Cassia Griswold, PharmD
Clinical Oncology Pharmacist
Huntsman Cancer Institute
Salt Lake City, UT

The 2019 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium took place February 14–16 in San Francisco, CA—with a focus on recent advancements in various genitourinary malignancies. Incorporation of immunotherapy was the predominant theme of the conference, which included a keynote address by internationally recognized immunotherapy expert James L. Gulley, chief of the genitourinary malignancies branch of the National Cancer Institute. Attention was also given to the cost-effectiveness of prostate cancer therapies, particularly in the metastatic castration-sensitive setting, with a provocative presentation by Ronald Chen.

The Era of Immunotherapy

Data for the phase 2 CheckMate 650 trial of nivolumab (NIVO) 1 mg/kg plus ipilimumab (IPI) 3 mg/kg in metastatic castration-refractory prostate cancer (mCRPC) were presented by Padamee Sharma.¹ Response rates were modest (26% in the treatment-naive population and 10% in patients previously treated with docetaxel); however, durable responses were noted in a small subset of each treatment arm. Of interest, higher rates of treatment-related adverse events (TRAEs) were noted in the prostate cancer group than in previously reported studies of NIVO/IPI in renal cell cancer and melanoma populations. Future studies are planned to evaluate alternate doses and administration schedules.

The results of two trials combining axitinib with immunotherapy in treating metastatic renal cell cancer (mRCC), KEYNOTE 426 and JAVELIN Renal 101, were the major highlights in renal cell cancer treatment this year. Thomas Powles presented the first interim analysis of KEYNOTE 426, a phase Ib trial of first-line treatment with axitinib (AXI) plus pembrolizumab (PEMBRO) compared to sunitinib in mRCC.² AXI/PEMBRO resulted in higher treatment response rates (59.3% vs. 35.7%) and longer overall survival (OS) at 12 months and 18 months (hazard ratio [HR] 0.53, p < .0001). Subgroup analysis showed benefit across all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups.³ Of significance is the higher-than-expected incidence of grade 3/4 liver function test elevations in the AXI/PEMBRO arm, which warrant close monitoring, particularly in the first 3-4 months of therapy. Toni Choueiri presented a subgroup analysis of JAVELIN Renal 101, the phase 3 trial of AXI plus avelumab compared to sunitinib in treating advanced RCC.⁴ Overall efficacy data were previously presented at the 2018 European Society for Medical Oncology (ESMO) Congress.⁵ New analysis of several subgroups including IMDC risk, smoking status, and body mass index (BMI) consistently demonstrated the superiority of AXI/avelumab across subgroups with regard to progression-free survival (PFS). However, the PD-L1-negative group failed to demonstrate significant improvements in PFS. Notably, fewer patients in the AXI plus avelumab group required next-line therapy during the study period (22.6% vs. 40.5%).

Updates in Prostate Cancer Therapy

The world of prostate cancer treatment has changed significantly over the past few years, with treatments now targeting specific patient populations, including nonmetastatic castration-refractory prostate cancer (nmCRPC or M0 CRPC) and metastatic castration-sensitive prostate cancer (mCSPC). On the basis of these data, the U.S. Food and Drug Administration (FDA) has recently recognized a novel endpoint: metastasis-free survival (MFS).

In the first report of the phase 3 ARAMIS trial of darolutamide in nmCRPC, significantly longer MFS was noted with the addition of darolutamide compared to androgen deprivation therapy (ADT) alone (40.4 months vs. 18.4 months, HR 0.41, p < .0001).⁶ An OS benefit was also noted (83% vs. 73% at 3 years), though survival data are not yet mature. Of note, 69% of patients treated had a prostate-specific antigen (PSA) doubling time of 6 months or less, representing more aggressive disease. Darolutamide is structurally dissimilar to both enzalutamide and apalutamide, the two other drugs studied in nmCRPC, and does not cross the blood-brain barrier. This therapy is expected to result in less fatigue and other central nervous system–altering effects than therapy with the aforementioned agents. Remarkably, discontinuation of darolutamide because of TRAEs was similar between treatment and placebo arms (incidence ~9%).

Andrew Armstrong presented an interim analysis of the ARCHES trial, comparing enzalutamide to placebo in patients with mCSPC.⁷ Treatment with enzalutamide improved radiographic PFS at 12 months (84% vs. 64%, HR 0.39, p < .0001). Notably, PFS benefit was maintained in a subgroup analysis of higher-risk groups, including high-volume disease, prior treatment with docetaxel, and presence of soft-tissue metastases. Enzalutamide also increased time to PSA progression and time to next line of therapy.

Final data from the LATITUDE trial, comparing abiraterone acetate (AA) plus ADT to ADT plus placebo in patients with mCSPC, were presented.⁸ Median OS was significantly longer with the addition of AA (53.3 months vs. 36.5 months, HR 0.66, p < .0001). Of importance, the majority of the OS benefit was seen in patients with high-volume disease; no statistical difference in survival was seen in the low-volume group.

Novel Therapy for Metastatic Urothelial Carcinoma

Scott Tagawa presented data from a phase 1/2 multicenter single-arm trial of sacituzumab govitecan (IMMU-132) in previously treated metastatic urothelial carcinoma (mUC).⁹ Sacituzumab govitecan is an antibody drug conjugate directed at Trop-2, an epithelial cell surface marker overexpressed in UC. A humanized anti-Trop-2 antibody is bound to SN-38, the active metabolite of irinotecan, through a hydrolyzable linker that results in drug release both intracellularly and in the tumor microenvironment. Tagawa reported an overall response rate of 31.1%, with comparable rates seen across high-risk subgroups, including patients with liver metastases (33.3%) and those previously treated with checkpoint inhibitors (23.5%, 71% had 3 or more prior lines of therapy). Median OS was 16.3 months, with a median duration of response of 12.9 months. The most common TRAEs were diarrhea, nausea, and neutropenia (all grades: 69%, 67%, and 51%, respectively). Primary grade 3/4 TRAEs were anemia and neutropenia, with 24% of patients requiring granulocyte colony-stimulating factor (GCSF). Incidence of febrile neutropenia was 7%. Approximately 11% of patients on the trial discontinued therapy for TRAEs. Therapy options in mUC after progression through platinum-based chemotherapy and immunotherapy are limited, making novel treatment options like IMMU-132 of particular interest.

The 2020 ASCO GU Cancers Symposium will be held February 13-15 in San Francisco, CA. For more information on the symposium, visit www.asco.org.

References

1. Sharma P, Pachynski RK, Narayan V, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). J Clin Oncol. 2019;37(suppl; abstr 142).
2. Powles T, Plimack ER, Stus V, et al. Pembrolizumab (PEMBRO) plus axitinib (AXI) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(suppl; abstr 543).
3. Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-148.
4. Choueiri TK, Motzer RJ, Campbell MT, et al. Subgroup analysis from JAVELIN Renal 101: outcomes for avelumab plus axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). J Clin Oncol. 2019;37(suppl; abstr 544).
5. Motzer RJ, Penkov K, Haanen J, et al. JAVELIN Renal 101: a randomized, phase 3 study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Ann Oncol. 2018;29:LBA6.
6. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl; abstr 140).
7. Armstrong, AJ, Szmulewitz RZ, Petrylak DP, et al. Phase 3 study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. J Clin Oncol. 2019;37(suppl; abstr 687).
8. Fizazi K, Tran N, Rein LE, et al. Final analysis of phase III LATITUDE study in patients (pts) with newly diagnosed high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC) treated with abiraterone acetate + prednisone (AA+P) added to androgen deprivation therapy (ADT). J Clin Oncol. 2019;37(suppl; abstr 141).
9. Tagawa, ST, Faltas BM, Lam ET, et al. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): results from a phase I/II study. J Clin Oncol. 2019;37(suppl; abstr 354).