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A phase III single-arm study to evaluate the efficacy and safety of paclitaxel-hyaluronic acid conjugate administered intravesically to patients with BCG-unresponsive carcinoma in situ of the bladder with or without Ta-T1 papillary disease (Orion-BC study).
TPS885 Background: Non-muscle invasive bladder cancer (NMIBC) is the most common bladder cancer, with Carcinoma in situ (CIS) being a precursor to muscle-invasive disease. Intravesical BCG is the first-line treatment for high-risk NMIBC, including CIS; however over 50% of patients experience recurrence. Radical cystectomy (RC) is recommended for patients with BCG-unresponsive CIS, but it is associated with high morbidity and mortality. Consequently, some patients are ineligible or decline this option, posing a challenge in the management of the disease. Currently, there is a lack of alternative treatments for patients with BCG-unresponsive CIS in Europe, highlighting an unmet clinical need, while FDA-approved treatments are associated with significant adverse events (AEs). A new conjugate of hyaluronic acid (HA) and paclitaxel (Oncofid-P-B) enhances intracellular drug concentration up to 800-fold by targeting CD44, overexpressed on bladder cancer cells. In a phase I clinical trial, the conjugate showed promising complete response rates (CRR) of 75% at the end of the induction, and of 40% at the end of one-year maintenance phase in patients with BCG-unresponsive CIS, with no significant Grade 3-5 AEs (Hurle 2021). Methods: This is a phase III, single-arm, multicenter study (Clinical trial ID: NCT05024773) assessing the efficacy and safety of intravesical instillations of Oncofid-P-B in BCG-unresponsive patients with CIS +/- Ta-T1 unfit or refusing RC. The study is ongoing at 34 centers in Europe and the US (8 in Italy, 11 in Spain, 7 in France, 3 in Poland, 5 in US). Patients receive 12 weekly intravesical instillations of the drug (600 mg) (induction phase), followed by 12 monthly instillations in those achieving a CR (maintenance phase). Eligibility criteria include an ECOG performance status of 0-2 and persistent or recurrent CIS +/- Ta-T1 within 12 months post-BCG. Tumor response is evaluated by cystoscopy and cytology at the end of the induction, every 3 months for up to 24 months during the maintenance/follow-up, and every 6 months for additional two years. Biopsies are performed at the end of the induction and in case of positive cystoscopy/cytology during treatment and follow-up. Random biopsies are conducted at 9, 15, and 21 months in responding patients. Primary efficacy objective is to evaluate the antitumor activity with centrally assessed CRR following induction. Secondary efficacy objectives include measures of CR rates, duration of response, progression rates, time to progression, and cystectomy rates. Safety evaluation over the study represents the safety objective. The study is currently enrolling in Europe and US. So far, 63 patients were screened and 49 were enrolled (Ta/T1 subgroup: 10 subjects). Clinical trial information: NCT05024773 .
Comparing the effectiveness of IO-based combination regimens as first-line treatment for advanced clear-cell renal cell carcinoma (ccRCC).
498 Background: IO-based combination therapies - either in combination with tyrosine kinase inhibitors (TKI) or as double checkpoint inhibition - have revolutionized first-line treatment of ccRCC patients. We compared tolerability and effectiveness of ipilimumab plus nivolumab (ipi/nivo), cabozantinib plus nivolumab (cabo/nivo), axitinib plus pembrolizumab (axi/pem), and lenvatinib plus pembrolizumab (len/pem) as first-line treatment in real-world cohorts. Methods: Data from retrospective, multicenter cohorts of advanced ccRCC patients were analyzed. Best response was evaluated by local investigators. Adverse events (AE) were assessed according to CTCAE v5.0. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to calculate statistical differences between the cohorts. Results: A total of 543 patients were included in this analysis. Median age of all patients was 65 years (range 21-88), most patients were male (70%). Median number of affected organs were 2 and sites of metastases were comparable between treatment regimens. Key data on IMDC risk group distribution, median follow-up (FU), best response, disease control rate, median PFS, median PFS by IMDC risk group, 1-year OS-rate and occurrence of AEs by treatment regimens are depicted in the table. PFS was significantly superior for IO/TKI combinations compared to Ipi/Nivo (p=0.021). At a median FU of 21.2 months (95%CI 19.7-22.7) for all patients, 51% of patients had disease progression and 26% of patients died. Conclusions: IO/TKI combinations demonstrated significantly better PFS compared to IO/IO as first-line treatment for ccRCC patients. However, no specific IO/TKI regimen showed clear superiority over others, and 1-year OS rate was encouraging across all cohorts. Factors such as IMDC risk, comorbidities, AE profiles and individual treatment goals should be considered when tailoring therapy. Key limitations include the retrospective design, which introduces potential selection and recall biases, varying cohort sizes, the different and limited follow-up time between cohorts and limited OS events. Ipi/Nivo(n=251) Cabo/Nivo(n=47) Axi/Pem(n=118) Len/Pem(n=127) IMDC risk group- fav. risk- int./poor risk 8%92% 34%60% 24%72% 27%73% Median FU in mo. (95%CI) 32.1 (27.5-36.7) 14.0 (10.1-17.8) 22.5 (19.7-25.3) 14.7 (11.3-18.1) Best Response (CR rate) 40% (10%) 49% (2%) 64% (7%) 67% (7%) Disease control rate 64% 68% 86% 78% Median PFS (95%CI)- IMDC fav. risk- IMDC int./poor risk 9.0 (5.8-12.2)7.3 (6.9-7,7)9.7 (6.3-13.1) 16.1 (4.9-27.3)13.0 (6.8-19.2)10.7 (n.e.) 16.8 (10.4-23.2)25.4 (10.0-40.8)12.9 (9.4-16.4) 22.2 (11.7-23.7)22.2 (15.6-28.8)12.2 (0-24.6) 1 y OS rate (95%CI) 81.0 (75.8-86.2) 78.0 (63.8-92.2) 90.6 (84.8-96.4) 78.7 (70.5-86.9) AEs any grade 78% 79% 92% 95% AEs ≥ grade 3 40% 47% 47% 61%
Extreme bipolar androgen therapy: Alternating darolutamide and testosterone cypionate in patients with metastatic castration-resistant prostate cancer (mCRPC; ExBAT trial/LACOG 0620).
178 Background: Sequencing androgen-receptor signaling inhibitors (ARSi) has limited activity in metastatic castration-resistant prostate cancer (mCRPC). Bipolar Androgen Therapy (BAT), consisting of supraphysiological doses of exogenous testosterone, followed by a decline to castrate levels, has shown benefit in a subset of patients (pts) with mCRPC, by the downregulation of AR levels, a therapeutic vulnerability which led to resensitization to ARSi in trials. We hypothesize that BAT could significantly enhance the efficacy of subsequent ARSi darolutamide in pts who had progressed to abiraterone. Methods: The ExBAT/LACOG 0620 ( NCT04558866 ) study is a phase II, single-arm, multi-center trial investigating a pre-planned regimen of alternating BAT and darolutamide in mCRPC pts after progression on abiraterone. Prior docetaxel for hormone-sensitive disease was allowed. Pts received intramuscular testosterone cypionate 400 mg on day 1, followed by oral darolutamide 1200 mg/day from day 29 to day 56, followed by a washout period of 7 days, in 63-day cycles. The primary endpoint was radiographic progression-free survival (rPFS) at 12 months. Secondary endpoints include median rPFS, PSA50 response, overall survival (OS), quality of life (QoL) and safety. Results: From Jun2021 to Mar2023, 51 pts were enrolled in 9 centers and 48 pts were eligible for efficacy analysis. Median age was 69y (range, 48-92), 23.5% had received abiraterone on castration-sensitive setting and 76.5% on mCRPC. The rPFS rate at 12 months was 40.9% (95% CI, 26.3 – 55.0) and median rPFS was 9.0 months (95% CI, 3.9 – 12.9). PSA50 response was 16.7% (95% CI, 7.4–30.2) and median OS was 23.0 months (95% CI, 17.7 – not reached). At cut-off date (22Mar24), 10 pts remained on treatment. QoL was maintained during the treatment. Treatment-related adverse events (TRAEs) rates of any grade and grade 3-4 were 64.7% and 9.8% respectively, and no grade 5 TRAE was reported. The most common AEs were bone and breast pain. Conclusions: ExBAT study demonstrated durable (12 months or more) antintumor activity of alternating BAT and darolutamide in around 40% of pts, with manageble safety profile. Further studies evaluating ExBAT are needed to identify biomarkers of response and the impact of ARSi sequencing in subsequent lines of therapy. Clinical trial information: NCT04558866 .
EPIC-A: Phase II trial of cemiplimab plus standard of care chemotherapy followed by maintenance cemiplimab in locally advanced or metastatic penile carcinoma.
1 Background: Platinum-based combination chemotherapy remains the Standard of Care (SoC) treatment for patients with locally advanced/metastatic penile cancer (la/mPC). Prognosis is poor and treatment options are limited. PDL1 is upregulated in 40–60% of cases making a case for immunotherapy as a treatment option for la/mPC. PD-1 inhibitor cemiplimab is approved for patients with locally advanced or metastatic cutaneous SCC. We evaluated efficacy and safety of cemiplimab in combination with SoC chemotherapy in patients with la/mPC. Methods: EPIC-A is a National Cancer Research Network badged phase II non-randomised multi-centre trial evaluating the efficacy and safety of cemiplimab plus platinum-based chemotherapy as first-line treatment in la/mPC. Patients with la/mPC (Tany,N2-3,M0 or T4,Nany,M0 or M1) not amenable for radical treatment received: cemiplimab 350mg IV D1 every 3 weeks (Q3W) + SoC chemotherapy cisplatin/5FU (PF, 27 patients) or docetaxel, ifosfamide, cisplatin (TIP, 2 patients) for 4 cycles followed by cemiplimab alone 350mg IV Q3W up to a total of 34 cycles. The primary end point was investigator assessed Clinical Benefit Rate (CBR) at 12 weeks using RECIST 1.1. The study was designed as an A’Hern (2001) study α=0.05 + power (1-β)=0.8, assuming 25% meeting the clinical end point is a poor treatment (p0=0.25) and 50% is a good treatment (p1=0.5). Assuming a 10% drop out rate, 29 patients were recruited. Results: 29 patients from 11 UK sites were enrolled from Jan 2022- Dec 2023. Median age was 61 years (range 38-76). 93% were ECOG 0-1 and 7% ECOG 2. 76% had metastatic disease (6 bone 23%, 2 liver 6.9%, 16 lung 55.2%). Median number of cycles was 5 (range 1-34) and median follow-up was 8.3 (IQR 5.5-11.5) months. At 12 weeks CBR was 62.1% (95%CI 44.4%, 79.7%) and Objective Response Rate (ORR) was 51.7% (95%CI 34.4%, 68.6%) with 15 PR and no CR. Benefit was maintained at 21 weeks with CBR 48.3% (95%CI 31.4%, 65.6%) and ORR 44.8% (95%CI 28.4%, 62.4%) with 12 PR and 1 CR. Median Progression Free Survival (PFS) was 6.2 (95%CI 3.7, 8.7) months and Overall Survival (OS) is currently estimated to be 15.5 (95%CI 6.0, 25.0) months. Of the reported adverse events (AEs) of any grade, 23% were related to cemiplimab and 31% to chemotherapy. Safety profile is in keeping with reported data on cisplatin based chemotherapy and immunotherapy. There were 2 grade 5 AEs, neither related to cemiplimab but 1 related to chemotherapy. 7 patients discontinued treatment due to an AE, 4 related to cemiplimab (14%). Conclusions: The EPIC-A Trial demonstrates the efficacy and safety of cemiplimab in combination with platinum-based chemotherapy as a treatment for la/mPC. Investigations into potential biomarkers and Quality of Life analysis is ongoing. These data support cisplatin based combination chemotherapy + cemiplimab as a first line SoC treatment option in this rare cancer. Clinical trial information: 95561634.
Efficacy and safety of ifosfamide and mesna in metastatic castration-resistant prostate cancer after taxane-based chemotherapy and novel hormonal therapy failure.
174 Background: Limited treatment options exist for patients with metastatic castration-resistant prostate cancer (mCRPC) after the failure of taxane-based chemotherapy and novel hormonal therapy. Here, we report the safety and efficacy of ifosfamide and mesna in patients with mCRPC after the failure of taxane-based chemotherapy and novel hormonal therapy (NCT06236789). Methods: Patients with histologically confirmed prostate cancer who had failed taxane-based chemotherapy and novel hormonal therapy received ifosfamide 2,500 mg/m2 and mesna 1,500 mg/m2 on days 1–3, repeated every 21 days. Safety, objective response rate, disease control rate, reduction in serum prostate-specific antigen (PSA) concentration by >50% (PSA50) or >90% (PSA90), radiographic progression-free survival (rPFS), and overall survival (OS) were analyzed. Results: A total of 47 patients with mCRPC were included in the study. The median number of lines of treatment was 5 (range: 3–7). All patients were previously administered docetaxel and novel hormonal therapies including abiraterone (51.1%) and/or enzalutamide (61.7%). Thirty-eight patients (80.9%) were administered cabazitaxel. The objective response and disease control rates were 21.3% and 80.9%, respectively. PSA50 and PSA90 were achieved in 31.9% and 10.6%, respectively. During a median follow-up duration of 54.3 months, rPFS and OS were 5.0 and 9.0 months, respectively. All the patients experienced treatment-related adverse events of any grades; however, no new safety signs were detected. Genomic biomarker analysis revealed that alterations in the TP53 pathway were associated with inferior rPFS and OS. Conclusions: Ifosfamide and mesna showed appreciable efficacy and manageable safety profiles in heavily treated patients with mCRPC, warranting further investigation. Clinical trial information: NCT06236789 .
Second primary malignancy in bladder cancer: A retrospective population-based analysis.
676 Background: Bladder cancer is responsible for about 4% of cancers in the United States. It is the fourth most common cancer in men. A second primary malignancy is a significant complication in cancer survivors, with dire effects on morbidity and mortality. The data on second primary malignancies (SPM) in bladder cancer is limited. Therefore, we aim to evaluate and discuss this risk. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) database, comparing secondary cancer rates among bladder cancer cases diagnosed from 2000 to 2021. A second primary malignancy was defined as a malignancy developing six or more months after an index bladder cancer diagnosis. We used the SEER MP-SIR session to obtain the p-value, observed/Expected (O/E) ratio, and absolute excess risk (AER) per 10,000. Results: 238,358 bladder cancer cases from 2000-2021 met our inclusion criteria and were included in our study. Of these cases, 46,859 (19.7%) developed second primary malignancies. The mean age of SPM was 75.03 years. The risk of developing SPM was significantly higher than the general population, with an O/E ratio of 1.48 (CI 1.46-1.49, AER 99.85, p < 0.05). Most common SPMs included Hypopharynx (O/E ratio 1.3 CI 1.0-1.67, p < 0.05), Esophagus (O/E ratio 1.15 CI 1.05-1.26, p < 0.05), Liver (O/E ratio 1.14 CI 1.05-1.23, p < 0.05), Lung (O/E ratio 1.89 CI 1.85-1.93, p < 0.05), Vagina (O/E ratio 2.58 CI 1.71-3.73, p < 0.05, Prostate (O/E ratio 1.39 CI 1.36-1.42, p < 0.05, Acute Myeloid Leukemia (AML) (O/E ratio 1.58 CI 1.01-2.34, p < 0.05). Conclusions: Compared to the general population, there is a statistically significant increased risk of secondary primary malignancies in bladder cancer patients. Bladder cancer survivors would benefit from proactive screening modalities and follow-up for the development of SPM.
Efficacy and safety of immune checkpoint inhibitors (ICI) for the treatment of metastatic penile squamous cell carcinoma (mPSCC).
4 Background: Metastatic penile squamous cell carcinoma (mPSCC) is a rare and aggressive malignancy with limited treatment options. Standard systemic therapies include paclitaxel, ifosfamide, cisplatin (TIP), fluorouracil and cisplatin (5-FU + cis), paclitaxel monotherapy and cetuximab. These regimens were evaluated as small single-arm studies. The HERCULES trial, a single-arm phase 2 clinical study, demonstrated the safety and efficacy of combining immunotherapy with chemotherapy, signaling a potential benefit of immunotherapy. Our retrospective analysis evaluates the safety and efficacy of single-agent immunotherapy at the University of Kansas and Aurora St. Luke’s Medical Center. Methods: We conducted a multicenter retrospective, IRB-approved study of mPSCC patients treated with single-agent immunotherapy from 2015 to 2023. Objective response rates were assessed per RECIST version 1.1, and progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events were graded per CTCAE version 5.0, with only grade 3+ immune-related adverse events being recorded. Results: Nine patients with mPSCC were included, with a median age of 75 years (range, 50-92). Over half (n=5) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more, and most (n=8) had visceral metastasis. Single-agent immunotherapy was administered as first-line (n=3), second-line (n=4), and third-line or beyond (n=2). Pembrolizumab was used in six patients, with two receiving nivolumab and one cemiplimab. The objective response rate was 33.3% (n=3), including one complete response. Median PFS was 2.82 months (range, 1.0-14.3), and median OS was 4.3 months (range, 1.0-24.9). Patients who responded had PFS exceeding 12 months, with two still ongoing at data cutoff. No grade 3 or higher treatment-related adverse event has been observed during the treatment period. Additional analyses to correlate the response with HPV positivity are ongoing. Conclusions: Our findings suggest that single-agent immunotherapy can yield favorable response rates and durations in older and/or frail mPSCC patients. While our sample size is small and retrospective, response rates are comparable to those in the HERCULES trial (33.3% vs. 39.4% with chemoimmunotherapy). Notably, grade 3+ treatment-related adverse events were lower in our study compared to 51.4% of HERCULES patients. This underscores the potential of single-agent immunotherapy as a safe and effective option for this rare malignancy. Further prospective studies are needed to optimize treatment strategies for mPSCC.
Impact of baseline PSMA PET in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) starting first-line (1L) androgen receptor signaling inhibitor (ARSI) therapy.
46 Background: The prognostic significance of PSMA positron-emission tomography (PET) uptake on prostate cancer (PC) outcomes is not well established. Higher uptake predicts recurrence in men with localized PC, but may be associated with improved survival in pts with mCRPC receiving chemotherapy or radioligand therapy. We sought to evaluate the predictive and prognostic value of baseline PSMA PET uptake in mCRPC pts starting 1L ARSI therapy. Methods: A retrospective analysis of consecutive mCRPC pts who underwent PSMA PET imaging at our institution from 2016 to 2023 was undertaken. Pts were included if a PSMA PET scan performed in the setting of mCRPC showed ≥1 lesion with SUV max ≥3 and 1L ARSI was initiated as the immediate next-line of therapy after scan. PSMA PETs were analyzed and manually segmented by a trained radiologist using MIM Software and SUV threshold of 3; physiologic uptake was removed. SUV max , SUV mean , tumor volume (TV) and total lesion PSMA (TL-PSMA = SUV mean x TV) were obtained for each patient. PSA response on 1L ARSI therapy, PSA progression-free survival (PSA-PFS), time to next treatment (TNT), and overall survival (OS) were retrospectively assessed from start of ARSI. Baseline PSMA PET characteristics were compared across pts with vs without PSA response to 1L ARSI. Time-to-event statistics were performed using the Kaplan-Meier method and Cox proportional hazards model. Statistical significance was declared for p < 0.05. Results: Forty-nine mCRPC pts with PSMA PET imaging performed prior to 1L ARSI (abiraterone in 27, 2 nd generation AR antagonist in 22) were identified. Median SUV max , SUV mean , TV and TL-PSMA were 30.5, 7.2, 22.5 mL and 221.1, respectively. Pts who achieved a greater than ≥90% decline in PSA on ARSI therapy (n=24) had significantly lower SUV max (median 17.7 vs 40.2, p=0.029) and SUV mean (median 6.3 vs 9.9, p=0.017) at baseline. Baseline SUV mean , SUV max , and TV did not predict PSA-PFS, TTNT or OS; however, baseline log10-transformed TL-PSMA was associated with inferior PSA-PFS (HR 1.76, 95% CI 1.07-2.91 p=0.026) on univariate analysis. On Kaplan-Meier analysis, pts in the highest quartile of TL-PSMA had a significantly shorter median OS compared to others (25.3 vs 67.3 months, log-rank p=0.039). Conclusions: In this cohort of mCRPC pts treated with 1L ARSI, those achieving a PSA90 response had significantly lower SUV max and SUV mean on baseline PSMA PET. However, PSMA uptake did not predict longer-term outcomes such as PSA-PFS, TTNT and OS. Pts with higher PSMA-TL had a higher risk of PSA progression and shorter OS. These hypothesis-generating results suggest that although lower PSMA PET uptake may predict initial response to ARSI, tumor burden (PSMA-TL) is a stronger predictor of long-term outcomes. Prospective validation is needed.
National cancer system characteristics and prostate cancer outcomes: A global analysis.
24 Background: The number of prostate cancer cases globally is projected to double from 2020 to 2040. However, significant global variation exists in prostate cancer incidence and mortality. A more specific understanding of health system levers specific to prostate cancer may inform health system planning. Therefore, we used global health system data from the World Health Organization (WHO), the World Bank, the Directory of Radiotherapy Centres (DIRAC), the United Nations Development Programme (UNDP), and the International Agency for Research on Cancer (IARC) to evaluate predictors of prostate cancer outcomes globally. Methods: National estimates of age-standardised incidence and mortality rates were obtained from the IARC 2022 database for male patients with prostate cancer of all ages (available for 185 countries). Mortality-to-incidence ratio (MIR), a proxy for survival, was calculated for each country. The following were taken from the World Bank: health spending as a percent of gross domestic product (GDP, 2021), physicians per 1000 population (2016-2021), nurses and midwives per 1000 population (2016-2021), surgical workforce per 1000 population (2013-2018), and GDP per capita. Universal healthcare (UHC index) and availability of pathology services were taken from the WHO. The gender inequality index (GII) and human development index (HDI) were taken from UNDP. Number of radiotherapy centers from DIRAC was used to derive number of radiotherapy centers per 1000 people. The association between prostate MIR and each of the ten metrics was evaluated using univariable linear models; Bonferroni corrected P<0.005 associations were included in the multivariable regression (MVA). We then assessed multicollinearity through variation inflation factor (VIF) analysis (VIF>10 excluded). α=0.10 defined statistical significance in the MVA. R2 evaluated goodness of fit. Results: Data availability ranged from 144 (77.8%, surgical workforce per 1000 population known) to 185 (100%, GDP per capita, RT centers per 1000 population). On univariable analysis, each of the ten metrics were significantly associated with MIR of prostate cancer (<0.001 for all). In MVA (N=123), VIF for HDI was 19.06. The final model (N=123 countries) with nine metrics had an R2 of 0.84. Therefore, the following variables were associated with lower (improved) MIR for prostate cancer: 1) surgical workforce per 1000 population, 2) UHC index, 3) radiotherapy centers per 1000 population, 4) GDP per capita. MIR plotted individually against these four metrics illustrates these associations. Conclusions: Analysis of global data and health-system metrics suggest that surgical workforce, availability of radiotherapy centers, degree of UHC, and GDP per capita are associated with improved prostate cancer outcomes. In leveraging individual countries’ health systems as data points, these findings may guide health system planning and prioritization.
Final overall survival of ARIES trial evaluating first line avelumab monotherapy for patients with advanced urothelial cancer (aUC) unfit for cisplatin and outcome analysis based on baseline characteristics.
797 Background: ARIES trial evaluated avelumab monotherapy in PD-L1+ve aUC patients (pts) not eligible to cisplatin-based chemotherapy, reaching its primary endpoint (Iacovelli R et al. ASCO-GU 2022). Treatment landscape for aUC has changed since enfortumab-vedotin and pembrolizumab (EV+P) has become the new standard for platinum-eligible pts reporting also a mPFS of 10.6 mos and 1-y OS rate of about 80% in cisplatin ineligible (carboplatin-eligible) pts. Unfortunately, up to 20% of pts are not eligible to platinum-based chemotherapy (PBC) and guidelines continue to recommend immunotherapy alone. Methods: Pts with PDL1+ve aUC and not eligible for cisplatin-based chemotherapy were enrolled and treated with avelumab until progression of disease. Here we reported the final OS, and we evaluated the baseline differences between pts with longer PFS compared to those who immediately progressed. Baseline characteristic included in this analysis were sites of metastases, performance status, body mass index (BMI), haematological values and the Neutrophils-to-Lymphocytes Ratio (NLR). Results: 71 pts were enrolled, the median age was 75 years (range 38 – 88); bladder cancer was the primary tumour in 73.2% of cases, 25.3% had liver metastases, 31% had ECOG=2 and 31% had renal function <50ml/min. After a median FU of 52 mos, the median OS was 10.3 mos (95%CI 5.3 – 15.3) and the median PFS was 2.1 mos (95%CI 1.8 – 2.4). 26 pts (37%) received subsequent therapies, with gem+carbo as most frequently used (15 pts, 21%). A total of 18 pts (25%) had a PFS ≥9 mos while 44 (62%) had a PFS ≤3 mos. Significant differences between these two groups were the presence of liver mets (11% vs. 36%; p=0.047), the presence of node only disease (39% vs 5%; p<0.001) and the rate of pts with NLR>4 (22% vs. 61%; p=0.005). At multivariable analysis only NLR>4 and liver mets were confirmed to be independent prognostic factors. The 27 pts (38%) without liver mets and with NLR>4 had significantly (p=0.001) prolonged mPFS (7.7 vs. 1.9 mos), mOS (20.4 vs. 5.7 mos), and 1y OS rate (67% vs. 32%). Conclusions: ARIES trial confirmed the activity of avelumab in cisplatin-ineligible aUC pts including those not eligible to PBC. This analysis also identified the absence of liver mets and low values of NRL as potential markers of significant benefit from immunotherapy alone. This evidence can be used for a personalized approach in the evolving treatment landscape of aUC. Clinical trial information: NCT03891238 .
Equal-depth sequencing of white blood cells (WBC) and plasma from prostate cancer (PCa) liquid biopsies (LBx) and association with clonal hematopoiesis (CH) confounders in clinically relevant genes.
221 Background: CH results from fitness-enhancing mutations in hematopoietic stem cells that accumulate with age. Deep sequencing of LBx, a standard of care for guiding therapy selection in advanced PCa, can be confounded by sensitive detection of variants (vars) arising from both ctDNA and CH-derived DNA. Here we report the prevalence of CH vars in PCa and other cancers and describe an algorithmic method for accurately distinguishing CH from tumor signal, even at low variant allele frequencies (VAF). Methods: Plasma cell-free DNA from 1813 patients with cancer (n = 270 PCa) was sequenced using FoundationOneLiquid CDx (F1LCDx) in a CLIA lab setting. In parallel, DNA from buffy coats was extracted, sheared, and sequenced on F1LCDx to identical depth, to establish ground truth for CH var identity. This cohort was used to train a machine learning variant origin prediction (VOP) model incorporating fragmentomics and other sequencing features to assign probabilities of origin (germline, tumor, or CH) to all short variants across the 324 genes baited on the assay. Only pathogenic vars were considered. Results: 1247/1813 (69%) of LBx detected ≥1 CH var, including 209/270 (77%) of PCa LBx (mean 1.8 vars/sample). CH contributed confounding vars in clinically relevant genes including CHEK2, ATM, BRAF, TP53, and BRCA2 in 90/270 (33%) of PCa LBx (Table). Median VAF of CH vars in these genes was 0.3% in LBx and 0.7% in WBC. CH vars enriched in PCa vs other cancers were: TET2 (23.0% of PCa LBx vs 13.6% of non-PCa), ASXL1 (14.4% vs 7.5%), SF3B1 (7.0 vs 2.3%), and TERT promoter (5.2% vs 1.3%), FDR <0.05 for all. In the pan-cancer cohort, the VOP algorithm identified CH vars with 95.2% (2613/2745) sensitivity, 94.1% (3741/3975) specificity, and 91.8% (2613/2847) positive predictive value (PPV). For CH vars with VAF<1%, VOP had 95.0% (1622/1707) sensitivity, 1021/1169 (87.3%) specificity, and 91.6% (1622/1770) PPV. Conclusions: Equal-depth DNA sequencing of plasma and matched WBC reveals higher CH prevalence in LBx than previously reported: 77% of PCa LBx with a CH var, including 33% with a CH var in clinically relevant genes . Many potentially actionable vars have low VAF in LBx, and filtering CH via shallower depth WBC sequencing than that of LBx risks leaving low VAF CH vars to be mistaken for tumor vars. Equal-depth WBC sequencing or an algorithmic method validated using equal-depth WBC sequencing is required for accurate identification of low VAF CH confounders in LBx. Percentages of LBx with only CH vars/total LBx with vars detected in genes clinically relevant in PCa. Gene PCa Pan-cancer CHEK2 19/25 (76%) 143/168 (85%) ATM 18/29 (62%) 156/227 (69%) BRAF 2/5 (40%) 10/48 (21%) TP53 46/120 (38%) 235/996 (24%) BRCA2 2/12 (17%) 3/37 (8%) PALB2 0/3 (0%) 4/17 (24%) BRCA1 0/2 (0%) 5/28 (18%) CDK12 0/7 (0%) 3/17 (18%)
Efficacy and safety of organoid-based drug sensitivity screening to guide the treatment of mCRPC patients progressed after first-line treatment.
TPS278 Background: Treatment for metastatic castration-resistant prostate cancer (mCRPC) patients progress after first-line therapy remains challenging due to limited options and heterogeneous response. Organoid-based drug sensitivity screening offers an innovative approach by simulating the tumor microenvironment in vitro, potentially allowing for personalized treatment strategies based on individual tumor responses to various drugs. This study aims to assess the efficacy and safety of using organoid-based drug sensitivity screening to guide treatment decisions in mCRPC patients. Methods: This is a prospective, open-label, single-arm observational study designed to recruit 30 mCRPC patients with bone metastases who have progressed after first-line therapy. Residual tissue from biopsies of bone metastatic lesions will be used to culture organoids for drug sensitivity screening. Screening regimens include at least Olaparib, Docetaxel or platinum-based chemotherapy, and Abiraterone plus Niraparib, as recommended by current guidelines. Additionally, 141 other drugs from a previously established library are available for screening, based on investigator and patient preferences. The treatment regimen will be selected based on the agent that demonstrates the highest sensitivity in the screening process. The primary endpoint is PSA response rate, defined as a 50% decrease in PSA levels from baseline. Secondary endpoints include radiologic progression-free survival (rPFS), objective response rate (ORR), duration of response (DOR), and overall survival (OS). Patient recruitment is ongoing at Sun Yat-sen University Cancer Center, with 5 patients (5/30, 16.7%) enrolled as of September 3, 2024. Data analysis is expected to begin in 2025, following the completion of recruitment. Clinical trial information: NCT06529549 .
Safety and tolerability of relugolix in combination with abiraterone or apalutamide for treatment of advanced prostate cancer: Data from a 52-week clinical trial.
156 Background: Relugolix (REL) is the only oral androgen deprivation therapy (ADT) indicated for advanced prostate cancer (aPC). Combining ADT with androgen receptor signaling inhibitors (ARSIs) has shown improved clinical outcomes in hormone-sensitive and castration-resistant PC. This study evaluated the safety and tolerability of REL with the ARSIs abiraterone (ABI) or apalutamide (APA). Methods: In this open-label, two-part study, patients (pts) with aPC, including ADT-experienced, were treated for 52 weeks (wks). In Part 1, pts received REL 120 mg qd + ABI 1000 mg qd + either prednisone 5 mg qd or bid or methylprednisolone 4 mg bid. In Part 2, pts received REL 240 mg qd + APA 240 mg qd. Pts with metastatic castration-sensitive PC were eligible for Part 1 & 2. Castration-resistant pts were eligible for Part 1 with metastatic and for Part 2 with non-metastatic PC. The primary objective was to assess safety and tolerability. Testosterone (baseline, wk 2, 4, 12) and PSA (baseline, wk 12) levels were also evaluated. REL, APA, and N-desmethyl APA concentrations were determined at baseline, wks 2, 4, 8, and 12 in Part 2. REL adherence was measured by pill count. Results: Twenty-four pts were enrolled in each part, with 21 and 20 completing Part 1 & 2, respectively. Most pts were white with a mean age of 71 and 69 years in Part 1 & 2, respectively. Mean REL treatment adherence was > 97% in the study. The majority of reported adverse events (AEs) were mild (grade 1 or 2) in Part 1 & 2. The most commonly reported AE was hypertension in Part 1 and rash in Part 2. No relevant post-treatment changes in laboratory, ECG, or vital sign parameters were noted. Mean testosterone levels were maintained below castration level (50 ng/mL) through the 12-wk treatment. Mean (SD) and median PSA levels were 28.1 (127.1) and 0.04 ng/mL (1 pt with 611 ng/mL) in Part 1 and 0.2 (0.3) and 0.04 in Part 2 at wk 12, respectively. REL, APA, and N-desmethyl APA concentrations were stable over 12 wks indicating steady-state conditions. Conclusions: REL used in combination with ABI or APA showed safety profiles consistent with individual drugs over 52 wks. REL levels were stable, and testosterone was sustained below castration level. These findings support the safety and tolerability of REL combination therapy with ABI or APA for aPC. Clinical trial information: NCT04666129 . Part 1 (N=24) Part 2 (N=24) Age 1 (years), mean (SD) 71 ± 7 69 ± 7 Race 1 , White, n (%) 19 (79) 16 (67) Adherence 2 , mean (SD) 98.5% (3.2) 97.8% (8.0) Any TEAE, n (%) 22 (91.7) 21 (87.5) Most common TEAE 2 , n (%) Hypertension, 6 (25.0) Rash 5 (20.8) Any Serious TEAE 2 , n (%) 3 (12.5) 1 (4.2) Testosterone 3 (ng/dL), mean (SD) 2.9 (6.9) 15.3 (12.4) Relugolix 4 (ng/dL), mean (SD) - 10.9 (10.7)/11.1 (9.7) Apalutamide; N-desmethyl apalutamide 4 (ng/dL), mean (SD) - 4088.3 (1046.8)/3666.4 (1154.0);4767.4 (1133.3)/4717.5 (1362.7) 1 Baseline; 2 Week 52; 3 Week 12; 4 Weeks 2/12. TEAE = treatment emergent adverse events.
Casdatifan (Cas) monotherapy in patients (pts) with previously treated clear cell renal cell carcinoma (ccRCC): Safety, efficacy and subgroup analysis across multiple doses from ARC-20, a phase 1 open-label study.
441 Background: ccRCC, the most common histologic subtype of renal cancer, is universally associated with dysregulation of the VHL pathway, leading to HIF-2α accumulation and upregulation of multiple oncogenic pathways. Cas is an orally bioavailable, small-molecule HIF-2α inhibitor that potently inhibits transcription of HIF-2α-dependent genes. Methods: ARC-20 (NCT05536141) is a phase 1, open-label study evaluating Cas monotherapy in pts (age ≥18) with ccRCC who are HIF-2α inhibitor naïve and previously treated with anti-PD-(L)1 and VEGFR-TKI therapies. Trial endpoints included incidence of treatment-emergent adverse events (TEAES) and objective response rate (ORR) by RECIST v1.1. Results: Prior to dose expansion, dose escalation occurred in 4 pts with ccRCC (3 pts 50 mg BID; 1 pt 50 mg QD) of which 2 pts had SD,1 pt had PR, and 2 remain on study as of 30Aug2024. In dose expansion, 64 pts received Cas (33 pts 50 mg BID, 31 pts 50 mg QD). Median prior lines of treatment were 3 (range 1–7) across doses. Median follow-up (months, range) was 11 (3–15+) and 8 (4–10+) for 50 mg BID and 50 mg QD, respectively. Cas-related grade ≥3 TEAE occurred in 42% (n=14) and 36% (n=11) of pts, respectively. Notably 36% of pts experienced grade 3 anemia, regardless of dose, and grade 3 hypoxia occurred in 9% and 6% of pts, respectively. No grade ≥4 TEAEs occurred. Activity was seen across all IMDC risk groups, regardless of dose, and in pts with or without prior mTOR inhibitor (Table). Cas 100 mg demonstrated optimal sustained EPO reduction. Biomarker analysis, including HIF-1α and HIF-2α immunohistochemistry, mutational status of VHL/ccRCC relevant genes, predictive transcriptomic signatures and efficacy data with longer follow up will be presented. Conclusions: In heavily pretreated pts with ccRCC, Cas monotherapy was well tolerated with promising early clinical activity across IMDC risk groups. Cas 100 mg QD will be combined with VEGFR-TKI (cabozantinib) in the phase 3 PEAK-1 trial and immunotherapy (volrustomig) in a separate upcoming first-line trial. Clinical trial information: NCT05536141 . Cas50 mg BID(n = 32 a ) Cas50 mg QD(n = 28 a ) IDMC Favorable(n=15) IMDC intermediate/ poor/unknown(n=45) Without prior mTOR inhibitor treatment (n=51) With prior mTOR inhibitor treatment (n=9) Unconfirmed ORR, % (n) (95% CI) 34 (11 b )(19, 53) 25 (7)(11, 45) 40 (6)(16, 68) 27 (12)(15, 42) 31 (16)(19, 46) 22 (2)(3, 60) Confirmed ORR, % (n) (95% CI) 25 (8)(11, 43) 21 (6)(8, 41) 33 (5)(12, 62) 20 (9)(10, 35) 26 (13)(14, 40) 1 (11)(<1, 48) Disease control rate, % (95% CI) 81(64, 93) 86(67, 96) 93(68, 100) 80(65, 90) 82(69, 92) 89(52, 100) a Efficacy-evaluable pts: all pts who had measurable disease at BL, received ≥1 dose and had ≥1 post-BL efficacy assessment, or who discontinued study treatment due to progression or death. Disease control rate: ORR+SD. b Includes 1 pt who achieved PR after data cut-off.
Characterization of circulating tumor DNA (ctDNA) burden and its association with real-world overall survival among prostate cancer (PC) patients.
69 Background: Circulating tumor DNA (ctDNA) from blood-based liquid biopsies is emerging as a promising biomarker with potential prognostic and predictive value for managing patients across tumor types and therapeutic areas. Yet data and understanding of how ctDNA might be used as a prognostic biomarker in prostate cancer (PC) are limited. This study used real-world data (RWD) to evaluate the association between ctDNA burden and clinical characteristics and outcomes in PC. Methods: Prostate cancer patients were identified from the Guardant INFORM real-world clinical-genomic database, which connects ctDNA results obtained through the plasma-based next-generation sequencing Guardant360 assay (G360) to de-identified claims data. U.S. PC patients who underwent a G360 test between June 2014 and June 2023 were included. A 6-month baseline period prior to the first G360 test (index) was used to gather clinical information on these patients. ctDNA burden for each patient was defined as the maximum variant allele frequency (MVAF) of all somatic variants. The median MVAF across all samples was used to classify patients into high or low ctDNA burden groups. The association between ctDNA and real-world overall survival (rwOS) was assessed using log rank tests and multivariable Cox proportional hazards models adjusted for age, race/ethnicity, year of test, comorbidity indices, metastasis status, PC clinical state, and presence of androgen receptor ligand binding domain (AR LBD) mutations. Results: 16,757 PC patients were identified, of which, 13% had undetectable ctDNA burden. Using a median MVAF cut-off of 1.9% (range: 0.01% to 96.4%), 7,216 had low ctDNA burden and 7,330 had high ctDNA burden. Among patients with detectable ctDNA, higher ctDNA burden was observed in patients with metastatic castration resistant prostate cancer (N=5,996, median=2.4%), smokers (N=2,580, median=2.5%), with higher comorbidity burden (N=3,336, median=3.0%), and those AR LBD mutations (N=2,624, median=8.6%). Patients with high ctDNA burden showed significantly shorter rwOS after the index date (16.4 months [95%CI: 15.8-17.0]) than low and undetectable ctDNA burden groups (34.8 [95%CI: 32.8-37.0] and 53.1 months [95%CI: 48.6-65.9], respectively). Multivariable Cox models showed similar results (high ctDNA vs undetectable ctDNA hazard ratio [HR] = 3.16; low ctDNA vs undetectable ctDNA HR = 1.45; high ctDNA vs low ctDNA HR = 2.18). Conclusions: In this real-world study with large PC population, ctDNA burden varied by severity of disease and was negatively associated with overall survival after adjustment for other prognostic features. Our study adds to the body of evidence suggesting the utility of ctDNA as a potential prognostic biomarker in PC patients to monitor disease progression and patient outcomes in routine clinical practice.
Association between radiation therapy to the recurrence sites and oncological outcomes in patients who experienced local recurrence and/or pelvic lymph node metastases after radical cystectomy: A multicenter retrospective study.
788 Background: Local recurrence and/or pelvic lymph node metastases after radical cystectomy (RC) are often observed in patients with muscle-invasive bladder cancer (MIBC). Although chemotherapy and immune checkpoint inhibitors are the main treatment strategies in such patients, radiation therapy (RT) to the recurrence sites might be one of the treatment options. However, its effects on oncological outcomes remain unclear. Methods: This multi-institutional retrospective study included 106 patients who experienced local recurrence and/or pelvic lymph node metastases without distant metastases after RC. Patients were divided into two groups: patients who were treated with RT to the recurrence sites (RT group) and without (non-RT group). Multivariable Cox-proportional hazards regression analyses were performed to evaluate the effects of RT on cancer-specific survival (CSS) and overall survival (OS) after recurrence. Results: The median age at recurrence was 72 years, and the median follow-up period after recurrence was 13 months. Of the 106 patients, 65 (61%) received neoadjuvant chemotherapy (NAC) and 30 (28%) were treated with RT after recurrence. CSS and OS were not significantly different between the two groups ( P = 0.569 and P = 0.456, respectively). In univariable analyses, NAC, pure urothelial carcinoma, tumor grade, and lymphovascular invasion were significantly associated with CSS. Similarly, NAC, pure urothelial carcinoma, tumor grade, lymphovascular invasion, and pathological lymph node involvement were significantly associated with OS. After adjustment for these confounding variables, RT to recurrence sites was not significantly associated with prolonged CSS and OS (Table). Conclusions: RT to recurrence sites might have no effects on oncological outcomes in patients who experienced local recurrence and/or pelvic lymph node metastases after RC. Multivariable analyses for CSS and OS. CSS Factor P value HR 95% CI NAC Received 0.080 0.649 0.400–1.053 Pure urothelial carcinoma Positive 0.059 0.577 0.326–1.022 Tumor grade Grade 3 0.644 1.167 0.606–2.247 LVI Positive 0.003 2.407 1.353–4.283 Radiation therapy Positive 0.244 0.735 0.438–1.234 OS Factor P value HR 95% CI NAC Received 0.030 0.552 0.323–0.944 Pure urothelial carcinoma Positive 0.113 0.574 0.289–1.141 Tumor grade Grade 3 0.694 0.868 0.428–1.759 LVI Positive 0.005 2.438 1.305–4.556 Pathological N stage ≥ pN1 0.328 1.372 0.728–2.584 Radiation therapy Positive 0.161 0.652 0.359–1.186
Treatment (Rx) patterns and attrition rates in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
75 Background: The Rx landscape of pts with mCRPC has recently evolved with the approval of lutetium-177-PSMA-617 (Lu-177) and poly(ADP) ribose polymerase inhibitors (PARPi) either as single agents or as combinations with an androgen receptor pathway inhibitor (ARPI) [PMID: 37442702]. However, real-world data on the uptake of these agents are lacking. Herein, we sought to assess the Rx patterns and attrition rates of pts with mCRPC in the era of newly approved therapies. Methods: The de-identified nationwide Flatiron Health Electronic-Health Record (EHR)-derived database was used to extract pt-level data. Eligibility criteria: diagnosis of mCRPC and Rx line (L) information. The data cut-off date was 5/31/2024. Rx patterns in each line of therapies were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Of the overall cohort of 24,105 pts with metastatic prostate cancer, 12,333 pts diagnosed with mCRPC between 1/1/2013 and 5/9/2024 met the eligibility criteria and were included. Rx trends are summarized (Table). Of pts receiving 1L Rx, 61% of pts received 2L therapy, and 35% received 3L therapy. Androgen receptor pathway inhibitor (ARPI) was the most common Rx in the 1L setting (73.7%), followed by taxane (10%) and sipuleucel-T (3.8%). In 2L, ARPI was again the most frequent Rx (46.8%), followed by taxane (23.6%). In 3L, taxane became the most frequent Rx (35.4%), followed by ARPI (26.2%) and radium-223 (4.9%). Rx trends per year will be presented in the meeting. Conclusions: In the current era,a high proportion of pts with mCRPC receiving 1L Rx do not receive a subsequent line of Rx (39% of pts do not receive 2L, and 65% do not receive 3L Rx). ARPIs and taxanes remain the most frequently used Rx options in most L of therapy. These findings highlight the need for better tolerated Rx, therapies with a novel mechanism of action, and improved access to care for our pts. Rx trends per year will be presented in the meeting. Rx patterns in pts with mCRPC. Rx 1L, n (%)N = 12,333 2L, n (%)N = 7475 3L, n (%)N = 4316 4L, n (%)N = 2339 5L, n (%)N = 1225 ARPI 9085 (73.7) 3503 (46.8) 1130 (26.2) 356 (15.2) 157 (12.8) PARPi-based therapies 93 (0.8) 185 (2.5) 142 (3.3) 98 (4.2) 47 (3.9) Platinum-based therapy 127 (1) 216 (2.9) 198 (4.6) 148 (6.3) 130 (10.6) Lu-177-based therapies 50 (0.4) 109 (1.5) 169 (3.9) 143 (6.3) 103 (8.4) Radium-223 183 (1.5) 241 (3.2) 213 (4.9) 125 (5.3) 79 (6.4) Sipuleucel-T 474 (3.8) 94 (1.3) 53 (1.2) 18 (0.8) 8 (0.7) Taxane 1240 (10) 1763 (23.6) 1526 (35.4) 935 (40) 393 (32) Pembrolizumab 24 (0.2) 41 (0.5) 36 (0.8) 27 (1.2) 29 (2.4) Other*/not-applicable** 665 (5.4)/392 (3.2) 1000 (13.4)/323 (4.3) 602 (14)/247 (5.7) 320 (13.7)/169 (7.2) 162 (13.3)/117 (9.5) *Includes drugs approved for mCRPC in combination with unapproved agents or clinical trial drugs. **Includes agents not approved for prostate cancer.
Evaluation of ctDNA alterations in lethal mCRPC.
245 Background: Circulating tumor DNA (ctDNA) can be used as a prognostic biomarker in mCRPC patients, with changes in ctDNA providing insight into patient survival. In this study, we evaluate the ctDNA landscape of patients with mCRPC prior to their death. Methods: A retrospective clinical data review, 2015-2024, was conducted at Tulane Cancer Center to identify mCRPC patients who underwent ctDNA testing prior to death. All ctDNA data were obtained through a multi-gene cancer panel via the Guardant 360 assay (70-83 genes). Lethal mCRPC was defined as patients who underwent ctDNA testing ≤3 months prior to death. A matched control group (CTRL) was defined as mCRPC patients with ctDNA collection ≥2 years prior to death or most recent follow-up. Statistical analyses were performed using Pearson Chi-Square Test or Fisher Exact Test whenever appropriate. Furthermore, survival analysis was conducted using the Kaplan-Meier method. Results: There were 70 patients in lethal mCRPC group and 157 patients in CTRL group. Compared to the CTRL group, in lethal mCRPC, somatic mutations and/or amplifications in BRAF(OR=2.1549, 95% C.I. [1.1136,4.1523], p=0.0298), CCND2 (OR=3.7925, 95% C.I.[1.1937,13.3380], p=0.03326), MYC (OR=2.6332, 95%C.I. [1.4158, 4.9120], p=0.0029), PDGFRA (OR=2.5235, 95% C.I. [1.1438, 5.5793], p=0.0291), and PIK3CA (OR=2.0328, 95% C.I. [1.1098, 3.7166], p=0.02846) were significantly more frequent. Additionally, lethal mCRPC patients were more likely to have missense (OR=4.3194, 95% C.I. [1.443456,19.3338], p=0.01687) and nonsense (OR=1.9364, 95% C.I. [1.06091,3.5250], p=0.04112) mutations at the end-of-life. Patients with a higher allelic fraction (≥0.6%) of TP53 alterations had a shorter median survival (p-value= 0.034). Conclusions: ctDNA mutations and/or amplifications in BRAF, CCND2, MYC, PDGFRA, and PIK3CA were more frequently detected in lethal mCRPC compared to matched CTRLs. Additionally, mCRPC patients with a lethal phenotype were more likely to have missense and nonsense mutations compared to the CTRL group. CtDNA assessment of copy number alterations was limited to amplifications only; additionally, with this assay, distinguishing between gene level and large scale chromosomal amplification is not assessable. Though this study is limited to a single-institution with retrospective analyses of clinical testing, understanding the somatic landscape of lethal mCRPC is critical for development of new biomarkers, strategies and ultimately druggable targets.
<sup>68</sup> Ga-FAPI-46 PET/CT for cancer imaging: Results of a single-center, prospective, interventional, single-arm clinical trial.
457 Background: Fibroblast activation protein (FAP) is highly expressed on tumor-associated fibroblasts. FAP-directed radioligand positron emission tomography ( 68 Ga-FAPI-46 PET) is a novel tool for cancer imaging. However, its diagnostic performance, especially in genitourinary (GU) cancers, is still unclear. Here, we aim to compare diagnostic performance of 68 Ga-FAPI-46 and 18 F-FDG PET, validated by histopathology. Methods: Patients (pts) at initial staging/restaging with (a) proven or suspected malignancy, (b) any tumor diameter > 1 cm, (c) planned or performed biopsy/surgery within 8 weeks prior to or after 68 Ga-FAPI-46 PET, and (d) no prior external beam radiation or systemic tumor therapy within 1 month underwent 68 Ga-FAPI-46 and clinical 18 F-FDG PET on subsequent days. For comparison, patient-based and region-based (local, nodal, distant organ or soft tissue, bone) image analysis was performed by three blinded nuclear medicine physicians, separate for each PET modality. Positive predictive value (PPV) and sensitivity (SE) were evaluated based on histopathologic results, and compared in the subgroups of GU cancers, sarcoma, and others. Inter-reader reproducibility was assessed using Fleiss‘ kappa. Results: A total of n=158 pts (median age: 62 years, male/female: n=101 (63.9%)/57 (36.1%)) were enrolled. 155 (98.1%)/152 (96.2%) pts underwent 68 Ga-FAPI-46/ 18 F-FDG PET/CT. Histopathologic validation was available in n=145 (91.8%) pts. N=54 (34.2%)/28 (17.7%)/76 (48.1%) pts were diagnosed with GU cancers/sarcoma/others. Patient-based PPV/SE for 68 Ga-FAPI-46 ( 18 F-FDG) PET were 94/72% (97/71%) for GU cancers, 100/96% (100/96%) for sarcoma, and 100/91% (100/88%) for others. Region-based PPV/SE for 68 Ga-FAPI-46 ( 18 F-FDG) PET were 93/71% (97/70%) for GU cancers, 100/94% (97/90%) for sarcoma, and 99/90% (93/85%) for others. Patient-based inter-reader reproducibility for 68 Ga-FAPI-46 ( 18 F-FDG) PET was 0.71 (0.43) for GU cancers, 1.0 (0.21) for sarcoma, and 0.6 (0.53) for others. Conclusions: 68 Ga-FAPI-46 and 18 F-FDG PET demonstrate similar accuracy for tumor detection and localization of GU cancers. However, inter-reader reproducibility was superior for 68 Ga-FAPI-46 (substantial agreement) compared to 18 F-FDG PET (moderate agreement). Clinical trial information: NCT05160051 . Patient characteristics. All patients n=158 All regions n=186 Diagnosis n (pts) % (pts) n (regions) % (regions) Genitourinary CancersRenal cell carcinomaUrothelial carcinomaProstate cancerSeminomaOthers 54 3314322 34.2 20.98.91.91.31.3 63 3816414 33.9 20.48.62.20.52.2 Sarcoma 28 17.7 32 17.2 Others* 76 48.1 91 48.9 *Including breast cancer, cholangiocarcinoma, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, lymphoma, multiple myeloma, neuroendocrine, NSCLC, pancreatic cancer, thyroid cancer, unknown primary, others.
Feasibility of enriched amplicon circulating tumor DNA sequencing to detect minimal residual disease (MRD) after prostatectomy in localized prostate cancer.
402 Background: Nearly one third of men with prostate cancer experience relapse after radical prostatectomy, often despite achieving undetectable PSA nadir. An assay to detect minimal residual disease would be valuable to identify patients who could benefit from adjuvant therapy. Methods: Eligible patients had biopsy proven prostate cancer and planned to undergo prostatectomy for definitive therapy. Blood was drawn at pre-specified timepoints (TP) including prior to prostatectomy (TP1), on the day after surgery or at the 1-week post-op catheter removal visit (TP2), and at 1-month post-op with no interval treatment (TP3). We performed tumor-guided plasma DNA analysis using a novel method based on single-stranded adapter ligation, incorporation of unique molecular identifiers (UMIs), targeted PCR, normalization of amplicons using hybrid-capture, and targeted sequencing. Using tumor and germline exome sequencing, we designed and validated multiplexed assays to target somatic founder mutations. We prepared targeted sequencing libraries using a median of 6.7 ng input plasma DNA. Results: 11 patients were enrolled after IRB approval. 1 (9.09%) had grade group 2, 1 (9.09%) grade group 3, 5 (45.45%) grade group 4, 4 (36.36%) grade group 5 disease. Median PSA pre-op was 9.3 ng/mL (range: 1.7 – 21.47). Tumor DNA sequencing was successful and targeted assays were generated for all patients (11/11). Median number of targets tested was 20 (range 4 to 88). We analyzed 31 plasma DNA samples obtained from 11 patients. Median on-target rate in plasma DNA was 90.5% (range 76.0% to 96.3%). Prior to surgery (TP1), 5/11 (45%) patients had detectable ctDNA at a median tumor fraction of 0.077% (range: 0.006% to 3.4%). At post-op TP (TP2), the ctDNA was detectable in 7/11 patients (64%) at a median tumor fraction of 0.024% (range: 0.004% to 3.1%). Detectable ctDNA was observed at 1 month (TP3) in 5/8 patients (62.5%) at a median tumor fraction of 0.022% (range 0.010% to 0.037%). For an exploratory analysis, we examined whether persistent ctDNA detection at the 1 month TP3 was associated with later relapse. Of the 5 patients with PSA relapse, 3 (60%) of patients had detectable residual ctDNA at TP3 with median follow up time of 61.75 months. Conclusions: Localized prostate cancer has been noted to have low tumor shed, limiting meaningful ctDNA detection rates with prior assays (Hennigan 2019). Our results show promising feasibility of a novel tumor-informed ctDNA assay in this setting. In addition, there was preliminary evidence of residual ctDNA detection predicting relapse.