Showing papers by "Cora N. Sternberg published in 2023"
TL;DR: The results of the phase 3 JAVELIN Bladder 100 trial (NCT02603432) showed significantly longer OS and progression-free survival (PFS) from start of maintenance (randomization) with avelumab maintenance + best supportive care (BSC) vs BSC alone (median OS, 23.8 vs 15.0 months) as mentioned in this paper .
Abstract: 508 Background: For platinum-eligible patients (pts) with advanced UC, 1L cisplatin- or carboplatin-based chemotherapy regimens followed by avelumab maintenance in pts without progression has become the standard of care. This is based on the results of the phase 3 JAVELIN Bladder 100 trial (NCT02603432), which showed significantly longer OS and progression-free survival (PFS) from start of maintenance (randomization) with avelumab maintenance + best supportive care (BSC) vs BSC alone (median OS, 23.8 vs 15.0 months; HR, 0.76 [95% CI, 0.63-0.91]; p=0.0036). We report post hoc analyses of long-term outcomes by 1L chemotherapy regimen and OS from start of 1L chemotherapy. Methods: Pts with unresectable locally advanced or metastatic UC that did not progress with 4-6 cycles of 1L cisplatin + gemcitabine or carboplatin + gemcitabine were randomized 1:1 to receive avelumab + BSC (n=350) or BSC alone (n=350). The primary endpoint was OS measured from randomization. Secondary endpoints included PFS and safety. Results: At data cutoff (June 4, 2021), median follow-up from randomization was ≥38 months in both arms. In subgroups treated with 1L cisplatin + gemcitabine or carboplatin + gemcitabine, OS and PFS (measured from start of maintenance [randomization]) were longer in the avelumab + BSC arm than in the BSC alone arm (Table). Safety findings were similar in both subgroups. In the overall population, median OS measured from the start of 1L chemotherapy was 29.7 months (95% CI, 25.2-34.0) in the avelumab + BSC arm and 20.5 months (95% CI, 19.0-23.5) in the BSC alone arm (HR, 0.77 [95% CI, 0.635-0.921]). Conclusions: Long-term follow-up from the JAVELIN Bladder 100 trial confirms that avelumab 1L maintenance provides similar OS and PFS benefits in pts with advanced UC who are progression free following standard-of-care 1L cisplatin- or carboplatin-based chemotherapy, with an acceptable safety profile. The median OS measured from start of chemotherapy further supports the use of avelumab 1L maintenance as standard of care in this setting and provides a benchmark for future clinical trials. Clinical trial information: NCT02603432 . [Table: see text]
5 citations
TL;DR: In this paper , the effect of DARO on overall survival (OS) was consistent across prespecified subgroups, including de novo and recurrent disease, with similar overall incidences of treatment-emergent adverse events (TEAEs) between groups.
Abstract: 15 Background: In ARASENS (NCT02799602), DARO plus ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI: 0.57–0.80; P<0.0001) vs placebo (PBO) + ADT + DOC in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC), with similar overall incidences of treatment-emergent adverse events (TEAEs) between groups. The effect of DARO on overall survival (OS) was consistent across prespecified subgroups, including de novo and recurrent disease. For pts with mHSPC, outcomes based on disease volume and risk provide additional information to clinicians. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, with ADT + DOC. High-volume disease was defined as visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis (CHAARTED criteria). High-risk disease was defined as ≥2 risk factors: Gleason score ≥8, ≥3 bone lesions, and presence of measurable visceral metastasis (LATITUDE criteria). OS for these subgroups was assessed using an unstratified Cox regression model. Results: Of 1305 pts in the full analysis set, 1005 (77%) had high-volume disease, 912 (70%) had high-risk disease, 300 (23%) had low-volume disease, and 393 (30%) had low-risk disease. DARO + ADT + DOC prolonged OS regardless of high- or low-volume disease with HRs of 0.69 and 0.68 vs PBO + DOC + ADT, respectively. OS benefit of DARO vs PBO was also similar for pts with high- or low-risk disease. DARO improved clinically relevant secondary endpoints vs PBO in high/low-volume and risk subgroups, with HRs generally in the range of those observed in the overall population. Incidences of TEAEs were consistent with the overall ARASENS population across subgroups by high/low volume and high/low risk. Conclusions: In pts with mHSPC, the benefits of early treatment intensification with DARO + ADT + DOC on OS and key pt-relevant secondary efficacy endpoints vs PBO + ADT + DOC were similar in patients with high- and low-volume as well as high- and low-risk mH+SPC. The favorable safety profile of DARO was reconfirmed in high/low-volume and high/low-risk populations. DARO + ADT + DOC sets a new standard of care for pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]
4 citations
TL;DR: In the ARASENS trial, patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel as mentioned in this paper .
Abstract: PURPOSE For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk. METHODS Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases. RESULTS Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel. CONCLUSION In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population.
3 citations
TL;DR: Tagawa et al. as discussed by the authors reported the results of the phase 2 TROPHY-U-01 Cohort 2 study and showed that SG monotherapy demonstrated a high response rate with an overall manageable safety profile in PT-ineligible pts with locally advanced or mUC who progressed after CPI therapy.
Abstract: 520 Background: Pts with PT-ineligible mUC have limited treatment options following CPI therapies; thus, new treatment options are needed. SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, a topoisomerase-I inhibitor, via a proprietary hydrolyzable linker. SG received accelerated FDA approval in April 2021 for pts with mUC who progressed after PT and CPI therapies based on the positive results of the pivotal TROPHY-U-01 Cohort 1 study. In Cohort 1, SG demonstrated an objective response rate (ORR) of 27%, a median overall survival (OS) of 10.9 mo, and a manageable safety profile in 113 pts with locally advanced or mUC (Tagawa, et al. J Clin Oncol. 2021). SG demonstrated an ORR of 28% in PT-ineligible pts with mUC who progressed after CPI therapy in preliminary results of the phase 2 TROPHY-U-01 Cohort 2 study (Petrylak et al. J Clin Oncol. 2020). Here, we report the primary analysis of TROPHY-U-01 Cohort 2. Methods: Cohort 2 pts (≥18 y) were PT-ineligible at screening, had ECOG PS 0-1, and creatinine clearance ≥30 mL/min. Pts received 10 mg/kg of SG on D1 and D8 of 21-day continuous cycles. The primary endpoint was ORR per central review by RECIST 1.1. Secondary endpoints included duration of response (DOR) and progression-free survival (PFS), per central review, and OS. Target enrollment was approximately 40 pts. Assuming the second-line ORR of 40%, 40 pts would give a 95% CI with a lower limit of 25% (CI is 0.25 to 0.57) for ORR. Results: As of July 26, 2022, the median follow-up was 9.3 mo (range, 0.5-30.6) for treated pts (N=38); median age, 72.5 y (range, 41-87), 61% male, 50% ECOG PS 1, and 66% visceral metastases (29% liver). Median number of prior therapies was 2 (range, 1-5); 50% received prior (neo)adjuvant PT, 18% received prior enfortumab vedotin, and 3% received prior erdafitinib. Median time since last prior anticancer therapy was 1.6 mo (range, 1-8) and median duration of last prior anticancer therapy was 4.2 mo (range, 1-12). Per central review, ORR was 32% (95% CI, 17.5-48.7; 32% partial response); median DOR was 5.6 mo (95% CI, 2.8-13.3; n=12); and median PFS was 5.6 mo (95% CI, 4.1-8.3). Median time to response was 1.4 mo (range, 1.3-1.5) and median OS was 13.5 mo (95% CI, 7.6-15.6). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 68% of pts; the most common Grade ≥3 TRAEs were neutropenia (34%), anemia (21%), leukopenia (18%), fatigue (18%), and diarrhea (16%). TRAEs resulted in an 18% discontinuation rate. No treatment-related deaths were reported. Conclusions: SG monotherapy demonstrated a high response rate with an overall manageable safety profile in PT-ineligible pts with mUC who progressed after CPI therapy. No new safety signals were observed. These data support further evaluation of SG in pts with mUC post CPI therapy. Clinical trial information: NCT03547973 .
2 citations
TL;DR: Grivas et al. as discussed by the authors showed that SG plus Pembro demonstrated a high ORR with a manageable safety profile in 2L mUC in CPI-naive pts who progressed after PT-based therapy.
Abstract: 518 Background: Pembro is standard of care for pts with mUC who progress after 1L PT therapy but only ~21% of pts respond, highlighting an unmet need (Bellmunt, et al. NEJM. 2017). SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker. In Cohort 1 of the TROPHY-U-01 study, SG demonstrated a 27% objective response rate (ORR) with manageable safety in 113 pts with locally advanced or mUC who previously received PT and a checkpoint inhibitor (CPI; Tagawa, et al. J Clin Oncol. 2021), leading to accelerated FDA approval in this pt population. Preliminary results of the phase 2 TROPHY-U-01 Cohort 3 study showed that SG plus Pembro demonstrated a high ORR (34%) as a 2L therapy in 41 CPI-naive pts with mUC who progressed after PT (Grivas et al. J Clin Oncol. 2021). Here we present the primary analysis of Cohort 3. Methods: Cohort 3 pts (≥18 y) had progression of mUC following PT in the metastatic setting or following ≤12 mo of PT in the (neo)adjuvant setting and ECOG PS 0-1. Pts received 10 mg/kg of SG on D1 and D8 and 200 mg of Pembro on D1 of a 21-D cycle for ≤2 y. The primary endpoint was ORR [complete response (CR) + partial response (PR)] per central review by RECIST 1.1. Secondary endpoints include clinical benefit rate [CBR; CR + PR + stable disease for at least 6 mo], duration of response (DOR) and progression-free survival (PFS) per central review; and safety. Target enrollment was approximately 41 pts based on a Simon two-stage design for 90% power at one-sided α of 0.05 to demonstrate 21% improvement in ORR, with a null hypothesis of historical ORR ≤20% and an alternate hypothesis of ORR ≥41%. Results: As of July 26, 2022, median follow-up was 12.5 mo (range, 0.9-24.6) for treated pts (N=41); median age, 67 y (range, 46-86), 83% male, 61% ECOG PS 1, 76% ≥1 Bellmunt risk factors, and 78% visceral metastases (29% liver). Median duration of last prior anti-cancer therapy was 2.7 mo (range, 0-13). Per central review, ORR was 41% (95% CI, 26.3-57.9; 20% CR); CBR was 46% (95% CI, 30.7-62.6); median DOR was 11.1 mo (95% CI, 4.8-NE [not estimable]; n=17); and median PFS was 5.3 mo (95% CI, 3.4-10.2). Median time to response was 1.4 mo (95% CI, 1.3-2.7) and median OS was 12.7 mo (95% CI, 10.7-NE). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 61% of pts; most common Grade ≥3 TRAEs were neutropenia (37%; 10% febrile neutropenia), leukopenia (20%), and diarrhea (20%). TRAEs led to a 15% discontinuation rate. Systemic steroid and G-CSF use were both 34%. No treatment-related death occurred. Conclusions: SG plus Pembro demonstrated a high ORR and CBR with a manageable safety profile in 2L mUC in CPI-naive pts who progressed after PT-based therapy. No new safety signals were observed with the combination. These data support further evaluation of SG plus CPI in mUC. Clinical trial information: NCT03547973 .
2 citations
TL;DR: Avelumab 1L maintenance treatment is now a standard of care for urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy as discussed by the authors .
Abstract: Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 [95% CI, 0.63 to 0.91]; 2-sided P = .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.
1 citations
TL;DR: Pazopanib as mentioned in this paper is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptors, and c-Kit targeting renal cell carcinoma.
Abstract: PURPOSE
Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC).
PATIENTS AND METHODS
Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed.
RESULTS
Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo.
CONCLUSION
Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
1 citations
TL;DR: In this article , the authors presented phase I dose-escalation results of a phase I/II trial investigating a combination of dual-PSMA targeting with mAb + SML and alpha + beta is feasible with follow up ongoing.
Abstract: 5018 Background: PSMA may be targeted by antibodies (mAb) or small molecules (SML), with different kinetics and biodistribution. mAb with longer circulation time and marrow exposure, but decreased access to luminal PSMA expression (e.g. salivary glands, intestine, kidney). SML diffuse to all sites of PSMA expression and then excreted. Alpha radionuclides emit more energy over shorter range vs beta. Pre-clinical data combining mAb and SML supports synergy, with enhanced uptake and retention of SML. Here, we present phase I dose-escalation results of a phase I/II trial investigating combo 225Ac-J591 with 177Lu-PSMA-I&T (aka PNT2002). Methods: Eligibility criteria include progressive mCRPC, ≥1 prior AR pathway inhibitor (ARPI), prior chemo (or unfit/refuse), ≥1 lesion with SUVmax >liver. Doses: 177Lu-PSMA-I&T (6.8 GBq); 225Ac-J591 (30, 35, or 40 KBq/kg), up to 2 doses of combo TRT 8 weeks (wks) apart with 177Lu SPECT following each dose. Primary objectives: dose-limiting toxicity (DLT) and recommended phase II dose; phase II will test the proportion of patients (pts) obtaining >50% PSA decline (PSA50). DLT defined as G4 myelosuppression lasting >1 wk, Gr>2 non-hematologic adverse event (AE), any Gr attributed AE delaying therapy >3 wks. Additional endpoints include progression-free and overall survival, radiographic response rate, safety, circulating tumor cell (CTC) changes, pt reported outcomes, PSMA imaging, blood/tissue correlatives. Results: 18 pts treated (6 at each dose level); 3 did not receive the 2nd dose due to progressive disease or withdrawal. Median age 70 (range 54-86), PSA 54.4 (2.43-9614). 13 (72%) with bone, 9 (50%) lymph node, 2 (11%) liver, 2 (11%) lung mets. 10 (56%) pts CALGB risk category high, 7 (39%) intermediate, 1 low. Previous therapies: 11 (61%) with >1 ARPI, 12 (67%) chemo, 5 (28%) sip-T, 3 (17%) radium-223. 2 of 6 pts with DLT at 40 KBq/Kg (Gr 2 or 3 thrombocytopenia delaying cycle 2 by >3 wk); no DLT observed in other cohorts. As submission, 7 pts (39%) remain on study, including 1 without progression at 16 months and another with undetectable PSA at 10 months. With follow up ongoing, 17 (94%) with PSA decline, 9 (50%) with PSA50. Of those with paired CTC counts, 4 of 5 (80%) converted from unfavorable to favorable CTC count, 4 of 8 (50%) from detectable to undetectable, 1 of 2 (50%) remained undetectable. AEs include 3 (17%) neutropenia (all Gr <2), 12 (67%) thrombocytopenia (3 Gr 3), 10 (56%) anemia (3 Gr 3), 10 (56%) pain flare (1 Gr3 in pt with cord compression), 12 (67%) xerostomia (one Gr2), 11 (61%) nausea (all Gr 1), 9 (50%) fatigue (all Gr 1). Conclusions: The combination of dual-PSMA targeting with mAb + SML and alpha + beta is feasible with follow up ongoing. Efficacy will formally be tested in the upcoming phase II portion of the study with 225Ac-J591 at 35 KBq/Kg and 177Lu-PSMA I&T at 6.8 GBq. Clinical trial information: NCT04886986 .
1 citations
TL;DR: The results of the voting provided a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making as discussed by the authors , which can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting.
Abstract: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence.To present the voting results of the APCCC 2022.The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions.The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions.The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer.These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials.The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer.Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer.At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here.
1 citations
TL;DR: In this article , the authors developed and internally validated a prognostic model for patients with urothelial cancer (aUC) receiving postplatinum immunotherapy, which represents an improvement over the Bellmunt algorithm and could aid selection of patients with aUC for second-line immunotherapy.
Abstract: Background Bellmunt Risk Score, based on Eastern Cooperative Oncology Group (ECOG) performance status (PS), hemoglobin levels and presence of liver metastases, is the most established prognostic algorithm for patients with advanced urothelial cancer (aUC) progressing after platinum-based chemotherapy. Nevertheless, existing algorithms may not be sufficient following the introduction of immunotherapy. Our aim was to develop an improved prognostic model in patients receiving second-line atezolizumab for aUC. Methods Patients with aUC progressing after cisplatin/carboplatin-based chemotherapy and enrolled in the prospective, single-arm, phase IIIb SAUL study were included in this analysis. Patients were treated with 3-weekly atezolizumab 1200 mg intravenously. The development and internal validation of a prognostic model for overall survival (OS) was performed using Cox regression analyses, bootstrapping methods and calibration. Results In 936 patients, ECOG PS, alkaline phosphatase, hemoglobin, neutrophil-to-lymphocyte ratio, liver metastases, bone metastases and time from last chemotherapy were identified as independent prognostic factors. In a 4-tier model, median OS for patients with 0–1, 2, 3–4 and 5–7 risk factors was 18.6, 10.4, 4.8 and 2.1 months, respectively. Compared with Bellmunt Risk Score, this model provided enhanced prognostic separation, with a c-index of 0.725 vs 0.685 and increment in c-statistic of 0.04 (p<0.001). Inclusion of PD-L1 expression did not improve the model. Conclusions We developed and internally validated a prognostic model for patients with aUC receiving postplatinum immunotherapy. This model represents an improvement over the Bellmunt algorithm and could aid selection of patients with aUC for second-line immunotherapy. Trial registration number NCT02928406.
1 citations
TL;DR: In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression free following 1L platinum-based chemotherapy, leading to regulatory approval in various countries as mentioned in this paper .
TL;DR: In this article , a chromosomal instability tolerance mechanism was proposed as a therapeutic vulnerability of therapy-refractory lethal prostate cancer (PCa) in metastatic therapy-resistant PCa cells.
Abstract: Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa.
TL;DR: In this paper , the authors performed a global, prospective, observational study of radium-223 in men with mCRPC, where the authors sought to understand longterm safety and treatment patterns in men who received radium223 in real-world clinical practice.
TL;DR: In this paper , a phase I dose-escalation study of 225Ac-J591 was conducted for prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) in mCRPC patients.
Abstract: TPS288 Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based targeting (e.g., J591) and potent alpha emitting payloads (e.g., 225Ac) impact drug kinetics, biodistribution, and resultant clinical toxicities. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg without achievement of maximal tolerated dose (MTD). One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of Gr 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had Gr > 3 heme toxicity or Gr > 2 non-heme toxicity. Although not intentionally preselected for prior exposure, 55% (12/22) of patients had 177Lu-PSMA previously. With approval of 177Lu vipivotide tetraxetan, we amended an ongoing phase I dose-escalation study to include a post-177-Lu-PSMA cohort. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function, and prior receipt of AR pathway inhibitor and chemotherapy (or refused/ineligible). There is no limit to prior lines of therapy except alpha-emitting therapies (i.e., PSMA-TRT, 223Ra) and in this amended dose-escalation cohort, all patients must have had prior treatment with 177Lu-PSMA. Treatment will be given in a single fractionated cycle of 225Ac-J591 administered on D1 and D15. The phase I component is a 3+3 dose-escalation study design with up to 18 patients, with the goal of identifying MTD. The phase II component will include up to 16-19 patients in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG3-modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment to the post-177Lu-PSMA cohort began in August 2022. Clinical trial information: NCT04506567 .
TL;DR: In this article , the authors presented preliminary phase I results of a phase I/II study, including an unexpected cytokine release syndrome (CRS), which was characterized by morbilliform rash, fever >101F, and low blood counts.
Abstract: 181 Background: Only a small fraction of patients with PC respond to immunotherapy; radiation increases responses. PSMA targeted radionuclide therapy (PSMA-TRT) radiates multiple sites of disease simultaneously. ARSI can lead to radiosensitization and upregulate PSMA and PD-L1 expression. We hypothesize that the addition of potent alpha-PSMA-TRT (225Ac-J591) will lead to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, thereby increasing the response proportion and duration to pembrolizumab plus ARSI. Here, we present preliminary phase I results of a phase I/II study, including an unexpected cytokine release syndrome (CRS). Methods: Eligibility: Progressive mCRPC by PCWG3 criteria (at least one ARSI, no chemotherapy in the mCRPC setting). Patients received ARSI of physician’s choice, pembrolizumab (400mg every 6 weeks), and single infusion of 225Ac-J591 at two different dose levels (65 or 80 KBq/kg). The primary endpoint for phase I is determination of 225Ac-J591 dose for phase II in a pick-the-winner design. Results: 12 patients were treated (6 at 65 KBq/kg, 6 at 80 KBq/kg). 7 (58%) received enzalutamide, 3 (25%) apalutamide, and 2 (17%) darolutamide. Median age 66.5, median PSA 7.75 ng/mL, 6 (50%) CALGB intermediate risk, 4 (33%) low risk, 11 (92%) with bone metastases, 3 (25%) with nodal metastases. 7 (58%) with prior abiraterone, 6 (50%) prior enzalutamide, 5 (42%) sip-T. All patients experienced PSA decline following therapy, 6 (50%) with >50% decline. With >6 months follow-up, 4 (33%; all at 80 KBq/kg) remain progression-free and on study. Of note, 7 (58%) developed an unexpected CRS 7-14 days following treatment characterized by morbilliform rash, fever >101F, and low blood counts. Inflammatory markers were elevated: IL-6 (2.1-7.7 pg/mL), D-Dimer (306-2378 ng/mL), ferritin (361.3-513.4 ng/mL), fibrinogen (386-461 mg/dL), ESR (16-42 mm/hr). After pausing the ARSI, this reaction improved within 1 week. Thrombocytopenia and/or neutropenia occurred during this syndrome, then typically improved before counts fell again at expected nadir 4 weeks after 225Ac-J591. Overall AEs on study include: 9 (75%) thrombocytopenia (3 with g≥3; 1 g4 with PC marrow infiltration), 7 (58%) neutropenia (none g≥3), 6 (50%) nausea, 7 (58%) g1-2 fatigue, 9 (75%) g1-2 xerostomia, 7 (58%) g1 AST. In contrast to heme AEs with unexpected initial occurrence during CRS followed by typical nadir from TRT, the described non-hematologic AEs were generally independent of CRS. 4 (33%) developed typical irAEs: 2 with rash (D60, D62) and 2 hypothyroidism (D77, D82). Conclusions: Combination therapy with alpha-PSMA-TRT, ARSI, and pembrolizumab demonstrates efficacy in the phase I run-in. A key safety signal that has emerged with triplet therapy is CRS that can be managed supportively. The randomized phase II component is accruing with additional safety visits and sample collection for cytokine analysis. Clinical trial information: NCT04946370 .
TL;DR: The TROPHY-U-01 Cohort 1 study as discussed by the authors showed that SG monotherapy demonstrated a 27% objective response rate (ORR) and med overall survival (OS) of 10.9 mo in 113 patients with locally advanced or mUC progressing after receiving at least a PT-based therapy and a CPI.
Abstract: 526 Background: SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, a topoisomerase-I inhibitor, via a proprietary hydrolyzable linker. SG received accelerated FDA approval in April 2021 in pts with mUC who previously received PT-based therapy and a CPI based on the primary analysis of the pivotal TROPHY-U-01 Cohort 1 study. With 9.1 mo median (med) follow-up, SG monotherapy demonstrated a 27% objective response rate (ORR) and med overall survival (OS) of 10.9 mo in 113 pts with locally advanced or mUC progressing after receiving at least a PT-based therapy and a CPI (Tagawa, et al. J Clin Oncol. 2021). Here we report updated Cohort 1 outcomes. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase 2 study. Cohort 1 pts (≥18 y) had progression of mUC following PT (as first-line metastatic therapy or as (neo)adjuvant therapy with recurrence/progression ≤12 mo) and CPI, had ECOG PS 0-1, and creatinine clearance ≥30 mL/min. Pts received 10 mg/kg of SG intravenously on D1 and D8 of 21-D cycles. The primary endpoint was ORR per central review by RECIST 1.1. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR), OS, and safety. Results: As of July 26, 2022, med follow-up was 10.5 mo (range, 0.3-40.9) for treated pts (N=113). As previously reported, pts (78% men; med age, 66 y; 66% with visceral metastases, 34% liver), were heavily pretreated with a med of 3 prior therapies (range, 1-8). Med time since last prior therapy was 1.5 mo (range, 0-60.0). At data cutoff, per central review, ORR was 28% (95% CI, 20.2-37.6); CBR was 38% (95% CI, 29.1-47.7), med DOR was 6.1 mo (95% CI, 4.7-9.7, n=32) and med PFS was 5.4 mo (95% CI, 3.5-6.9). Med time to response was 1.6 mo (range, 1.2-5.6) and med OS was 10.9 mo (95% CI, 8.9-13.8). DOR, PFS, and OS rates (95% CI) at 12 mo were 30% (13.6-48.8), 14% (7.2-23.3), and 45% (35.4-53.8), respectively, with 7 (6%) pts still receiving SG at 12 mo. In pts who received prior enfortumab vedotin (n=10) and prior PT in the (neo)adjuvant setting (n=39), results were consistent with the overall population. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 65% of pts and were similar to prior reports; the most common Grade ≥3 TRAEs were neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%). One treatment-related death occurred due to febrile neutropenia-related sepsis. Conclusions: At 10.5-mo med follow-up, the response rate remains high in pts with heavily pretreated mUC, including pts with visceral metastases, prior EV therapy and prior (neo)adjuvant PT therapy. No new safety signals were observed. These data support the use of SG in pts with mUC who received PT and a CPI and further evaluation of SG in earlier lines of therapy. Clinical trial information: NCT03547973 .
TL;DR: In this paper , the authors reported a significant reduction in the risk of death by 32.5% in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and significantly delayed the time to pain progression.
Abstract: e17075 Background: In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced risk of death by 32.5% (hazard ratio [HR] 0.68, 95% confidence interval [CI[ 0.57–0.80; P< 0.0001) and significantly delayed time to pain progression (HR 0.79, 95% CI 0.66–0.95; P= 0.006) vs placebo (PBO) + ADT + docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We report time to pain progression in patients (pts) with high/low disease volume (HV/LV). Methods: Pts with mHSPC were randomized to oral DARO 600 mg twice daily or PBO, both + ADT + docetaxel. Pain was assessed by the Brief Pain Inventory short form “pain at its worst” score (WPS). Pain progression was defined as WPS increase ≥2 points from nadir (and absolute WPS ≥4 if > 0 at baseline) or initiation of opioid therapy for ≥7 consecutive days. A sensitivity analysis assessed pain progression after completion of docetaxel. HV/LV subgroups were defined per CHAARTED. Results: 1305 pts (DARO 651, PBO 654) were analyzed. At baseline, the mean WPS was 1.5 (standard deviation 1.9) vs 1.4 (1.8) in the DARO vs PBO groups; 258 (40%) vs 274 (42%) pts had no pain (WPS 0). DARO + ADT + docetaxel had a robust impact on delaying time to pain progression vs PBO + ADT + docetaxel in the post-docetaxel sensitivity analysis (stratified HR 0.75, 95% CI 0.62–0.90) and in the HV subgroup (unstratified HR 0.75, 95% CI 0.61–0.93) (Table). Overall, median time to pain progression was longer in the LV vs HV subgroup. WPS change from nadir was the main driver of pain progression events. Conclusions: In pts with mHSPC, the addition of DARO to ADT and docetaxel provided clinically meaningful benefit through delayed time to pain progression, notably in pts with HV disease. Increased overall survival, a delay in time to pain progression, and a favorable safety profile set DARO + ADT + docetaxel as a new standard of care for pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]
TL;DR: In this paper , the authors report clinical outcomes in North American (NA) pts in ARASENS, and show that darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced the risk of death by 32.5% (HR 0.68, 95% CI 0.57-0.80; P<0.
TL;DR: In this article , the demographic data (namely race and ethnicity) on patients with prostate cancer (PC) enrolled on clinical trials at Weill Cornell Medicine (WCM) were retrospectively assessed to determine changing patterns of enrollment and to determine if their efforts have improved access to these novel treatments for this underrepresented, but high-risk population of patients.
Abstract: 36 Background: At Weill Cornell Medicine (WCM), we have had a research program utilizing anti-PSMA mAb J591 since the year 2000. With the addition of PSMA ligand-based therapies in 2017, we have enrolled around 300 patients on investigational PSMA-TRT clinical trials. Since the approval of 177Lu-PSMA-617 (Pluvicto; Lu-177 vipivotide tetraxetan), we began standard-of-care (SOC) treatment, co-enrolling willing patients into a research registry. Recognizing the low numbers of AA patients enrolled on therapeutic clinical trials in the U.S., we made a concerted effort to increase the number of AA patients with prostate cancer (PC) enrolled on clinical trials at WCM. We retrospectively assessed the demographic data of patients enrolled on PSMA-TRT clinical trials to determine changing patterns of enrollment, and to determine if our efforts have improved access to these novel treatments for this under-represented, but high-risk population of patients. Methods: We collected demographic data (namely race and ethnicity) on patients with PC from WCM who were included on our PSMA-TRT investigational clinical trial databases or enrolled on our SOC 177Lu-PSMA-617 research registry. We used self-reported race and, when not available (due to patient death or loss of follow-up), demographic information documented in the medical record. Patients were grouped into 5-year cohorts based on either the date of consent for trial enrollment, or the start date of PSMA-TRT treatment (based on available information). Institutional tumor registry data was used as a comparator to assess the total percentage of AA patients with PC seen at WCM. Results: The percentages of patients included on PSMA-TRT clinical trials at WCM who were identified as AA were as follows: 2000-2004: 3.1% (2/65), 2005-2009: 5.1% (3/59), 2010-2014: 6.1% (2/33), and 2015-2019: 5.9% (5/85). The percentage of AA patients on PSMA-TRT studies from 2020 through July 2022 was 18.2% (16/88, inclusive of 8/72 investigational TRT subjects and 8/16 SOC registry participants). The total percentages of AA patients seen at Cornell based upon analysis of our tumor registry data were as follows: 2000-2004: 10.5% (182/1728), 2005-2009: 6.9% (250/3607), 2010-2014: 10% (326/3255), 2015-2019: 11.5% (278/2413), and 2020: 14.1%. Tumor registry data for 2021-present were not yet available. Conclusions: The percentage of AA patients on investigational PSMA-TRT trials at our institution notably increased from 2000-2019 (3.1%-6.1%) to 2020-2022 (11.1%). Moreover, 50% of those treated with 177Lu-PSMA-617 since its FDA approval and co-enrolled on our research registry identified as AA. These data suggest that outreach and increasing access to AA patients for novel PC treatment such as PSMA-TRT can result in increased numbers of underrepresented patients enrolling on clinical trials and receiving the most modern standards of care (i.e., PSMA-TRT).
TL;DR: The SAUL study as mentioned in this paper reported the final analysis 4 y after enrolling the last pt. The primary endpoint was safety and secondary endpoints included overall survival (OS) and duration of response (DoR).
Abstract: 4569 Background: In the SAUL study (NCT02928406), clinical outcomes in a broad population were similar to findings from phase 3 trials of anti-PD-(L)1 in highly selected pts. We report the final analysis 4 y after enrolling the last pt. Methods: Eligible pts had locally advanced/metastatic urothelial or non-urothelial UTC that had progressed during or after 1–3 prior lines of therapy for advanced UTC (or within 12 months of [neo]adjuvant therapy). Unlike most phase 3 immunotherapy trials, pts with autoimmune disease (AID), ECOG PS 2, creatinine clearance (CrCl) ≥15–30 mL/min, and/or stable CNS metastases were eligible. Pts took atezo 1200 mg q3w until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included overall survival (OS) and duration of response (DoR). Results: Among 997 treated pts, 10% had ECOG PS 2, 5% had CrCl <30 mL/min, 4% had a history of AID, and 7% had 2–3 prior lines of therapy. At data cutoff (Dec 20, 2022; median follow-up 55 mo), 78% of pts had died. Median treatment duration was 2.8 mo (range 0–62 mo; mean 9.5 mo), 96 pts (10%) took atezo for >3 y, and 68 (7%) for >4 y. Grade ≥3 adverse events (AEs) occurred in 51%; AEs led to atezo discontinuation in 8%. We show outcomes overall and in key subgroups. OS was >4 y in 136 pts (14%); 132 responders had OS >2 y. Conclusions: After 55 mo median follow-up, median OS was 8.6 mo and 3-y OS was 21% in a real-world population including important understudied subgroups. Long-term safety data continue to support the tolerability of atezo in pts with complex comorbidities. AESIs were not increased in pts typically considered to be at increased risk of immune-related AEs. OS was similar to trials in highly selected pts. Ongoing analyses are characterizing pts with exceptional long-term outcomes. Clinical trial information: NCT02928406 . [Table: see text]
TL;DR: In this paper , the evolution of the genomic signatures caused by endogenous and external mutagenic stimuli and their interplay with complex structural variants was investigated for urothelial cancer, and it was shown that APOBEC3-induced mutations are clonal and early, whereas mutational bursts comprising hundreds of late subclonal mutations are induced by chemotherapy.
Abstract: Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity. In this study, we investigate the evolution of the genomic signatures caused by endogenous and external mutagenic stimuli and their interplay with complex structural variants. We superimposed mutational signatures and phylogenetic analyses of matched serial tumors from patients with urothelial cancer to define the evolutionary patterns of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas mutational bursts comprising hundreds of late subclonal mutations are induced by chemotherapy. Using a novel genome graph computational paradigm, we observed frequent circular high copy-number amplicons characteristic of extrachromosomal DNA (ecDNA) involving double-minutes, breakage-fusion-bridge, and tyfonas events. We characterized the distinct temporal patterns of APOBEC3 mutations and chemotherapy-induced mutations within ecDNA, gaining new insights into the timing of these events relative to ecDNA biogenesis. Finally, we discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA amplicons. These CCND1 ecDNA amplification events persisted and increased in complexity incorporating additional DNA segments potentially contributing selective fitness advantage to the evolution of treatment resistance. Our findings define fundamental mechanisms driving urothelial cancer evolution and have therapeutic implications for treating this disease.
TL;DR: In this article , a WFPBD and behavior intervention was proposed to promote weight loss and a reduction in adiposity in overweight/obese patients with PC on ADT and decrease biomarkers of metabo-inflammation.
Abstract: TPS5098 Background: Obesity promotes a chronic inflammatory state that is associated with PC progression. ADT can cause significant side effects including weight gain, accumulation of body fat, insulin resistance, and an increased risk of diabetes and cardiovascular disease. A WFPBD has been shown to promote weight loss, decrease chronic inflammation, and shift gut microbial profiles to a microbiome that promotes insulin sensitivity. We hypothesize that a WFPBD and behavior intervention will promote weight loss and a reduction in adiposity in overweight/obese patients with PC on ADT and will decrease biomarkers of metabo-inflammation; and that a WFPBD, which is enriched in fiber, will modulate the fecal microbiota and metabolites, and alter study participants’ serum metabolome. Correlative studies will offer insight into the impact of nutrition on metabolic pathways that are known to be affected by PC, ADT and/or excess body fat, including steroid metabolism, ketogenesis, and fatty acid metabolism. Methods: Key eligibility criteria include pts with PC with a BMI ≥ 27 receiving ADT with an LHRH/GnRH analogue for >24 weeks pre-study (+ androgen receptor pathway inhibitor for >3 mos) with anticipation of >26 more weeks of ADT. 60 patients randomized 1:1 between two cohorts. Cohort 1: pts receive 12 prepared meals (provided by Plantable) per weeks 1-4 and 6 meals weeks 5-8 plus Plantable coaching, nutritional counseling and education to assist in self-prepping plant-based meals (weeks 9-26); Cohort 2 (control): pts receive general nutritional counseling from a Registered Dietician weekly for 8 weeks, then monthly x 4. Collection of baseline and serial measurements (pre-intervention, weeks 4, 8 and 26) including weight, serum carotenoid levels (to monitor dietary compliance), dual energy x-ray absorptiometry (DXA) scans, MnSOD polymorphisms, and biomarkers of inflammation and metabolism. The primary comparison is weight loss at 4 weeks (with an 80% power to detect an effect size 0.74 standard deviations with a 2-sided significance level of 0.05 using a two-sample t-test). Secondary objectives will assess and compare changes in: a) biomarkers of metabolic disorders (Hemoglobin A1c, fasting insulin/glucose) and cardiovascular risk (LDL cholesterol, HDL cholesterol, triglycerides); b) pro-inflammatory markers (IL-6, hsCRP) and adipokines (leptin, adiponectin); c) fecal microbiota; and d) quality of life measurements. Exploratory objectives will assess the effects of a WFPBD on serum and fecal metabolomics and on clonal hematopoiesis. Trial is open at Weill Cornell Medicine (WCM), John Hopkins University and Columbia University. First pt enrolled at WCM September 2022. Funding support from the Prostate Cancer Foundation; PC Clinical Trials Consortium c22-301. Clinical trial information: NCT05471414 .
TL;DR: In this paper , the authors designed a Phase 2 study in men with hormone-naïve, metastatic PCa who harbored a germline HRD mut treated with rucaparib monotherapy (without ADT).
Abstract: 190 Background: Androgen deprivation therapy (ADT) is the backbone of treatment for patients (pts) with metastatic prostate cancer (PCa), but many pts find this difficult to tolerate. Treatment with non-castrating regimens may avoid or delay the toxicities of hormonal therapy. The activity of PARP inhibitors (PARPi) in pts with homologous recombination DNA-repair (HRD) mutations (muts) and metastatic castration-resistant PCa has been established. We hypothesized here that the benefit of ARPi can be maintained in the absence of ADT in a biomarker-selected (HRD mutated) population with PCa. We designed a Phase 2 study in men with hormone-naïve, metastatic PCa who harbored a germline HRD mut treated with rucaparib monotherapy (without ADT). Methods: This was a multi-center, single arm Phase 2 study (NCT03413995) in men with asymptomatic hormone-sensitive metastatic PCa who received rucaparib 600mg by mouth daily. During consenting, pts were informed and had to opt out of ADT-based therapy. Pts must have had a germline mutation in an HRD gene on clinical-grade testing. The primary endpoint was confirmed PSA50 response rate. Key secondary endpoints included safety, objective response rate (ORR), and radiographic progression-free survival (rPFS). The trial was designed to detect a 25% absolute increase in PSA50 response from a null of 50%. Results: 12 pts were enrolled, 7 with BRCA1/2 and 5 with CHEK2 muts. The confirmed PSA50 response rate to rucaparib was 41.7% (N=5/12, 95% CI: 19.3-68.1%), which did not meet the pre-specified efficacy boundary to enroll additional patients to 2nd stage. In pts with measurable disease, the ORR was 60% (N=3/5, all with BRCA2). Median rPFS on rucaparib was 10.3 months (95% CI: 4.0 mo - NR). At the time of the interim analysis, 3 pts remained on study. The majority of adverse events (AE) were Grade ≤2 and expected. Translational studies are ongoing. Conclusions: Rucaparib can induce clinical responses in a biomarker-selected PCa population without concurrent ADT. However, the pre-specified threshold of PSA50 response was not met. Although durable responses were observed in a subset of pts, PARPi without ADT in metastatic hormone sensitive PCa will not be pursued. Clinical trial information: NCT03413995 . [Table: see text]
TL;DR: Bego~ na Valderrama, Seville, Spain; Thomas Powles, London, United Kingdom; Srikala Sridhar, Toronto, Canada; Claudia Caserta, Terni, Italy; Yohann Loriot, Villejuif, France; Shilpa Gupta*, Cleveland, OH; Joaquim Bellmunt, Boston, MA, Cora Sternberg, New York, NY; Jing Wang, Cambridge, MA; Nuno Costa, Porto Salvo, Portugal; Robert Laliberte, Cambridge- MA; Alessandra di Pietro, Milano, Italy, Se Hoon Park, Seoul, Korea, Republic of; Petros Grivas, Seattle, WA
TL;DR: In this article , the role of the LIPI score, a biological score based on 2 factors, derived neutrophils/(leukocytes minus neutrophILS) ratio and lactate dehydrogenase, in population with unresectable urothelial cancer treated with immune checkpoint inhibitor (ICI).
Abstract: Simple Summary In this report, we studied the role of the LIPI score, a biological score based on 2 factors, derived neutrophils/(leukocytes minus neutrophils) ratio and lactate dehydrogenase, in population with unresectable urothelial cancer treated with immune checkpoint inhibitor (ICI). This score was associated with clinical outcomes for ICI in several tumor types. In total, 137 and 541 patients were respectively enrolled in a retrospective ICI cohort and a validation cohort. LIPI classified the population of these cohorts in good (52–56%), intermediate (35–36%) and poor (9–12%) prognosis groups. Poor LIPI was associated with a poorer OS for the 2 cohorts. In patients with good prognosis according to the Bellmunt score, LIPI identifies a subset of patients with poorer outcomes. To conclude the LIPI score was associated with survival in unresectable urothelial cancer patients treated by ICI. Future prospective studies will be required to test the combination of Bellmunt score and LIPI score as a more accurate prognosis tool. Abstract Few prognostic factors have been identified in patients with metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibitors (ICIs). The Lung Immune Prognostic Index (LIPI) was associated with clinical outcomes for ICIs in several tumor types. We aim to assess the value of the LIPI in patients with mUC treated with ICIs. A retrospective ICI cohort and a validation cohort (SAUL cohort) included, respectively, patients with mUC treated with ICI in 8 European centers (any line) and patients treated with atezolizumab in a second or further line. A chemotherapy-only cohort was also analyzed. The LIPI score was based on 2 factors, derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) > 3 and lactate dehydrogenase > upper limit of normal, and defined 3 prognostic groups. The association of LIPI with progression-free survival (PFS) and overall survival (OS) was assessed. In the ICI and SAUL cohorts, 137 and 541 patients were respectively analyzed. In the ICI cohort, mPFS and mOS were 3.6 mo (95% CI; 2.6–6.0) and 13.8 mo (95% CI; 11.5–23.2) whereas in the SAUL cohort the mPFS and mOS were 2.2 mo (95% CI; 2.1–2.3) and 8.7 mo (95% CI; 7.8–9.9) respectively. The LIPI classified the population of these cohorts in good (56%; 52%), intermediate (35%; 36%) and poor (9%; 12%) prognostic groups (values for the ICI and SAUL cohorts respectively). Poor LIPI was associated with a poorer OS in both cohorts: hazard ratio (HR) for the ICI cohort = 2.69 (95% CI; 1.24–5.84, p = 0.035); HR = 2. 89 for the SAUL cohort (CI 95%: 1.93–4.32, p < 0.0001). Similar results were found in the chemo cohort. The LIPI score allows to identify different subgroups in patients with good prognostis according to the Bellmunt score criteria, with a subset of patients with poorer outcomes having an mOS of 3.7 mo compared to the good and intermediate LIPI subgroups with mOS of 17.9 and 7.4 mo, respectively. The LIPI score was associated with survival in mUC patients treated by ICIs. Future prospective studies will be required to test the combination of Bellmunt score and the LIPI score as a more accurate prognosis tool.
TL;DR: In this paper , a prognostic model for overall survival in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel was presented.
Abstract: PURPOSE We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model. METHODS Data from 8,083 docetaxel-naïve mCRPC men randomly assigned on seven phase III trials were used to validate the prognostic model of OS. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low and high) and three-risk prognostic groups (low, intermediate, and high). RESULTS The tAUC was 0.74 (95% CI, 0.73 to 0.75), and when adjusting for the first-line androgen receptor (AR) inhibitor trial status, the tAUC was 0.75 (95% CI, 0.74 to 0.76). Similar results were observed by the different racial, age, and treatment subgroups. In patients enrolled on first-line AR inhibitor trials, the median OS (months) in the low-, intermediate-, and high-prognostic risk groups were 43.3 (95% CI, 40.7 to 45.8), 27.7 (95% CI, 25.8 to 31.3), and 15.4 (95% CI, 14.0 to 17.9), respectively. Compared with the low-risk prognostic group, the hazard ratios for the high- and intermediate-risk groups were 4.3 (95% CI, 3.6 to 5.1; P < .0001) and 1.9 (95% CI, 1.7 to 2.1; P < .0001). CONCLUSION This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.
TL;DR: In this paper , the authors evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer.
TL;DR: In this article , Trop-2-directed antibody-drug conjugate with accelerated FDA approval for pts with LA unresectable or mUC who previously received platinum (PT) and a checkpoint inhibitor (CPI).
Abstract: 4579 Background: Patients (pts) with mUC have an estimated 5-year overall survival (OS) rate of 14%. Trop-2 is a transmembrane glycoprotein with elevated expression in many cancers, including UC. SG is a Trop-2–directed antibody-drug conjugate with accelerated FDA approval for pts with LA unresectable or mUC who previously received platinum (PT) and a checkpoint inhibitor (CPI). SG has demonstrated activity in 3 phase 2 TROPHY-U-01 mUC cohorts: Cohort 1 (C1), 28% objective response rate (ORR); Cohort 2 (C2), 32% ORR; and Cohort 3 (C3), 41% ORR. Here, we assess efficacy outcomes in C1-3 by Trop-2 archival tumor expression. Methods: Pts (≥18 years) with previously treated (PT [C3], CPI [C2], or both [C1]) LA or mUC received SG (10 mg/kg IV) on D1 and D8 of 21-D cycles; C3 pts also received pembrolizumab (200 mg) on D1 of 21-D cycles. The primary endpoint was ORR by independent review. Archival tumor samples collected at enrollment were assessed for Trop-2 protein expression using SP295 anti–Trop-2 antibody by IHC with assessment by histological scores (H-scores; scale, 0-300) and % of membrane-positive tumor cells (Roche Tissue Services). Trop-2 association with clinical endpoints was evaluated using unstratified Cox proportional hazards models for survival data and logistic regression for ORR. Results: At data cutoff, 192 pts were enrolled in C1-3; 144 pts (75%) had samples evaluable for Trop-2 prevalence and 139 pts (72%) were evaluable for efficacy analysis by Trop-2 expression (5 pts not assigned to any cohort were excluded). Baseline characteristics for pts with evaluable samples were consistent with the overall population. Median (IQR) Trop-2 H-score and % of membrane-positive tumor cells for evaluable pt samples were 215 (180-247) and 92% (75-98), respectively; these readouts were highly correlated (ρ=0.82, P<0.001). ORRs for C1 samples with below (n=42) and above (n=45) median Trop-2 H-scores were 24% and 29% ( P=0.59), respectively; median progression-free survival (PFS) was 3.4 and 6.7 months (HR=0.765, P=0.262), respectively; and median OS was 9.9 and 10.9 months (HR=0.978, P=0.927), respectively. Median PFS for C1 samples with below and above median Trop-2 membrane positivity were 3.9 and 6.2 months (HR=0.835, P=0.443), respectively. Analyses of efficacy endpoints for C2 and C3 pt samples by Trop-2 expression were consistent with C1 results. Conclusions: In this analysis of archival tumor samples from pts with pretreated LA or mUC, Trop-2 protein was highly expressed across cohorts, supporting prior Trop-2 expression analyses in UC. Similar outcomes were observed between C1 pts with samples that were below and above median Trop-2 H-score with most pronounced numerical differences observed for PFS. These results suggest that SG activity may be independent of Trop-2 expression in UC, but additional studies are needed to confirm these results. Clinical trial information: NCT03547973 .
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TL;DR: In this paper , Meta-analysis of the currently available clin- ical data sets is performed using a meta-analysis approach based on the current available data sets and meta-data sets.