Countless Options to Improve Future Outcomes in Subgroups of Patients With GU Cancers

October 30, 2020
Nichole Tucker
Nichole Tucker

In genitourinary cancers, presentation of subgroup analysis data from large randomized clinical trials demonstrated findings that will change practice for oncologists who treat patients with prostate cancer, bladder cancer, and renal cell carcinoma.

In genitourinary cancers, presentation of subgroup analysis data from large randomized clinical trials demonstrated findings that will change practice for oncologists who treat patients with prostate cancer, bladder cancer, and renal cell carcinoma (RCC).

The analyses conducted included closer looks at mutational status and prostate-specific antigen (PSA) levels in patients with prostate cancer, efficacy from long-term follow-up for bladder cancer, as well as 2 difficult-to-treat RCC subgroups.

Prostate Cancer Research

PROfound Brings Precision Medicine to Prostate Cancer

Treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) were already expanded earlier this year with the FDA approval of olaparib (Lynparza). The approval was based on data from the phase 2 PROfound study (NCT02987543) of olaparib in patients with mCRPC and homologous recombinant repair (HRR) gene alterations whose disease had progressed on prior treatment with new hormonal treatments.1

Results of the final analysis were reported at ESMO showed a significant improvement in overall survival (OS) with olaparib compared with either enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in cohort A, which included patients with BRCA1, BRCA2, and/or ATM alterations.

The OS observed with olaparib in the study was 19.1 months compared with 14.7 months with enzalutamide/abiraterone (HR, 0.69; 95% CI, 0.50-0.97; P = .0175). An OS benefit was also observed in cohort B, which included patients with alterations in 12 other HRR genes aside from BRCA1/2 and ATM, of 14.1 months in the olaparib arm versus 11.5 months in the control arm, but the difference was not statistically significant (HR, 0.96; 95% CI, 0.63-1.49). The overall OS result was 17.3 months with olaparib treatment versus 14.0 months with enzalutamide or abiraterone (HR, 0.79; 95% CI, 0.61-1.03). This finding was not statistically significant in the overall study population.

Joaquin Mateo, MD, a principal investigator for the Prostate Cancer Translational Research Group at Vall d’Hebron Institute of Oncology and medical oncologist and attending physician in the Medical Oncology Department at Vall d’Hebron University Hospital in Spain, who presented these data at ESMO, explained that PROfound is the first clinical trial to show an OS improvement with olaparib in a molecularly defined subset of patients with prostate cancer.

Another PROfound study investigator, Maha Hussain, MD, the Genevieve E. Teuton Professor of Medicine at Northwestern Medicine Feinberg School of Medicine, further explained the value of molecularly defined disease management during an interview with Targeted Oncology, stating, “I think we have reached a major benchmark in the management of this disease. Ever since the original observations on androgen deprivation in prostate cancer and subsequent treatments when I entered the field in the 1990s, prostate cancer treatment has been more of a one-size-fits-all approach. On fact, when we give chemotherapy, we don’t preselect and when we give hormone treatment, we don’t preselect. I think what is exciting about this particular trial is that it showed the feasibility of personalizing care by using precision medicine strategies to preselect patients, so that we could maximize the chance of benefit.”

PROSPER Delays Metastasis With Enzalutamide in nmCRPC

Hussain was also a key investigator in the phase 3 PROSPER clinical trial (NCT02003924), which evaluated the safety and efficacy of enzalutamide as treatment of male patients with nonmetastatic CRPC (nmCRPC).

The overall result of the PROSPER study was that in patients whose PSA levels were quickly rising, responses to enzalutamide led to a longer metastasis-free survival (MFS) compared with placebo, according to a poster Hussain presented.2

The Kaplan-Meier plot demonstrated a median MFS of 36.8 months with enzalutamide compared with only 7.7 months in the placebo arm (HR, 0.12; 95% CI, 0.09-0.17; P <.0001) in patients with PSA decline of≥50% from baseline. In those who had a PSA decline from baseline of≥90%, the median MFS was not reached in the enzalutamide arm compared with 18.7 months in the placebo arm (HR, 0.26; 95% CI, 0.20-0.34; P <.0001).

It was noted that even though HRs were different in the 2 arms, there was no difference in risk reduction, considering that the 2 confidence intervals overlapped.

“The 2 things that I would point out here are that this is reassuring for patients that not brining the PSA down just because it’s the number, but this is actually a reflection on how their cancer is likely to behave, Hussain stated. “From a physician perspective, hopefully this is useful for monitoring patients and deciding who’s getting benefit, who’s not getting benefit, and when to do imaging.”

Hussain et al concluded from this analysis that PSA response could be a potential intermediate biomarker to help evaluate novel agents or combination regimens in men with nmCRPC.

Bladder Cancer Research

JAVELIN Bladder 100

In a subanaylsis of the phase 3 JAVELIN Bladder 100 trial (NCT02603432), the combination of frontline maintenance avelumab (Bavencio) and best supportive care (BSC) showed an OS and progression-free survival (PFS) benefit when compared with BSC alone in patients with advanced urothelial carcinoma.3

First, the presenter, Petros Grivas, MD, recapped the primary analysis data, which showed an OS of 21.4 months in the avelumab arm compared with 14.3 months in the BSC arm (HR, 0.69; 95% CI, 0.56-0.86).

In the 179 patients in the subanalysis who had a complete response (CR) to therapy, the median OS was not evaluable (95% CI, 20.8 to NE) with the addition of avelumab to BSC compared with not evaluable (95% CI, 18.5 to NE) in the BSC alone arm (HR, 0.81; 95% CI, 0.47-1.38).

The median PFS observed in this study was 7.4 months (95% CI, 4.3-16.5) in the avelumab/BSC arm versus 3.8 months (95% CI, 2.1-5.6) in the BSC alone arm (HR, 0.65; 95% CI, 0.45-0.96).

Overall, the subanalysis data from JAVELIN Bladder 100 supported the FDA approval of frontline avelumab maintenance and solidified its place in the National Comprehensive Cancer Network and ESMO guidelines.

As a key takeaway from this research, Grivas stated in an interview with Targeted Oncology, “I think if you start with chemotherapy in advanced urothelial cancer and your patient has stable disease after 4 to 6 chemotherapy cycles, consider avelumab as switch maintenance therapy.”

Renal Cell Carcinoma Research

CheckMate 214 Provides Treatment Option for Hard-to-Treat RCC Subgroup

When the immunotherapy combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) was administered as frontline treatment in patients with advanced renal cell carcinoma (RCC) who had not received a nephrectomy, it was discovered that a subset of patients who traditionally have a poor prognosis derived benefit. Four-year follow-up results from this study (CheckMate 214, NCT02231749) were presented in a poster from Laurence Albiges, MD, PhD, et al. In the study, nivolumab plus ipilimumab was compared with sunitinib (Sutent).4

The exploratory population consisted of patients with target kidney lesions, which included 53 patients in the nivolumab-plus-ipilimumab arm and 55 patients in the sunitinib arm. It was first explained that the combination of nivolumab and ipilimumab reduced the target lesion size by ≥30% in 35% of patients compared with 20% of the patients who were treated with sunitinib.

In terms of tumor responses, patients with target kidney lesions had an ORR of 34% (95% CI, 22%-48%) with nivolumab/ipilimumab versus 14.5% (95% CI, 7%-27%) with sunitinib.

In response to how these data have impacted her practice, Albiges, a medical oncologist in the Genitourinary group of the Department of Cancer Medicine at the Institute Gustave Roussy told Targeted Oncology in an interview that “these data are providing us long-term activity information. The doublet is being used in patients with low- and intermediate-risk [disease] in France, where I work. I think it’s important to understand that there’s a lot of translational and biomarker work that helped to define those patients that could derive benefit from this doublet.”

Aside from the population with target kidney lesions, the intention-to-treat population also responded to the doublet with an OS that was not reached (NR) in the doublet arm (95% CI, 46.7-NR) versus 38.4 months (95% CI, 32.0-45.0) in the sunitinib arm.

COSMIC-021 Reveals Promise for Cabozantinib Combination in ccRCC

Patients with advanced clear cell RCC treated with the frontline combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) in the phase 1b COSMIC-021 clinical trial (NCT03170960) demonstrated encouraging clinical activity.5

“COSMIC-021 is fundamentally based on the premise that VEGF-directed therapies considerably attack angiogenesis in the context of immune-based treatment. It has been nicely demonstrated with cabozantinib,” Sumanta Pal, MD, a medical oncologist at City of Hope, told Targeted Oncology in an interview. “COSMIC-021 is a great opportunity for us to interrogate the combination of cabozantinib and atezolizumab in patients with advanced kidney cancer.”

The ORR observed in the 34 patients who received cabozantinib 40 mg plus atezolizumab 1200 mg was 53% (80% CI, 41%-65%), and those who received cabozantinib 60 mg with atezolizumab 1200 mg had an ORR of 58% (80% CI, 46%-70%).

Among those who received the lower dose of cabozantinib, the best response was a CR observed in 1 patient. Fourteen patients in the low-dose cohort had a partial response (PR) and 2 patients had stable disease (SD). The disease control rate (DCR) in this cohort was 94%.

In the higher-dose cohort, CRs were observed in 4 patients, PRs in 17 patients, and SD in 7 patients. The DCR was 92%.

It was also noted during the data presentation that patients had reduction in their tumor size from baseline, specifically in those who had positive PD-L1 and CD8 expression. Eighty-six percent of patients with positive PD-L1 expression and high CD8 expression had a CR or PR compared with 31% with low/negative expression (P = .0003).

Both dose levels of cabozantinib were well tolerated by the study population, as was atezolizumab.

References:

1. De Bono JS, Mateo J, Fizazi K, et al. Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 6100.

2. Grivas P, Park sH, Voog E, et al. Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone with 1L chemotherapy (CTx) for advanced urothelial carcinoma (UC): Subgroup analyses from JAVELIN Bladder 100. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 704MO

3. Hussain M, Sternberg CN, Efstathiou E, et al. A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC): Outcomes by prostate-specific antigen (PSA) response. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 685P.

4. Albiges L, Tannir NM, Buroto M, et al. Nivolumab + ipilimumab (N+I) vs sunitinib (S) for first-line treatment of advanced renal cell carcinoma (aRCC) in CheckMate 214: 4-year follow-up and subgroup analysis of patients (pts) without nephrectomy. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 711P.

5. Pal K, Tsao CK, Suarez C, et al. Cabozantinib (C) in combination with atezolizumab (A) as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from the COSMIC-021 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 702O.