFS was shorter for patients with ctDNA fraction > versus ≤1% (HR 2.753; 95% CI 1.957–3.872; p<0.0001) (Table); ctDNA fraction >1% was also associated with worse RR and PSA50 response. Median rPFS was shorter for patients with detected versus undetected AR(HR 1.954; 95% CI 1.333–2.865; p<0.001), TP53(1.655; 1.13–2.426; p<0.01) and PTEN(1.62; 1.018–2.578; p<0.05) alterations. Median rPFS was longer with 177Lu-PSMA-617 versus ARPI change in patients with detected AR, TP53, PTEN(Table) , PI3K pathway and DNA repair pathway alterations. There was no significant association between ctDNA alterations and PSA50 or RR. Conclusions: ctDNA fraction >1% and AR, TP53and PTENalterations were associated with worse outcomes in PSMAfore regardless of treatment. Nonetheless, patients with these negative prognostic biomarkers did better with 177Lu-PSMA-617 than with ARPI change. Clinical trial information: NCT04689828 . [Table: see text]

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]