Jason Broderick

Patients with metastatic castration-resistant prostate cancer (mCRPC) and a high body mass index (BMI) have improved overall survival (OS) vs patients with lower BMI, according to retrospective findings presented during the 2021 European Association of Urology (EAU) Congress.

This phenomenon, a so-called “obesity paradox,” has been reported in other genitourinary malignancies as well.

In an analysis of nearly 1600 patients enrolled across 3 phase 3 trials, the OS rate at 36 months was approximately 30% in patients with obesity (BMI > 30 kg/m

) compared with 20% for patients who were overweight (BMI > 25 to < 30 kg/m

) and normal weight (BMI > 20 to < 25 kg/m

). Statistical modeling showed that the overall risk of death was 4% lower (HR, 0.96; 

 = .015) in patients with obesity when evaluating BMI as a continuous variable and 29% lower (HR, 0.71; 

 = .027) with BMI as a categorical variable.

The investigators also determined that the OS benefit was not caused by the higher chemotherapy dose received by patients with a higher BMI. They found no interaction between BMI subgroups and the dose of docetaxel chemotherapy (

“Looking at patients with metastasis of prostate cancer, we found that [patients with obesity] are living longer. This means that BMI could be used to predict survival in these patients,” study investigator Nicola Fossati, MD, of the Division of Oncology/Unit of Urology at Vita-Salute San Raffaele University in Milan, Italy, stated in a news release.

“This obesity paradox has been seen in some other cancers, possibly due to the relationship between tissue fat and cancer genomes, and more research is needed in this area. It’s also possible that improved survival may be due to the interaction of chemotherapy with other drugs. [Patients with obesity] in this older age group tend to be taking medication for other conditions, and we do not fully understand how these medicines interconnect,” Fossati noted. “Nevertheless, we would not recommend weight gain to anyone with this or another disease. Obesity is a risk factor for many cancers and other diseases, and patients should always aim for a healthy BMI of 18 to 24.”

The study examined 1577 patients with mCRPC enrolled across 3 phase 3 randomized, controlled trials: ASCENT-2 (NCT00273338), MAINSAIL (NCT00988208), and VENICE (NCT00519285). The median patient age was 69 years (interquartile range [IQR], 63-74), and the median BMI was 28 kg/m2 (IQR, 25-31). The median follow-up for survivors was 12 months.

observed with cancer-specific survival. Statistical modeling showed that the risk of cancer-related death was 6% (HR, 0.94; 

 = .002) lower in patients with obesity when evaluating BMI as a continuous variable and 35% lower (HR, 0.65; 

 = .018) with BMI as a categorical variable.

“There are many possible explanations for the association of body weight with positive outcome in metastatic cancers,” Peter Albers, MD, professor and chairman of the Department of Urology at Heinrich-Heine University Düsseldorf in Germany and chair of the EAU Scientific Congress Office, stated in the release.

 “It might be that patients with higher BMI are able to tolerate the toxicity of the treatments and their [adverse] effects better; in prostate cancer, it might be due to the protective impact of hormones found in tissue fat. And it is known that healthy men with slightly higher BMI have a higher overall life expectancy compared to very slim [men].

“However, at the moment, these are just hypotheses. Further research is needed to identify the biological mechanism behind these different outcomes. Until that mechanism is proven, we can’t recommend any change to treatment for patients with advanced prostate cancer.”

1. Cirulli GO, Martini A, Sfakianos JP, et al. The obesity paradox in metastatic castration resistant prostate cancer. Poster presented at: 36th Annual European Association of Urology Congress; July 8-12, 2021; virtual. Accessed August 23, 2021. https://resource-centre. uroweb.org/resource-centre/EAU21/221553/Presentation/

2. Obesity increases survival in advanced prostate cancer. News release. European Association of Urology. July 10, 2021. Accessed July 11, 2021. https://bit.ly/3kbHO7h

Articles

A phenomenon known as the “obesity paradox,” has been reported in prostate cancer as well as other genitourinary malignancies.






'Obesity Paradox’ Is Shown in Prostate Cancer

According to updated data from the phase 1b COSMIC-021 trial, treatment with cabozantinib (Cabometyx) and atezolizumab (Tecentriq) continued to demonstrate clinically meaningful activity in previously treated patients with locally advanced or metastatic castration-resistant prostate cancer (mCRPC), including those with high-risk clinical features.

The data presented during the ESMO Congress 2021 included 132 patients, all of whom had prior enzalutamide (Xtandi) and/or abiraterone acetate (Zytiga), and 101 (77%) of whom had high-risk disease. At the data cutoff of February 19, 2021, the investigator-assessed objective response rate (ORR) among all patients was 23%, including 3 complete responses (CRs); the ORR was 15% (all partial responses [PRs]) per independent review.

The investigator-assessed ORR in high-risk patients was 27%, comprising a 2% complete CR rate and a 25% PR rate. Per independent review, the ORR was 18%, comprising all PRs.

At a median follow-up of 15.2 months (range, 5.7-33.9), the median PFS per independent review was 6.8 months in high-risk patients and 5.7 months in the overall population. The median overall survival (OS) was 18.4 months in both the overall and high-risk populations. Based on available data from 75 patients, initial results did not indicate a link between tumor PD-L1 status and clinical activity.

“These detailed results confirm previous findings3 from cohort 6 of COSMIC-021, further suggesting the promise cabozantinib in combination with atezolizumab may hold for patients with high-risk metastatic castration-resistant prostate cancer whose disease progressed following treatment with novel hormone therapy,” Neeraj Agarwal, MD, professor of Medicine, Huntsman Cancer Institute, University of Utah and a trial investigator, stated in a news release.

“A significant number of these patients are looking for treatment options beyond chemotherapy, so these clinically meaningful response rates and progression-free survival results of cabozantinib in combination with atezolizumab are encouraging for this patient community and their physicians,” added Agarwal.

The multicenter, open-label, phase 1b COSMIC-021 trial is evaluating the combination of the PD-L1 inhibitor atezolizumab and the multikinase inhibitor cabozantinib in patients with locally advanced or metastatic solid tumors. The mCRPC cohort is cohort 6 of the trial. Patients in this cohort were allowed to have received prior docetaxel for hormone-sensitive disease. The study design defined high-risk disease as measurable visceral and/or extra-pelvic lymph node metastases. Cabozantinib was administered orally at 40 mg once daily and intravenous atezolizumab was given at 1200 mg every 3 weeks. The primary end point was ORR.

The median patient age was 70 years and 52% (n = 68) had an ECOG performance score of 0. Overall, 42 (32%) patients had visceral metastases and 79 (60%) patients had extra-pelvic lymph node metastases. Regarding prior treatment, 25% of patients had received docetaxel and almost half (45%) of patients had received 2 or more novel hormonal therapies.

The median follow-up time in the high-risk subgroup was 15.8 months. In these patients, the disease control rate was 88% per investigator assessment and 84% per the assessment of the BIRC.

There were no new safety signals that emerged in this updated, expanded cohort analysis as compared with the initial interim analysis. The most common treatment-related adverse events (TRAEs) were diarrhea (55%), nausea (42%), fatigue (43%), and decreased appetite (34%). Over half (55%) of patients experienced grade 3/4 TRAEs. There was 1 reported death related to a TRAE (dehydration in a 90-year-old patient).

Exelixis, the developer of cabozantinib, reported in a news release that based on discussions with the FDA, they will not be filing for regulatory approval of the combination based on the cohort 6 data from COSMIC-021. Instead, the company has launched the phase 3 CONTACT-02 trial (NCT04446117). This ongoing randomized, open-label, study is exploring cabozantinib plus atezolizumab versus second novel hormone therapy (abiraterone, enzalutamide, etc) in patients with mCRPC who previously received 1 NHT to treat metastatic castration-sensitive prostate cancer, non-metastatic CRPC, or mCRPC.

Primary outcomes measures for the trial are OS and PFS, with ORR as a secondary outcome measure. The target enrollment is 580 patients, and there are 62 study locations for the trial in the United States and worldwide. Exelixis noted in their news release that results of this study may support regulatory submissions for the cabozantinib/atezolizumab regimen.

1. Agarwal N, McGregor BA, Maughan BL, et al. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of expanded cohort 6 of the COSMIC-021 study. Presented at: 2021 European Society for Medical Oncology Congress. September 16-21, 2021. Abstract LBA24.

2. Exelixis Announces Detailed Phase 1b Results from Cohort 6 of COSMIC-021 Trial in Patients with Metastatic Castration-Resistant Prostate Cancer Presented at ESMO 2021. Published online September 18, 2021. Accessed September 18, 2021. https://yhoo.it/3CvZG2N.

3. Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: Results of cohort 6 of the COSMIC-021 study. 

 38: 2020 (suppl; abstr 5564). doi: 10.1200/JCO.2020.38.15_suppl.5564.

According to updated data from the phase 1b COSMIC-021 trial, treatment with cabozantinib and atezolizumab continued to demonstrate clinically meaningful activity in previously treated patients with locally advanced or metastatic castration-resistant prostate cancer, including those with high-risk clinical features.

Atezolizumab Combined With Cabozantinib Shows Efficacy in High-Risk mCRPC

Alan Lombard, PhD, shared insight on mechanisms of resistance to PARP inhibition with olaparib (Lynparza) and explained how this resistance may be overcome, during a presented given as part of AUA 2021 Annual Meeting.

“PARP inhibitors represent the dawn of precision medicine in prostate cancer,” said Lombard, of the University of California, Davis. “The PARP inhibitors olaparib and rucaparib (Rubraca) were both approved by the FDA [for prostate cancer] in 2020 and have been shown to be highly effective in biomarker selected patients. Several ongoing trials are exploring additional PARP inhibitors, various combinations, and varying disease stages.”

Despite all of this progress, Lombard said key questions about PARP inhibitors remain regarding how to optimize the use of these agents in prostate cancer. Specifically, he noted that the mechanism of action of PARP inhibition is not fully understood and, “Additionally the questions of how do PARP inhibitor–sensitive prostate tumor cells respond to treatment and what mechanisms will drive resistance to these drugs need to be addressed.”

For their study, Lombard and his coinvestigators sought to address these questions by modeling PARP inhibitor treatment and resistance in prostate cancer.

Olaparib-sensitive and -resistant cell lines

Through their modeling process, Lombard et al first determined that the LNCap and C4-2B cell lines are sensitive to olaparib, which they determined was likely due to a 

mutation. Next, through chronic olaparib exposure of these 2 cell lines, the investigators developed the olaparib-resistant cell lines LN-OlapR and 2B-OlapR.

“Cell growth assays demonstrated that both OlapR cell line models are robustly resistant to olaparib. We additionally found that both LN-OlapR and 2B-OlapR are cross-resistant to the additional PARP inhibitors rucaparib, niraparib, and talazoparib. Altogether, these results suggest that OlapR cells are models of pan–PARP inhibitor resistance,” said Lombard.

The investigators then conducted Western blot testing which provided insight on why OlapR cells are resistant to PARP inhibition. Specifically, the DNA double strand break marker gamma-H2AX demonstrated that olaparib induces DNA damage in the sensitive LNCap and C4-2B cells, but it does not induce this damage in OlapR cells. 

Western blotting “for cleaved-PARP showed that olaparib leads to cell death in sensitive [LNCap and C4-2B] cells, but not resistant cells,” said Lombard. “Interestingly, we also observed that a significant proportion of treated sensitive [LNCap and C4-2B] cells appear to undergo cytostasis and exhibit a flattened morphology reminiscent of senescence. We did not observe this in OlapR cells.”

Lombard and coinvestigators also found through flow cytometry that treatment with olaparib activates the G2/M checkpoint and this leads to significant arrest of cell growth in the sensitive LNCap and C4-2B cells, but not in resistant OlapR cells.

Further it was observed that beta-galactosidase activity is greatly increased in LNCap and C4-2B cells, “suggesting entry into senescence,” Lombard explained, adding that a similar degree of heightened beta-galactosidase activity did not occur in OlapR models.

“Taken together, these data suggest that OlapR cells override the G2/M checkpoint and may re-emerge from senescence during acquisition of resistance,” said Lombard.

The PARP inhibitor research also revealed that expression of the CDK inhibitor p21 was significantly augmented in LNCap and C4-2B cells but in OlapR cells, “thus providing a putative mechanism which may drive senescence,” noted Lombard.

The investigators examined the combined impact of olaparib and inhibition of p21 and discovered there was significantly reduced cellular viability, with increased DNA damage and cell death.

“These data suggest that blocking growth arrest and entry into senescence may promote cell death in the context of high levels of DNA damage. Thus, targeting PARP inhibitor-induced senescence may be a means to enhance PARP inhibitor efficacy,” said Lombard.

He added that, “Comparing gamma-H2AX levels in OlapR cells to respective sensitive cells indicates that resistant cells harbor increased levels of intrinsic DNA damage, which may suggest that resistance may depend on enhancing DNA repair activity to manage persistent stress.”

Prior research in the literature, along with their observations on the impact of CDK inhibition led the investigators to evaluate whether CDK1 inhibition could help reverse olaparib resistance and sensitize OlapR cells to the PARP inhibitor.

The investigators hypothesis was confirmed as the modeling showed that knockdown of CDK1 resulted in a higher incidence of DNA damage and cell death in both LN-OlapR and 2B-OlapR cells, and when combined with olaparib further reduced cellular viability.

Specifically, Lombard ed al found that BMS-265246, a small molecule inhibitor of CDK1, used combination with olaparib also produced this same effect.

“PARP inhibitor resistance can be overcome through CDK inhibition. Development of this strategy may enhance and/or prolong PARP inhibitor utility,” said Lombard. “CDK1 may be an attractive strategy for enhancing olaparib clinical efficacy.”

Lombard A, Lou W, Armstrong C, et al. Resistance to olaparib is dependent on re-emergence from G2/M arrested senescence. Presented during the 2021 American Urological Association Annual Meeting; September 10-13, 2021. PD44-10.

Alan Lombard, PhD, shared insight on mechanisms of resistance to PARP inhibition with olaparib and explained how this resistance may be overcome.









Potential for Overcoming Olaparib Resistance in Prostate Cancer

In patients with progressive prostate-specific membrane antigen (PSMA) positive metastatic castration-resistant prostate cancer (mCRPC) receiving treatment in the phase 3 VISION trial, the addition of the targeted radioligand therapy 177Lu-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 the 2021 American Society of Clinical Oncology (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 Memorial Sloan Kettering Cancer Center in New York, New York.

The open-label phase 3 VISION trial (NCT03511664) included 831 patients (1179 initially screened) with progressive PSMA- positive mCRPC who had 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.

Positron emission tomography (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 for 6 cycles; n = 551) plus SOC or SOC alone (n = 280). Individual investigators determined the SOC, but 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; P < .001).The rPFS was 8.7 versus 3.4 months, respectively (HR, 0.40; 99.2% CI, 0.29-0.57; P < .001).

There was also a statistically significant benef it favoring the LuPSMA arm for the key secondary end points 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%), 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 to 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%), 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, 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 the 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 III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(suppl 18):LBA4. doi:10.1200/ JCO.2021.39.15_suppl.LBA4

In patients with progressive prostate-specific membrane antigen positive metastatic castration-resistant prostate cancer receiving treatment in the phase 3 VISION trial, the addition of the targeted radioligand therapy 177Lu-PSMA-617 to standard of care led to a nearly 40% reduction in the risk of death versus SOC alone. 

Adding 177Lu-PSMA-617  to Standard of Care Significantly Prolongs Survival in mCRPC

A 4-fold increase in the risk of disease recurrence among patients with high level of the nicotine metabolite, urinary cotinine (UC), who had non–muscle invasive bladder cancer (NMIBC) and were smokers.

The findings were presented during the 2021 European Association of Urology Annual Congress by Maher Abdessater, MD, MPH, of Notre Dame de Secours University Hospital in Lebanon.

“[Cotinine is] the best marker for tobacco exposure, but little is known about its carcinogenic effect. Additionally, little is known whether the recurrence of bladder cancer can be related to the nicotine metabolites eliminated in urine,” Abdessater explained. To this end, the investigators sought to evaluate the association between UC level and NMIBC recurrence.

The investigators performed a cross sectional study between January 2018 and June 2019. The study enrolled patients who were smokers, received a diagnosis of NMIBC that was treated with resection only, and who were presenting for a follow-up cystoscopy. Cotinine was measured on a sample of voided urine prior to cystoscopy. Patients with a UC level less than 550 ng/mL were considered moderate smokers, whereas patients with a UC level greater than 550 ng/mL were considered heavy smokers. Tumor recurrence was evaluated via cystoscopy. A Fisher Exact Test was used for statistical analysis.

The cohort included 135 patients aged 36 to 78 years (mean age, 64). All patients were Caucasian and had a similar profile of exposure to carcinogens related to bladder cancer. Eighty-two percent of patients were male, and 12% were female.

The investigators found that 40.74% of the cohort were moderate smokers and 59.26% were heavy smokers. Overall tumor recurrence rate was 51.85%.

“Specifically, tumor recurrence was observed in 75% of heavy smokers and 18% of moderate smokers. This result was statistically significant,” Abdessater said, with a relative risk of 4.16 (

In a news release about the results, Abdessater discussed the ease of use and low cost of using cotinine levels to detect bladder cancer recurrence.

“One of the major advantages of using cotinine is that it can be detected using a simple urine test, which is a cheaper and less invasive alternative to cystoscopy. It can also pick up where patients are not accurately reporting their smoking levels, or where passive smoking combined with active smoking is pushing them into the heavy smoker category."

“Additional prospective studies are needed to better understand the relation between urinary cotinine levels and bladder cancer and to evaluate its usefulness in bladder cancer surveillance,” Abdessater said in his concluding remarks.

Although the data reported by the investigators were from the period between January 2018 and June 2019, the study is ongoing, and the investigators are seeking additional institutions to collaborate on the effort, according to the news release.

Commenting on the results in the news release, EAU Secretary-General Adjunct Professor Arnulf Stenzl said, “This study definitely gives food for thought, although as yet the findings are only in a small number of patients. We now need to test this in a larger trial, and also look at more precise indications of smoking levels and the type of cigarettes involved—particularly whether they are filtered or not. It would be interesting as well to look at whether cotinine levels are higher in patients with other risk factors for bladder cancer, such as exposure to arsenic or industrial benzole."

1. Abdessater M, Kanbar A, El Khoury J, et al. Role of urinary cotinine level in the recurrence of non-muscle invasive bladder cancer. Paper presented at: 2021 European Association of Urology Annual Congress. July 8-12; virtual. Abstract P0726

2. Nicotine by-product can predict recurrence of cancer. News release. European Association of Urology. July 8, 2021. Accessed July 12, 2021. 

A significant increase in the risk of disease recurrence among patients with high level of the nicotine metabolite, urinary cotinine, who had non–muscle invasive bladder cancer and were smokers.






High Urinary Cotinine Levels Correlate With Recurrence of Non-Muscle Invasive Bladder Cancer

In patients with muscle-invasive bladder cancer (MIBC) combining transurethral resection of the bladder tumor (TURBT) with nivolumab (Opdivo) and chemotherapy showed promise as a bladder-sparing treatment strategy, according to findings from the phase 2 HCRN GU16-257 trial 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.”

1. 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

In patients with muscle-invasive bladder cancer combining transurethral resection of the bladder tumor with nivolumab and chemotherapy showed promise as a bladder-sparing treatment strategy. 

Jason Broderick | Authors

Articles

'Obesity Paradox’ Is Shown in Prostate Cancer

Atezolizumab Combined With Cabozantinib Shows Efficacy in High-Risk mCRPC

Potential for Overcoming Olaparib Resistance in Prostate Cancer

Adding 177Lu-PSMA-617 to Standard of Care Significantly Prolongs Survival in mCRPC

High Urinary Cotinine Levels Correlate With Recurrence of Non-Muscle Invasive Bladder Cancer

Nivolumab-Based Strategy Shows Promise in MIBC