Jason M. Broderick

In patients with muscle-invasive bladder cancer (MIBC) treated in the phase 2 HCRN GU16-257 trial, the combination of transurethral resection of the bladder tumor (TURBT) with nivolumab (Opdivo) and chemotherapy showed promise, according to findings presented at the 2021 ASCO Annual Meeting.

In the study, the bladder-sparing approach achieved stringently-defined clinical complete responses (CRs) in a large subset of patients with MIBC. Commenting on the results, lead study author Matthew D. Galsky, MD, said, “Bladder-intact recurrence-free survival is possible [with this strategy], although the durability of responses requires longer follow-up.”

Explaining the rationale for the trial, Galsky said, “Radical cystectomy is a major operation and requires diversion of the urinary stream, which has life-altering implications. Clearly, if we could identify which patients can have their muscle-invasive bladder cancer eradicated with TURBT plus systemic therapy alone, a subset of patients could avoid cystectomy and enjoy long-term, bladder-intact disease free-survival.”

The phase 2 HCRN GU16-257 study enrolled 76 patients with cisplatin-eligible cT2 to T4aN0M0 clinically localized urothelial bladder cancer. Galsky noted that, “Due to COVID-19, there was some gap between enrollment of the first 64 patients and the remaining patients.” The median age was 69 years (range, 39-85) and 79% of patients were male. Tumor stages at baseline were cT2 (57%), cT3 (32%), and cT4 (12%). Regarding histology, 76% of patients had urothelial cancer that was transition cell and 24% of patients had urothelial cancer with variant histology.

Patients initially received 4 cycles of gemcitabine plus cisplatin plus nivolumab. Following these 4 cycles, all patients underwent clinical restaging, including MRI/CT of the bladder (unless otherwise contraindicated), urine cytology, and cystoscopy with bladder/prostatic urethral biopsies.

Patients with a clinical CR could then opt to proceed with cystectomy or proceed without cystectomy and instead receive an additional 4 months of single-agent nivolumab. For patients without a clinical CR, a cystectomy was recommended.

The study had two coprimary end points: 1) determine the clinical CR rate of this regimen and 2) determine the ability of a clinical CR to predict “benefit” from treatment. A clinical CR was defined as having no abnormalities on post–treatment cycle 4 imaging, no abnormalities on post–treatment cycle 4 urine cytology, and either no evidence of disease or no evidence of disease greater than low-grade papillary tumors (Ta) on post–treatment cycle 4 mapping biopsies of the bladder.



For the second primary end point, “benefit” was defined as being metastasis-free for 2 years in patients opting for no cystectomy or achieving a pathologic CR in patients receiving cystectomy.

At the time of the data cutoff, 64 patients had completed clinical restaging. Of these patients, 31 (48%; 95% CI, 36-61) achieved a clinical CR. Thirty of these patients chose not to undergo cystectomy and instead receive an additional 4 months of nivolumab monotherapy. Only 1 patient opted for immediate cystectomy. “On surgical pathology, that patient had a low-grade papillary tumor,” said Galsky. The remaining 33 patients did not reach a clinical CR and cystectomy was recommended.

Galsky noted that all 31 patients who achieved a clinical CR are still alive and “there are a number of patients who are now 12 months out since treatment initiation who have had no recurrence and whose bladders remain intact.”

There were 6 patients with a clinical CR who underwent delayed cystectomy after local recurrence. Of these patients there was 1 patient each with a pathological stage of ypT0N0, ypTaN0, YpTisN0, and ypT4N1, and 2 patients with a stage of ypT2N0.

Among 28 patients who did not reach a clinical CR and underwent immediate cystectomy, the pathological stages were ypT0N0 (n = 2), YpTisN0 (n = 5), ypT1N0 (n = 3), ypT2N0 (n = 5), ypT3N0 ( n = 3), ypT4N0 (n = 1), and ypTanyN+ (n = 9).

Galsky noted that no patients had to stop study treatment early for any of the trial-defined stopping rules, which included a high rate of grade 3/4 immune-related adverse events (AEs; all patients) or a high rate of muscle-invasive and/or metastatic recurrence rates (patients achieving a clinical CR). Further, the AE profile was consistent with other recent trials evaluating the combination of cisplatin-based chemotherapy with immune checkpoint blockade in this setting.

Regarding next steps, Galsky said, “A suite of genomic and radiomic biomarkers are being explored in an effort to refine the ability of clinical CR to predict long-term bladder-intact recurrence-free survival.”

Galsky MD, Daneshmand S, Chan KG et al. Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle- invasive bladder cancer (MIBC): HCRN GU 16-257. 

 39, 2021 (suppl 15; abstr 4503). doi: 10.1200/JCO.2021.39.15_suppl.4503

Articles

In patients with muscle-invasive bladder cancer treated in the phase 2 HCRN GU16-257 trial, the combination of transurethral resection of the bladder tumor with nivolumab and chemotherapy showed promise.

Encouraging Results Observed With Nivolumab-Based Regimen in MIBC

In patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) receiving treatment in the phase 3 VISION trial, the addition of the targeted radioligand therapy 

Lu-PSMA-617 (LuPSMA) to standard of care (SOC) led to a nearly 40% reduction in the risk of death versus SOC alone, according to findings presented during a presscast held as part of the 2021 ASCO Annual Meeting.

The findings showed that at a median follow-up of 20.9 months, the addition of LuPSMA improved the median overall survival (OS) by 4 months over SOC alone (HR, 0.62). Adding the targeted radioligand therapy also led to a 5.3-month improvement in median radiographic progression-free survival (rPFS), translating to a 60% reduction in the risk of progression or death (HR, 0.40). 

“These findings warrant adoption of LuPSMA as a new treatment option in patients with mCRPC, pending FDA approval,” said lead VISION trial author Michael J. Morris, MD, head of the Prostate Cancer Section at Sloan Kettering Cancer Center in New York.

The open-label phase 3 VISION trial (NCT03511664) included 831 patients (1179 initially screened) with progressive PSMA-positive mCRPC who received at least 1 novel androgen axis drug (eg, enzalutamide [Xtandi] or abiraterone acetate [Zytiga]) and were previously treated with 1 to 2 taxane regimens.

PET imaging with 68Ga-PSMA-11 was used to determine PSMA positivity. Patient demographics and baseline characteristics were well balanced at baseline.

Patients were randomized in a 2:1 ratio to LuPSMA (7.4 GBq every 6 weeks x 6 cycles; n = 551) plus SOC or SOC alone (n = 280). Individual investigators determined the SOC; however, radium-223 (Xofigo) and cytotoxic chemotherapy were not allowed. The coprimary end points of the trial were OS and rPFS.

The median OS was 15.3 months in the LuPSMA arm versus 11.3 months in the SOC alone arm, translating to a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.52-0.74; 

 <.001).The rPFS was 8.7 versus 3.4 months, respectively (HR, 0.40; 99.2% CI, 0.29-0.57; 

There was also a statistically significant benefit favoring the LuPSMA arm for the key secondary endpoints of objective response rate (ORR), disease control rate (DCR), and time to first symptomatic skeletal event (SSE). The ORRs and DCRs were 29.8% versus 1.7% and 89.0% versus 66.7%, respectively. The median time to first SSE was 11.5 months in the LuPSMA group compared with 6.8 months in the control arm (HR, 0.50).

The safety analysis included 529 patients in the LuPSMA cohort and 205 patients in the control group. The investigators considered LuPSMA treatment to be well tolerated. The most common adverse events (AEs) across all grades occurring in the LuPSMA arm were fatigue (49.1% vs 29.3% in the control arm), bone marrow suppression (47.4% vs 17.6%, respectively), dry mouth (39.3% vs 1%), nausea/vomiting (39.3% vs 17.1%), kidney effects (8.7% vs 5.9%), second primary malignancies (2.1% vs 1%), and intracranial bleeding (1.3% vs 1.5%).

High-grade treatment-emergent AEs occurred in 52.7% of patients receiving LuPSMA compared with 38% of patients treated with SOC alone. The most common grade 3-5 AEs reported in the LuPSMA arm were bone marrow suppression (23.4% vs 6.8% in the control arm), fatigue (7% vs 2.4%, respectively), kidney effects (3.4% vs 2.9%), and nausea/vomiting (1.5% vs 0.5%).

Regarding the next steps with LuPSMA, Morris said, “There are ongoing trials of LuPSMA in patients with prostate cancer at earlier phases of the disease.”

Commenting on the significance of the VISION study results, ASCO President Lori J. Pierce, MD, FASTRO, FASCO, said, “This is an important study, as the patients in this trial had mCRPC, so they had disease that grew even when testosterone in the body had already been reduced to very low levels, despite receiving 1 to 2 prior taxane regimens.”

She added, “This trial shows an alternative to traditional therapies by using radiation targeted to the PSMA antigen. So, it could be delivered directly to the prostate cancer cells, and by doing that, survival was significantly improved. Use of the PSMA radioligand therapy, if it obtains regulatory approval, could indeed become an important treatment option for these patients with refractory disease.

There are currently 2 PSMA PET imaging agents approved for patients with prostate cancer, Ga 68 PSMA-11 and 18F-DCFPyL (Pylarify). Novartis, the manufacturer of LuPSMA, plans to file for FDA approval of the radioligand therapy based on these positive findings from the VISION trial. If approved, LuPSMA would become the first PSMA theranostic approved in prostate cancer.

Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). 

LuPSMA added to standard of care led to a nearly 40% reduction in the risk of death versus standard of care alone in the phase 3 VISION study.

Addition of 177Lu-PSMA-617 to SOC Significantly Prolongs Survival in mCRPC

Improved outcomes for younger African American patients is associated with increased prostate-specific antigen (PSA) screening, according to findings presented on a presscast held ahead of the 2021 ASCO Annual Meeting.

In this population, an increase in the frequency of PSA screening was linked to a nearly 25% reduction in prostate cancer–specific mortality and an approximately 40% lower risk of having metastatic disease at the time of a prostate cancer diagnosis.

“We found that PSA screening was associated with a decreased risk of Gleason score ≥8, PSA >20, and metastatic disease at diagnosis, as well as prostate cancer–specific mortality. Taken together, these results would suggest that [increased] PSA screening may improve cancer outcomes for young African American men. Although the results of this study are just one step in addressing all of the other racial disparities that still exist in prostate cancer,” said lead author Edmund M. Qiao, BS, of the University of California San Diego.

Overall, the study included 4726 African American men diagnosed with prostate cancer. The mean patient age was 51.8 years. The mean number of previous PSA screening tests was 1.9. The “high PSA screening” group had received an average of 3 prior screening tests and the “low PSA screening” group had received an average of 0.5 prior screening tests.

Regarding disease severity at diagnosis, all key metrics showed that the high PSA screening group had lower severity. Specifically, the rate of patients with Gleason score ≥8 and PSA >20 at diagnosis was 15.3% versus 10.7% and 16.3% versus 7.2% in the lower versus higher screening groups, respectively. Further, the rate of metastatic disease at diagnosis was 4.2% versus 1.4%, respectively, translating to a 39% risk reduction (odd ratio, 0.61; 95% CI, 0.47-0.81; 

Qiao added, “In our statistical model, controlling for the confounders, we found that PSA screening was associated with about a 25% reduction in prostate cancer–specific mortality [hazard ratio, 0.75; 95% CI, 0.59-0.95; 

 = .02].” The confounding factors controlled for in the statistical model included primary care visit rate, age at diagnosis, year of diagnosis, Charlson comorbidity score, employment, marital status, college education, and income.

Regarding the importance of the research, Qiao said, “African American men have the highest mortality rate for prostate cancer; however, the data for PSA screening includes very few African American men and no young African American men between the ages of 40 and 55. This has led to discordant PSA screening recommendations for these patients and as a result, young African American men are an at-risk group that needs additional research to help guide their clinicians and themselves when deciding when to start PSA screening.”

In 2012, the US Preventive Services Task Force (USPSTF) issued a grade D recommendation against the use of PSA screening in the general US population, regardless of age. The current USPSTF PSA screening policy is slightly changed, with a grade C recommendation for men aged 55 to 69 years, meaning in this population, an individual decision on screening should be made based on a physician-clinician discussion of the potential benefits and risks.

While the USPSTF acknowledges that family history and African American race are two of the most significant risk factors for developing prostate cancer, the panel maintains that there is insufficient evidence to issue individualized screening recommendations in any age group based on those factors.

Commenting on the study during the presscast, ASCO President Lori J. Pierce, MD, FASTRO, FASCO, said, “We know African American men are nearly one-and-a-half times more likely to develop prostate cancer and more than twice as likely to die from prostate cancer as White patients. And despite this, young African American men are poorly represented in PSA studies from which evidence-based guidelines are developed. So, this really limits proper PSA guidance screening guidance for African American patients, especially for those who are younger than 55. And so, because we don't have adequate screening data, there are differences in opinion as to what the guidelines should be. And so, this abstract makes a very strong statement to discuss screening at a younger age in African American men.”

1. Qiao E, Kotha N, Nalawade V, et al. Association of increased intensity of prostate-specific antigen screening in younger African American men with improved prostate cancer outcomes. Presented at: 2021 ASCO Annual Meeting Virtual Embargoed Presscast; May 14, 2021. Abstract 5004.

Improved outcomes for younger African American patients is associated with increased prostate-specific antigen screening.

Improved Outcomes for Younger African Americans Linked to Increased PSA Screening

Localized metastatic lesions were detected with a high correct localization rate (CLR) and positive predictive value (PPV) with the investigational prostate-specific membrane antigen (PSMA)–targeted PET imaging agent 

F-DCFPyL, according to data from the pivotal phase 3 CONDOR study

The data were reported at the 2021 Genitourinary Cancers Symposium as the FDA prepares to make a decision on a new drug application (NDA) for the prostate-specific membrane antigen (PSMA) PET imaging agent.

The multicenter phase 3 CONDOR study (NCT03739684) enrolled men with rising prostate-specific antigen (PSA) after definitive therapy and negative or equivocal standard-of-care imaging. Patients were required to have a PSA level of 0.2 or higher if they had undergone radical prostatectomy (RP) or a PSA level of 2.0 or higher if they were treated with radiation therapy or cryotherapy.

F-DCFPyL targets the extracellular domain of PSMA. Imaging is supposed to begin 1 to 2 hours following intravenous administration of 

The primary end point of the study was CLR, defined as percentage of patients with a 1:1 correspondence between at least 1 lesion identified by Peel–PET/CT and the composite standard of truth (SOT; N = 132: pathology, correlative imaging, or PSA response). Peel scans were read by 3 blinded independent central readers. The key secondary end point was the percentage of patients in whom 

F-DCFPyL PET/CT led to a change in intended treatment.

Overall, there were 208 evaluable patients, about 85% of whom underwent RP, either alone or with radiation. Median PSA level of the cohort was 0.8 ng/mL, and 68.8% had a PSA level lower than 2.0 ng/mL. Some 27.9% had received at least 1 prior systemic therapy. Detection of disease as manifested by a positive 

F-DCFPyL–PET/CT scan was 65.9%, 59.6%, and 59.1% by the 3 readers.

The prespecified criterion for CLR success was for the lower limit of the 95% CI to exceed 20% for at least 2 of the 3 readers. For every reader, the lower bound of the 95% CI for the CLR was well in excess of the 20% benchmark, meeting the primary end point of the study.

The CLRs were 85.6% (95% CI, 78.8%-92.3%), 87.0% (95% CI, 80.4%-93.6%), and 84.8% (95% CI, 77.8%-91.9%) by the 3 readers.

PPV was also high, with a range of 88.7% to 90.7% across all 3 readers. Further, the high CLR and PPV were maintained across all 3 categories of SOT. For histopathology (n = 31) the CLR ranges were 78.6 to 82.8% and the PPV ranges were 92.9% to 93.3%. For correlative imaging (n = 100) the ranges were 86.1% to 88.6% and 87.% to 89.5%, respectively. The ranges were both 100% for PSA response.

“PSMA-targeted 18F-DCFPyL-PET/CT detected and localized metastatic lesions with high CLR and PPV regardless of which criterion defined CLR that was used, in men with BCR who had negative or equivocal baseline standard imaging,” first study author Frederic Pouliot, MD, PhD, assistant professor, Department of Surgery, Faculty of Medicine, Université Lavaland, Quebec, Canada, and coauthors wrote.

Regarding the secondary end point of treatment change, as measured through pre- and post-PET questionnaires, 63.9% of evaluable patients had a change in intended management due to 

F-DCFPyL-PET/CT. Of these changes, 78.6% were triggered by positive 

F-DCFPyL-PET/CT findings and 21.4% were caused by negative findings.

The changes included 58 patients switching from salvage local therapy to systemic therapy, 49 patients changing from observation to initiating therapy, 43 patients switching from noncurative systemic therapy to salvage local therapy, and 9 patients scaling back from planned treatment to observation.

F-DCFPyL-PET/CT being considered by the FDA also includes supportive data from the phase 2/3 OSPREY trial, in which 

F-DCFPyL-PET/CT was assessed in 2 patient cohorts.

 Cohort A included men with high-risk, locally advanced prostate cancer, and the researchers assessed the capacity of 

F-DCFPyL-PET/CT to detect prostate cancer in pelvic lymph nodes. Cohort B comprised patients with metastatic or recurrent disease and the researchers examined the performance of 

F-DCFPyL-PET/CT in detecting distant metastases.

F-DCFPyL-PET/CT in detecting disease in pelvic lymph nodes showed a specificity of 96% to 99%, a sensitivity of 31% to 42%, and a PPV of 78% to 91%. The sensitivity and PPV rates for detecting metastatic lesions in cohort B were 93% to 99% and 81% to 88%, respectively.

1. Pouliot F, Gorin MA, Rowe SP, et al. PSMA-targeted imaging with 18F-DCFPyL-PET/CT in patients (pts) with biochemically recurrent prostate cancer (PCa): A phase III study (CONDOR)—A subanalysis of correct localization rate (CLR) and positive predictive value (PPV) by standard of truth. 

. 2021;39(suppl 6):33. doi: 10.1200/JCO.2021.39.6_suppl.33

2. PDUFA action date of May 28, 2021 assigned by U.S. Food and Drug Administration. Published online December 9, 2020. https://bit.ly/2KtYerG. Accessed February 13, 2021

Localized metastatic lesions were detected with a high correct localization rate (CLR) and positive predictive value (PPV) with the investigational prostate-specific membrane antigen (PSMA)–targeted PET imaging agent 18F-DCFPyL. 

Jason M. Broderick | Authors

Articles

Encouraging Results Observed With Nivolumab-Based Regimen in MIBC

Addition of 177Lu-PSMA-617 to SOC Significantly Prolongs Survival in mCRPC

Improved Outcomes for Younger African Americans Linked to Increased PSA Screening

18F-DCFPyL, PSMA-Targeted PET Imaging Agent, Provokes High CLR and PPV