Rini Reviews Key ASCO 2020 Highlights in Genitourinary Cancers

As part of the 2020 ASCO Direct Highlights^™ webcast, a program developed by Physicians’ Education Resource^® (PER^®), LLC., Brian Rini, chief of clinical trials at Vanderbilt-Ingram Cancer Center and professor of medicine within the Division of Hematology/Oncology at Vanderbilt University Medical Center, led a discussion on some of key developments in genitourinary cancers that were presented during the 2020 ASCO Virtual Scientific Program.

Maintenance and Adjuvant Approaches in Bladder Cancer

The phase 3 JAVELIN Bladder 100 trial (NCT02603432) compared the efficacy of maintenance avelumab (Bavencio) in combination with best supportive care (BSC; n = 350) versus BSC alone (n = 350) in 700 patients with unresectable locally advanced or metastatic urothelial carcinoma whose disease did not progress on 4 to 6 cycles of standard gemcitabine combined with either cisplatin or carboplatin.

The trial met its primary end point by demonstrating a significant improvement in overall survival (OS) with frontline avelumab maintenance in both the overall population and the PD-L1–positive population. Results presented during the meeting showed that those who received avelumab plus BSC had an OS of 71% at 12 months and 61% at 18 months compared with 58% and 44%, respectively, in those who received BSC. The median OS was 21.4 months versus 14.3 months with BSC alone (HR, 0.69; 95% CI, 0.56-0.86; P < 0.001).¹The OS was also longer with the addition of avelumab across all prespecified subgroups.

“[This is] a very notable improvement and [it could be] the first time that a median survival above 20 months—even above 16 or 18 months—has ever been recorded in bladder cancer,” Rini said. “These data are striking and standard-of care-changing results.”

Investigators also saw an improvement in median progression-free survival (PFS) with the addition of the PD-L1 inhibitor. Specifically, the median PFS via independent radiology review in the overall population was 3.7 months in the avelumab arm versus 2 months in the BSC arm (HR, 0.62; 95% CI, 0.52-0.75; P <.001).

“The bladder cancer community was pleasantly surprised by these results,” Rini said. “Some of the other [efforts to combine] chemotherapy with immunotherapy [in this space]…have not been as strikingly positive. The integration of immuno-oncology in bladder cancer is ever-evolving and it’s going to be trickier than it has been for other diseases.”

Data from this trial led to the recent June 2020 FDA approval of avelumab for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-based chemotherapy.

Less positive were the results reported from the phase 3 IMvigor010 study (NCT02450331), which evaluated adjuvant atezolizumab (Tecentriq) versus observation in high-risk, muscle-invasive urothelial carcinoma (MIUC).

In order to be eligible for enrollment, patients with high-risk MIUC needed to have undergone radical cystectomy or nephroureterectomy with lymph node dissection within 14 weeks or less. For the trial, patients were randomized 1:1 to receive either 16 cycles of atezolizumab at 1200 mg every 3 weeks or observation only.

The trial did not meet its primary end point of disease-free survival (DFS) with the agent in the general population, nor in the prespecified subgroups.² Within the intent-to-treat (ITT) population, a median DFS of 19.4 months was reported in the atezolizumab arm versus 16.6 months in the observation arm. The 18-month DFS rate was 51% in the atezolizumab arm versus 49% in the observation-only arm (HR, 0.89; 95% CI, 0.74-1.08; P = .02446).

Although atezolizumab showcased a safety profile that proved to be consistent with what has been observed in previous studies in the advanced setting, higher frequencies of grade 1 or 2 adverse events of special interest were reported, along with treatment discontinuation because of events.

“The approach] was certainly safe but did [the trial] not meet its primary end point of DFS, either in the ITT or prespecified subgroups,” said Rini. “The OS follow-up is ongoing and other trials are examining other agents in this setting. However, [these are] somewhat disappointing initial result[s] as the first study to explore adjuvant immunotherapy in high-risk bladder cancer.”

First-Line Combination Therapy in Renal Cell Carcinoma

Rini also discussed updated data from the phase 3 KEYNOTE-426 trial (NCT02853331), which showed that pembrolizumab (Keytruda) in combination with axitinib (Inlyta) continued to demonstrate a clinically significant improvement in efficacy compared with standard-of-care sunitinib (Sutent) in untreated, advanced renal cell carcinoma (RCC).³

In order to be considered for the KEYNOTE-426 trial, patients needed to have had newly diagnosed or recurrent stage IV clear cell RCC, have received no prior systemic treatment for advanced disease, and had measurable disease per RECIST v1.1 criteria. A total of 861 patients were randomized 1:1 to receive either 200 mg of intravenous pembrolizumab every 3 weeks for up to 35 treatment cycles plus oral axitinib at 5 mg twice daily (n = 432) or 50 mg of oral sunitinib once daily for the first 4 weeks of each 6-week cycle (n = 429).

In the ITT population, the combination had an OS rate of 90% versus 79% with sunitinib at 12 months and 74% versus 66%, respectively, at 24 months (HR, 0.68; 95% CI, 0.55-0.85; P <.001). The combination also led to a PFS rate of 60% at 12 months versus 48% with sunitinib and 38% versus 27%, respectively, at 24 months.

“Most patients will experience some stability or tumor shrinkage while on the [pembrolizumab/axitinib] regimen,” noted Rini. “In fact, most patients will have an objective response.” The confirmed objective response rate (ORR) was 60.2% in the pembrolizumab/axitinib arm and 39.9% in the sunitinib arm (P <.0001).

“Approximately 70% of patients who discontinued sunitinib received subsequent therapy,” Rini added, “and [roughly] 50% of those patients received subsequent immunotherapy therapy; this really lends evidence that early immunotherapy and doublet [regimens] in kidney cancer is important.”

Another study that evaluated another novel immunotherapy combination in advanced RCC was the phase 2 HCRN GU16-260 trial, which looked at nivolumab (Opdivo) and salvage nivolumab plus ipilimumab (Yervoy) in treatment-naïve patients. While immunotherapy-based doublets such as nivolumab plus ipilimumab are commonly used in the treatment of patients with RCC, monotherapies still remain largely unexplored in the space, according to Rini.

"Doublets have toxicities, especially when you [incorporate an agent] like ipilimumab,” Rini said. “Studies are now looking at treating patients with previously untreated kidney cancer with immune monotherapy, largely nivolumab. [Investigators] found that, if [nivolumab is given] alone, and [patients] progress [on treatment] or have a lack of response, then they can add on ipilimumab.”

Patients who were given nivolumab monotherapy experienced an ORR of 31.7%, which Rini noted as being “quite high” for this untested monotherapy.⁴

The first part of the trial treated patients with a nivolumab monotherapy, which would continue if patients responded. Patients who were stable or didn’t respond to the treatment were then treated with nivolumab plus ipilimumab. Investigators found that hardly any patients were able to be salvaged through the doublet regimen. Ipilimumab/nivolumab led to an ORR of 13.3% with no complete responses (CR).

This is concurrent with other prior studies, which primarily saw ORR rates for nivolumab plus ipilimumab within the range of 4% and 20% (HCRN GU16-260 = 13%; OMNIVORE = 4%; FRACTION = 15%; TITAN RRC = 12%; Salvage Ipi/Nivo = 20%). CR rates were similar across the trials, with nearly every study seeing a rate of 0%; the TITAN RRC trial was the sole exception (3%).

“Patients generally need to receive combination therapy up front for maximal CR and benefit,” said Rini. “Unfortunately, pending biomarker work, we can’t get away with using monotherapy in most patients.”

Antiandrogens and PSMA-Based PET Scans in Nonmetastatic Prostate Cancer

In the prostate cancer space, the pivotal phase 3 ARAMIS trial (NCT02200614) evaluated darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) versus placebo plus ADT in nonmetastatic castration-resistant prostate cancer (CRPC).

In order to be eligible for enrollment, patients needed a nmCRPC diagnosis along with a prostate-specific antigen (PSA) doubling time of 10 months or less. A total of 1509 patients were randomized 2:1 to receive either the darolutamide at 600 mg twice daily plus ADT (n = 955) or placebo twice daily plus ADR (n = 554). The primary end point of the trial was met at the primary analysis of the trial, showing a median MFS of 40.4 months in the darolutamide arm versus 18.4 months with placebo.⁵

Survival results presented during the 2020 ASCO Virtual Scientific Program showed that the addition of darolutamide significantly improved OS compared with placebo, leading to a 31% reduction in risk of death (HR, 0.69; 95% CI, 0.53-0.88; P =.003).⁶ Notably, the survival benefit with the agent was evident even though many patients in the placebo group received subsequent life-prolonging therapy.

Additionally, all secondary end points also favored the darolutamide arm, including time to pain progression (median 40.3 months vs 25.4 months with placebo), time to first cytotoxic chemotherapy, and time to first skeletal-related event.

The PROSPER study (NCT02003924) had a very similar design to that of ARAMIS in that it focused on evaluating a novel agent plus ADT versus placebo/ADT in patients with nmCRPC and a PSA doubling time of 10 months or less. Specifically, patients were randomized 2:1 to receive either 160 mg of enzalutamide (Xtandi; n = 933) daily plus ADT or placebo/ADT (n = 468). Notably, there was also an optional open-label extension that crossed patients over from the placebo arm to receive enzalutamide.

Much like what had been seen with darolutamide, results showed that the addition of enzalutamide also led a significant reduction in risk of death of 27%.⁷ The median OS with enzalutamide plus ADT was 67 months versus 56.3 months with placebo/ADT (HR, 0.73; 95% CI, 0.61-0.89; P = .001).

The briefly mentioned SPARTAN study (NCT01946204), once again, was similar to the previously mentioned studies in terms of both patient eligibility and design. The trial compared the efficacy of apalutamide (Erleada) plus ADT with placebo/ADT and found that the agent significantly delayed the development of metastases. Not only that, but the trial was able to validate MFS as a primary end point, according to Rini. The final data from the trial were also presented at the meeting and showed a significantly longer median OS of 73.9 months in the apalutamide arm versus 59.9 months in the placebo/ADT arm.⁸

Finally, in the CONDOR study (NCT3739684), investigators analyzed the impact of 18F-DCFPyL-PET/CT, or micro radiotracers, on the clinical management of patients with biochemically recurrent prostate cancer. Prostate-specific membrane antigen (PSMA)–based imaging has shown great potential thus far within the space, according to Rini.

“If [a patient] has a rapidly rising PSA following prostatectomy, depending on the circumstance, standard imaging would be a CT of the abdomen and pelvis, and a bone scan,” Rini said. “In prostate cancer, we’ve always realized the clinical limitations of those scans. This disease has not been very easy to image with these conventional [modalities], hence these novel agents.”

In order to be considered for the trial, patients needed to have a rising PSA following therapy (Post-RP: ≥0.2 ng/mL; Post-RT: ≥2 ng/mL). Patients who had negative standard imaging were then able to receive the PSMA-based PET scan. From there, after reviewing questionnaires that were filled out by the attending clinicians, investigators determined whether a change in intervention was reported.

Results showed that 65.9% of the patients enrolled on the trial who had previously received negative results from standard imaging had positive results following the PSMA-based PET scan. It was also found to have a correct localization rate of 85.6% from reader 1, 87.0% from reader 2, and 84.8% from reader 3. Based on these data, this type of imaging proved to be reliable among the 3 reviewers who tested it, said Rini. Following the results of these scans, 63.9% of evaluable patients had a change in intended care.

“A fair number of patients went from being relegated to noncurative systemic therapy (ie hormone therapy) to salvage local therapy, which is potentially curative,” said Rini. “[If] the scan can provide us with the confidence to pursue potentially curative therapy, there is obviously great value in this [type of imaging].”

This modality has a long way to go, but according to Rini, PSMA is the best type of imaging within the space; however, integrating this modality into clinical practice remains a challenge.

References

1. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive case vs BSC alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma: JAVELIN Bladder 100 phase III results. J Clin Oncol. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1
2. Hussain MHA, Powles T, Albers P, et al. IMvigor010: primary analysis from a phase III randomized study of adjuvant atezolizumab vs observation in high-risk muscle-invasive urothelial carcinoma. J Clin Oncol. 2020;38(suppl 15):5000. doi:10.1200/JCO.2020.38.15_suppl.5000
3. Plimack ER, Rini BI, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma: updated analysis of KEYNOTE-426. J Clin Oncol. 2020;38(suppl 15):5001. doi:10.1200/JCO.2020.38.15_suppl.5001
4. Atkins MB, Jegede OA, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients with advanced renal cell carcinoma (HCRN GU16-260). J Clin Oncol. 2020;38(suppl 15):5006. doi:10.1200/JCO.2020.38.15_suppl.5006
5. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671
6. Fizazi K, Shore ND, Tammela T, et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;36(suppl 15):5514. doi:10.1200/JCO.2020.38.15_suppl.5514
7. Sternberg CN, Fizazi K, Saad F, et al. Final overall survival (OS) from PROSPER: a phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl 15):5515. doi:10.1200/JCO.2020.38.15_suppl.5515
8. Small EJ, Saad F, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516
9. Morris MJ, Carroll PR, Saperstein L, et al. Impact of PSMA-targeted imaging with 18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent prostate cancer: results from a phase III, prospective, multicenter study (CONDOR). J Clin Oncol. 2020;38(suppl 15):5501. doi:10.1200/JCO.2020.38.15_suppl.5501