Jason Harris

Findings presented at the 2022 AUA Annual Meeting showed that TROP-2 and Nectin-4, surface cell targets of sacituzumab govitecan (Trodelvy) and enfortumab vedotin (Padcev), respectively, are highly expressed in urothelial cancer (UC) and variant histology bladder cancer.

However, investigators found that those transmembranes are not highly expressed in patients with neuroendocrine histology. Investigators, including lead author Fady Ghali, MD, an acting instructor and Society of Urologic Oncology fellow at the University of Washington Department of Urology in Seattle, say they are launching clinical trials to assess the implications of these findings on treatment response for variant histology bladder cancer.

Nectin-4 localized primarily in the cytoplasm rather than the membrane in plasmacytoid UC and squamous cell carcinoma (SCC) in primary, lymph node, and metastatic sites. Investigators found that Nectin-4 distribution was relatively even between membrane and cytoplasm.

TROP-2 was expressed at equal levels in both membrane and cytoplasm for both plasmacytoid UC and SCC. Investigators added the high expression was conserved from primary to metastases.

In July 2021, the FDA approved enfortumab vedotin for adults with locally advanced or metastatic UC who are ineligible for cisplatin-containing chemotherapy and who have received 1 or more prior lines of therapy. The agent was previously indicated for patients with locally advanced or metastatic UC who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy.

The agency granted accelerated approval to sacituzumab govitecan for patients with locally advanced or metastatic UC who previously received a platinum-containing chemotherapy and either a PD-1 or a PD-L1 inhibitor in April 2021.

Fady et al noted that the role of these novel humanized monoclonal antibody-drug conjugates (ADCs) in the treatment of variant histology bladder cancer is unknown. They designed this study to better understand how these agents affect the disease at both primary and metastatic sites.

Investigators collected 68 metastatic bladder cancer tissue samples from 20 total patients. Twenty-seven samples were UC, 19 were SCC, 17 were plasmacytoid, and 5 were neuroendocrine. They then performed immunohistochemistry for Nectin-4 and TROP-2 on matched primary and metastatic tumors. Staining was scored by intensity (0-3) and multiplied by percent of positive cells resulting in a range of 0 to 300 H-score; H-score greater than or equal to 30% was considered positive for Nectin-4 and greater than or equal to 100 was considered positive for TROP-2. Investigators separately evaluated membranous and cytoplasmic staining for each sample.

Investigators collected 11 samples from primary tumor sites, 20 from the lymph nodes, and 37 from various metastatic sites. Seventeen (85%) patients previously received systemic chemotherapy and 35% had received immunotherapy. No patient had received enfortumab vedotin or sacituzumab govitecan.

For Nectin-4, investigators found that positive H scores were higher in cytoplasmic localization for primary tumors (60.0% vs 30.0%), lymph node tumors (80.0% vs 26.7%), and metastatic tumors (66.7% vs 23.8%) compared with membranous localization. When assessed by histology, positive H scores were higher in cytoplasmic localization vs membranous localization for UC (57.7% vs 30.8%), plasmacytoid UC (94.1% vs 5.9%), and SCC (78.9% vs 42.1%). Nectin-4 was not expressed in neuroendocrine tumors in either membranous (0%) or cytoplasmic (0%) localization.

For TROP-2, investigators found that positive H scores were 90.9% for both localizations for primary tumors and 90.2% in both localizations for metastatic tumors. However, positive H score was significantly higher for cytoplasmic lymph node tumors (93.8% vs 43.8%).

When assessed by histology, positive H scores favored cytoplasmic localization for UC (100% vs 96.2%) and plasmacytoid UC (100% vs 55.6%) but favored membranous localization in SCC (100% vs 89.5%). Again, the transmembrane was not highly expressed in neuroendocrine tumors at either the membranous (0%) or cytoplasmic localizations (20.0%).

Investigators added that it is not clear whether differences in membranous vs cytoplasmic localization affects response to treatment with ADCs.

Ghali, F, Roudier M, Vakar-Lopez F, et al. Antibody drug conjugates and variant histology muscle-invasive bladder cancer: are the targets present in primary and/or metastatic tumors? 

2022;207(suppl 5):e913. doi:10.1097/JU.0000000000002630.09

FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. News release. July 9, 2021. Accessed May 16, 2022. https://bit.ly/3lfWa5Y

FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. News release. April 13, 2021. Accessed May 16, 2022. https://bit.ly/38AQaSq

Articles

TROP-2 and Nectin-4, surface cell targets of sacituzumab govitecan and enfortumab vedotin, respectively, are highly expressed in variant histology bladder cancer.

Study provides clues on potential of antibody-drug conjugates in variant histology bladder cancer

Findings presented at the 2022 AACR Annual Meeting indicated that high genomic loss of heterozygosity (gLOH) may predict response to the PARP inhibitor talazoparib (Talzenna) in patients with metastatic castration-resistant prostate cancer (mCRPC).

In a post-hoc exploratory analysis of the phase 2 TALAPRO-1 trial (NCT03148795), 2 thresholds were used to evaluate gLOH-high and gLOH-low status: 8.8%, based on literature showing this cutoff was optimally distinguished from prostate cancers bearing 

 wild-type, and 9.2%, based on the median gLOH score in TALAPRO-1 in the gLOH-evaluable population. A total of 55 patients were included in this study.

The objective response rate with talazoparib among 30 patients with gLOH-high status at the 8.8% cutoff was 53.3% (95% CI, 34.3%-71.7%) vs 12.0% (95% CI, 2.5%-31.2%) for those with gLOH-low status (n = 25; odds ratio [OR], 8.38; 95% CI, 1.83-51.0; 2-sided 

 = .0017). The complete response (CR) rate was 10% vs 4%, respectively, and the partial response (PR) rate was 43.3% vs 8.0%, respectively.

In an analysis of patients using the 9.2% threshold, among the 28 patients with gLOH-high status, the ORR was 53.6% (95% CI, 33.9%-72.5%) vs 14.8% (95% CI, 4.2%-33.7%) for the 27 patients with gLOH-low status (OR, 6.64; 95% CI, 1.60-32.2; 2-sided 

 = .0041). The CR rates were 7.1% vs 7.4%, respectively, and the PR rates were 46.4% vs 7.4%, respectively.

gLOH scores are relatively low in prostate cancer and do not exhibit the dynamic range seen in breast and ovarian cancers. However, study author Johann de Bono, MB, ChB, FRCP, MSc, PhD, FMedSci, who is an honorary consultant in medical oncology, a professor in experimental cancer medicine, and director of The Drug Development Unit at The Institute of Cancer Research and Royal Marsden in London, notes that these findings suggest gLOH status is worthy of study in a larger patient population as a predictive biomarker.

“Based on these retrospective ad hoc exploratory analyses, gLOH-high status seems to associate with a higher enhanced response to talazoparib…in men with heavily pretreated mCRPC,” he said.

Investigators have previously shown that biallelic alterations in DNA damage response (DDR)/homologous recombination repair (HRR) genes are associated with increased response across several solid tumors that may benefit from treatment with PARP inhibitors. High gLOH is a known marker of sensitivity to platinum-based chemotherapy and PARP inhibitors.

de Bono said it is likely that patients with 

 mutations are driving the gLOH data compared with those who have 

 mutations. Not surprisingly, patients with BRCA mutations were more likely to display a positive ORR compared with 

Specifically, using the 8.8% threshold, 17 patients had gLOH-high status and 13 patients had gLOH-low status and a 

mutation. The ORR was 70.6% (95% CI, 44.0%-89.7%) vs 23.1% (95% CI, 5.0%-53.8%), respectively (OR, 8.0; 95% CI, 1.23-61.0; 2-sided 

 = .0253). The CR and PR rates were 11.8% and 58.8% for those with gLOH-high status, and were 7.7% and 15.4% for those with gLOH-low status.

-mutant disease, 4 patients had gLOH-high status and 6 patients had gLOH status. The ORR was 50% (95% CI, 6.8%-93.2%) vs 0% (95% CI, 0%-45.9%), respectively. One patient had a CR, and 1 patient had a PR following treatment with talazoparib in the gLOH-high cohort compared with no patients experiencing a response in the gLOH cohort.

gLOH status did not translate into longer radiologic progression-free survival (rPFS). At the 8.8% threshold, the median rPFS was 10.9 months (95% CI, 7.5-not evaluable) in the gLOH-high group (n = 30) compared with 11.1 months (95% CI, 2.1-19.2) in the gLOH-low group (n = 25).

“The gLOH cut-off did not define patients who were staying on PARP inhibition [the] longest,” de Bono said. “The Kaplan Meier plot shows gLOH-high and -low [status] was not significantly different and did not separate significantly in this analysis.”

The analysis follows the published findings of the TALAPRO-1 trial, in which heavily pretreated patients with mCRPC received at least 1 dose of 1 mg daily oral talazoparib at 43 medical facilities around the globe. Patients were previously treated with at least 1 taxane-based chemotherapy, as well as abiraterone acetate (Zytiga)/prednisone, enzalutamide (Xtandi), or both hormonal agents.

All patients had at least 1 HHR gene alteration from a panel of 11 genes likely to sensitize their tumor to PARP inhibition: 

ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C

At a median follow-up of 16.4 months (interquartile range, 11.1-22.1), the ORR was 29.8% (95% CI, 21.2%-39.6%) among 104 evaluable patients. Antitumor effects were most notable in patients with BRCA1/2 mutations, with a confirmed ORR of 45.9% and a median rPFS of 11.2 months.

In the safety analysis of 127 patients, the most common grade 3/4 treatment-emergent adverse events (TEAEs) were anemia (31%), thrombocytopenia (9%), and neutropenia (8%). Investigators observed serious TEAEs in 34% of patients. There were no treatment-related deaths.

1. de Bono JS, Mehra N, Laird D, et al. TALPRO-1: talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)-exploration of genomic loss of heterzygosity (gLOH) and potential association with antitumor activity. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT031. Accessed April 11, 2022. https://www.abstractsonline.com/pp8/#!/10517/presentation/20169

2. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264. doi:10.1016/S1470-2045(21)00376-4

High genomic loss of heterozygosity may serve as a predictive marker for response to talazoparib in patients with metastatic castration-resistant prostate cancer.

Potential response biomarker emerges for talazoparib in mCRPC

A post-hoc analysis of data from 2 phase 3 trials found that treatment with apalutamide (Erleada) yields a deep prostate-specific antigen response (PSA) that resulted in positive wellbeing scores, according to a recent study.

“Not only does a deep PSA response identify patients who will have improved survival and progression-free outcomes, but also it is also associated with maintenance of health-related quality of life, improved patient reported physical wellbeing, and a reduced risk of worsening pain and fatigue intensity,” said Eric Jay Small, MD, coleader of the UCSF Prostate Cancer Program and deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center. Small presented the results in a poster at the 2022 Genitourinary Cancers Symposium in San Francisco, California.

Small said that previous results from the phase 3 TITAN (NCT02489318) and SPARTAN (NCT01946204) trials showed that apalutamide plus androgen depravation therapy (ADT) was associated with improved overall survival (OS), preserved health-related quality of life (HRQoL), and rapid and deep reductions in PSA. In this analysis, he and his colleagues set out to determine the relationship between PSA decline and HRQoL following apalutamide.

Investigators assessed HRQoL in the 2 trials separately because each had “distinct” patient populations with different disease burdens and different prior therapies. Small said that at 3 and 6 months, patients whose PSA was at or below 0.2 ng/mL had prolonged time to deterioration in their Functional Assessment of Cancer Therapy-Prostate total (FACT-P) and FACT-P Physical Wellbeing scores on both studies. In TITAN, patients had better scores on the Brief Pain Inventory-Short Form (BPI-SF) worst pain intensity progression and Brief Fatigue Inventory (BFI) worst fatigue intensity progression (TABLE).

A total of 1052 patients with metastatic castration-sensitive prostate cancer enrolled in TITAN and were randomly assigned to apalutamide 240 mg daily plus or placebo. Both groups received standard ADT.

In findings published in 2021, the median OS for patients treated with apalutamide was not reached (NR) compared with 52.2 months for patients assigned to apalutamide (HR, 0.65; 95% CI, 0.53-0.79; 

 < .0001). At 48 months, the OS rate was 65.1% vs 51.8% in favor of apalutamide.

Patients with nonmetastatic castration-resistant prostate cancer in SPARTAN were assigned to apalutamide (n = 806) or placebo (n = 401). At a median follow-up of 52 months, the median OS was 73.9 months (95% CI, 61.2-NR) in the apalutamide group compared with 59.9 months (95% CI, 52.8-NR) with placebo (HR, 0.78; 95% CI, 0.64-0.96; 

The FDA approved apalutamide for this indication in February 2018 based on results from SPARTAN.

Small EJ, Chi KN, Chowdhury S, et al. Association between patient-reported outcomes (PROs) and changes in prostate-specific antigen (PSA) in patients (pts) with advanced prostate cancer treated with apalutamide (APA) in the SPARTAN and TITAN studies. J Clin Oncol. 2022;40(suppl 6; abstr 73). doi: 10.1200/JCO.2022.40.6_suppl.073

Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488

Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. Eur Urol. 2021;79(1):150-158. doi:10.1016/j.eururo.2020.08.011

FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. News release. Updated May 3, 2018. Accessed February 17, 2022. https://bit.ly/33sXJrU

Lowentritt B, Brown G, Kernen K, et al. Real-world effectiveness and treatment adherence of apalutamide in non-metastatic castration-resistance prostate cancer patients. J Urol. 2021;206(suppl 1):e58. doi:10.1097/JU.0000000000001969.08

“Not only does a deep PSA response identify patients who will have improved survival and progression-free outcomes, but also it is also associated with maintenance of health-related quality of life, improved patient reported physical wellbeing, and a reduced risk of worsening pain and fatigue intensity,” said Eric Jay Small, MD.

Apalutamide yields deep PSA response, improved patient-related end points

Patients receiving the metastatic castration-sensitive prostate cancer treatment apalutamide (Erleada) achieved a more significant prostate-specific antigen (PSA) reduction from baseline of 90% (PSA90) when compared enzalutamide (Xtandi), investigators reported at the 2022 Genitourinary Cancers Symposium in San Francisco, California.

Patients treated with apalutamide (n = 174) achieved a PSA90 response at a 70.4% rate compared with 62.5% of patients who received enzalutamide (n = 177) at the end of the 12-month follow-up (HR, 1.49; 95% CI, 1.05-2.11; 

 = .024). The median time to PSA90 response was 3.13 months and 5.20 months in the apalutamide and enzalutamide groups, respectively. Weighted Kaplan-Meier analysis was used to assess the proportion of patients who achieved a PSA90 response and to assess the median to PSA90.

“The clinical implications of these observations warrant further consideration given existing evidence on the association between attainment of rapid, deep, and durable PSA response with survival-related end points in patients treated with these medications,” study authors wrote.

Both apalutamide and enzalutamide are next-generation androgen receptor inhibitors. Enzalutamide was approved by the FDA on December 16, 2019, and apalutamide was approved in this indication on September 17, 2019.

The index date of the study was defined as the first dispensation of apalutamide or enzalutamide following the approval date of enzalutamide. Patients were assigned to mutually exclusive treatment cohorts based on the first dispensation of apalutamide or enzalutamide. The observation period went from the index date to either index treatment discontinuation, initiation of a different next-generation androgen inhibitor, the use of radiopharmaceuticals, the end of clinical activity, or the end of data availability, whichever occurred first.

In terms of statistical analysis methods, inverse probability of treatment weighting based on propensity score (PS) was used to account for the differences in baseline characteristics in the apalutamide and enzalutamide groups. PS was determined by a logistic regression model for apalutamide or enzalutamide treatment assignments with the baseline characteristics of age, race, index year, androgen deprivation therapy (ADT) use of 6 months or more, first-generation antiandrogen use, most recent PSA level, most recent testosterone level, Gleason score, and time between metastasis and the index date.

Investigators wanted to compare the proportion of patients with mCSPC newly treated with apalutamide versus enzalutamide who achieved a PSA90 response at 6 months and beyond. The data used in the study was sourced from Precision Point Specialty Analytics and was collected as part of routine clinical care from 69 United States urology clinics from February 1, 2017, to March 5, 2021. The data was de-identified and was Health Insurance Portability and Accountability Act compliant.

To be included in the study, patients had to be at least 18 on the index date, have at least 1 medication dispensation for apalutamide or enzalutamide, and have at least 12 months of clinical activity prior to the index date. Eligible patients also needed to have evidence of metastatic prostate cancer, defined by the presence of bone, nodal, visceral metastasis prior to or on the index date. A minimum of 1 PSA test during the 13 weeks prior to and including the index date was required.

Patients were excluded from the study if they had prior use of a radiopharmaceutical or a next-generation androgen inhibitor before the index date, or the use of 2 or more next-generation androgen inhibitors. If patients displayed evidence of castration resistance prior to or on the index date, they were not included in the study.

Baseline patient characteristics were evaluated in the 12 months preceding the index date. In the weighted apalutamide group, the median age was 76.0 compared with 75.0 in the enzalutamide cohort. Most patients in both groups were White (71.0% vs 70.5%, respectively), had an index date from 2019-2020 (77.2% vs 77.1%, respectively), and reported prior ADT use (91.4% vs 91.2%, respectively). The mean baseline PSA level was 18.4 ng/mL in the apalutamide cohort compared with 18.3 ng/mL.

PSA testing frequency was similar between the 2 cohorts; 73.6% and 69.5% of patients had a post-index PSA measurement by 6 months in the apalutamide and enzalutamide groups, respectively. A median of 3.8 PSA tests were done per year in the apalutamide cohort compared 3.3 in the enzalutamide cohort. Most patients in both groups had a PSA test every 6 months on average (71.2% vs 67.8%, respectively).

At 6 months follow-up, 69.3% of the apalutamide group achieved a PSA90 response versus 55.6% in the enzalutamide group (HR 1.56; 95% CI, 1.09-2.22; 

 = .014). Apalutamide also outperformed enzalutamide in terms of PSA90 response at the 9-month mark (70.4% vs 62.5%; HR, 1.49; 95% CI, 1.05-2.11; 

The investigators noted that the study was limited because some of the clinical data used could contain inaccuracies or omissions, and the data did not capture any clinical services obtained outside of the urology practice. The study didn’t address if the findings represent a clinically meaningful difference or if they translate into differences in longer-term outcomes. Additionally, the database that was used represented the community urology perspective and may not necessarily be representative of the entire United States population of patients with mCSPC.

Lowentritt B, Pilon D, Khilfeh I, et al. Attainment of early, deep prostate-specific antigen response in metastatic castration-sensitive prostate cancer: A comparison of patients initiated on apalutamide or enzalutamide. 

. 2022;40(suppl 6):43. doi:10.1200/JCO.2022.40.6_suppl.043

Patients treated with apalutamide achieved a PSA90 response at a 70.4% rate compared with 62.5% of patients who received enzalutamide at the end of the 12-month follow-up.

Jason Harris

Articles

Study provides clues on potential of antibody-drug conjugates in variant histology bladder cancer

Potential response biomarker emerges for talazoparib in mCRPC

Apalutamide yields deep PSA response, improved patient-related end points

Apalutamide sees greater PSA response compared with enzalutamide for patients with mCSPC