Update in systemic therapy of urologic malignancies.

C L I N I C A L F O C U S : C A R D I O V A S C U L A R E V E N T S , U R O L O G Y, F O R T H E P R I M A RY C A R E D O C T O R

Update in Systemic Therapy of Urologic Malignancies

Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 05/12/15 For personal use only.

DOI: 10.3810/pgm.2014.01.2724

David Mooney, MD 1 Ravikumar Paluri, MD, MPH 1 Amitkumar Mehta, MD 1 Jatinder Goyal, MD 1 Guru Sonpavde, MD 1 University of Alabama, Birmingham (UAB) Comprehensive Cancer Center, Birmingham, AL 1

Abstract: Systemic therapy of advanced prostate and renal cancers has gained several recent additions to the therapeutic armamentarium. Treatment of patients with castration-resistant prostate cancer now includes additional immunotherapy (sipuleucel-T), chemotherapy (cabazitaxel), androgen-signaling inhibitors (abiraterone acetate, enzalutamide), and a radiopharmaceutical (alpharadin), based on extension of patient survival. Similarly, therapy for patients with renal cell carcinoma, a chemoresistant malignancy, has undergone dramatic changes based on an understanding of the role of angiogenesis. Multiple vascular endothelial growth factor inhibitors (sorafenib, sunitinib, pazopanib, axitinib, bevacizumab) and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) have been added to the therapeutic arsenal. Additionally, immunotherapy retains an important treatment role, with a continuing application of high-dose interleukin-2 in select patients and the emergence of novel immunotherapeutic agents that may have significant benefit. Other major urologic malignancies, including urothelial, testicular, and penile cancers, have witnessed relatively few or no recent advances in therapy, although testicular germ cell tumors are one of the most curable malignancies. An agent for treatment of advanced urothelial cancer now has commercial approval, the chemotherapeutic agent, vinflunine, as second-line therapy in multiple countries—but not in the United States. Our review summarizes and updates the field of systemic therapy for advanced urologic malignancies, with a focus on castration-resistant prostate cancer and renal cell carcinoma. Keywords: systemic therapy; prostate cancer; renal cell carcinoma; urothelial cancer; immunotherapy; anti-androgen therapy

Introduction

Correspondence: Guru Sonpavde, MD, Associate Professor of Medicine, University of Alabama at Birmingham (UAB) Cancer Center, 1824 6th Ave S, WTI-520A, Birmingham, AL 35294. Tel: 205-975-3742 Fax: 205-934-9511 E-mail: [email protected]

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Systemic therapy of advanced prostate cancer and renal cell carcinoma (RCC) has gained multiple recent additions to the therapeutic armamentarium. In the case of castration-resistant prostate cancer (CRPC), such changes stem from a better understanding of the role of the immune system and the androgen-signaling pathway. In the setting of RCC, an appreciation of the function of proangiogenic molecules in promoting growth of the malignancy has led to dramatic changes in the therapeutic landscape. In contrast, few or no systemic therapy advances have occurred in the context of advanced urothelial cancer, which may be attributable to the relatively poor understanding of the molecular biology of the disease. Our review briefly describes and updates the field of systemic therapy for advanced urologic malignancies, with a focus on CRPC and RCC.

Castration-Resistant Prostate Cancer Therapy Until 2010

Castration-resistant prostate cancer is defined as disease progression despite castrate testosterone levels , 50 ng/dL. Until 2010, commercially approved treatments

© Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.



for patients with metastatic CRPC (mCRPC) were the chemotherapeutic agents, mitoxantrone and docetaxel. Mitoxantrone is an anthraquinone, an anthracycline analog that inhibits DNA replication by inhibiting topoisomerase-2. In 2 randomized trials reported in the late 1990s comparing prednisone with or without mitoxantrone,1,2 patients receiving mitoxantrone had a statistically significant palliative benefit in pain or quality of life (QoL) compared with patients who only received prednisone. However, there was no overall survival (OS) advantage with mitoxantrone therapy compared with placebo. Doctetaxel is a taxane-derived chemotherapy that stabilizes microtubule assembly and inhibits mitosis. In randomized trials reported in 2004,3–5 compared with mitoxantrone, docetaxel yielded a statistically significant but modest median (18.9 vs 16.5 months) and 3-year (18.6% vs 13.5%) OS advantage (doctetaxel vs mitoxantrone, respectively). Additionally, advantages were also observed with docetaxel for prostate specific antigen (PSA) response, pain response, and QoL.3 Thus, docetaxel was the first therapy to demonstrate an OS benefit and is still considered the frontline systemic chemotherapy agent of choice for treatment of patients with mCRPC.

Advances in the Understanding of the Molecular Biology of CRPC

There has been a growing understanding that progressive prostate cancer following androgen-deprivation therapy does not become androgen independent; instead, it is accepted that the androgen-signaling axis still plays a significant role, which has led to a shift in defining prostate cancer as castration-resistant rather than androgen independent. Indeed, in treatment trials of patients with CRPC, patients are required to have undergone a prior orchiectomy or continue to receive a gonadotropin-releasing-hormone analog.1,3 Castration-resistant prostate cancer is often associated with increased tumor levels of androgens (partly from cytochrome P [CYP]17 upregulation, leading to autocrine signaling), androgen receptors (AR), and mutant ARs, which may be constitutively active even in the absence of androgens.6–9 The androgen pathway appears to interact with other pathways, such as the Src kinase, c-MET, epidermal growth factor, Ras-Raf kinase, PI3 K-Akt, fibroblast growth factor, and insulin-like growth factor pathways.8,10 Loss of tumor-suppressor genes p53 and PTEN, has been identified, which may drive multiple signaling pathways. The tumor microenvironment, especially those molecules promoting angiogenesis and inhibiting the immune system, also appear to play tumorigenic roles.

Advances in Systemic Therapy for CRPC Since 2010 Cabazitaxel Chemotherapy

Cabazitaxel is a semisynthetic taxane-derived chemotherapeutic drug targeting microtubules. It was designed to have antitumor activity in cancer cells resistant to paclitaxel and docetaxel by having a lower affinity for the drug efflux pump known to be partly responsible for taxane-resistant tumors.11 Cabazitaxel was evaluated in the second-line setting of patients who had previously received docetaxel therapy but experienced disease progression. Patients were randomized to receive cabazitaxel and prednisone or mitoxantrone and prednisone. Those receiving cabazitaxel had statistically significantly longer median OS (15.1 months) compared with patients receiving mitoxantrone monotherapy (12.7 months).12 In June 2010, cabazitaxel was approved by the US Food and Drug Administration (FDA) for the treatment of patients with CPRC who had previously failed a treatment regimen containing docetaxel (Table 1).

Abiraterone Acetate Androgen-based pathways continue to have a clinically important role in the progression of CRPC, therefore, new drugs have been developed that target androgen-signaling apart from standard castration treatments. The newer agents include drugs that act by inhibiting enzymes (including CYP17) that produce androgens and drugs that inhibit the ARs.6 Abiraterone acetate (AA) is an oral, irreversible, selective inhibitor of CYP17 that is capable of significantly reducing androgen production in the tumor, as well as in the testes and adrenal glands.13 The feedback loop leads to mineralocorticoid excess, which has been generally abrogated by low-dose corticosteroids. Two phase III trials have established AA as an effective treatment in men with mCRPC.14,15 In 1 randomized controlled trial of patients who had previously received docetaxel, patients who received AA and prednisone displayed significantly better median OS than those in the placebo-prednisone group (14.8 months vs 10.9 months, respectively). All secondary endpoints, including time to PSA progression, progression-free survival (PFS), and PSA response rates also favored the AA-plusprednisone-treatment group.14 Abiraterone acetate was fairly well tolerated with mineralocorticoid-excess-related adverse events. Fluid retention, hypertension, and hypokalemia were the most common but manageable adverse effects. The AA trial14 led to FDA drug approval in April 2011, indicated for patients with mCRPC who had previously failed docetaxel chemotherapy (Table 1).

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Mooney et al


Table 1. Systemic Agents Demonstrated to Extend Survival in Patients With mCRPC Treatment

Mechanism

Route of Administration

Frequency

Indication

Median Overall Survival Benefit (mo)

Sipuleucel-T

IV

Every 2 weeks x 3

Minimally symptomatic or asymptomatic

4.122

Docetaxel Abiraterone

Autologous antigen presenting cell-based immunotherapy targeting prostate cancer antigen Microtubule inhibitor Androgen-synthesis inhibitor

IV PO

Every 3 weeks Daily

Any time Post-docetaxel Pre-docetaxel

Enzalutamide

Androgen-receptor antagonist

PO

Daily

Cabazitaxel Radium-223

Microtubule inhibitor Alpha particle emitting calciummimetic radiopharmaceutical

IV IV

Every 3 weeks Every 4 weeks

Post-docetaxel Pre-docetaxel Post-docetaxel Post-docetaxel or docetaxelineligible with symptomatic bone metastases

2.43 3.914 PFS benefit, strong trend for OS benefit15 4.817 Extended survival18 2.411 2.825

Abbreviations: IV, intravenous; mCRCP, metastatic castration-resistant prostate cancer; OS, overall survival; PFS, progression-free survival; PO, orally.

Treatment with AA plus prednisone subsequently demon strated significant improvement in radiographic PFS (PFS not reached vs 8.3 months; HR 0.43; P , 0.001); and a trend toward improved survival (OS not reached vs 27.2 months; HR 0.75; P = 0.0097) compared with placebo plus prednisone in chemo-naïve patients with mCRPC. These data from the COU-AA-302 phase III trial resulted in recent FDA approval of AA prior to a docetaxel-based chemotherapy regimen.15 The trial excluded patients with moderate-to-severe cancer pain or opiate use for cancer pain.

Enzalutamide Enzalutamide is another androgen-pathway-targeting agent that binds with high affinity to the androgen-ligand-binding domain of the AR and inhibits nuclear translocation of the receptor.16 Thus, AR, a transcription factor, is unable to promote transcription of multiple genes that promote tumor growth. Enzalutamide was tested in a phase III, randomized, placebo-controlled trial in patients with mCRPC who had progressed after docetaxel chemotherapy.17 Enzalutamide exhibited a median OS advantage (18.4 months vs 13.6 months) compared with placebo. Furthermore, enzalutamide demonstrated high response rates, time to PSA progression, and radiographic PFS.17 The most common adverse events were fatigue, diarrhea, and hot flashes, and a small increase in risk of seizures. On the basis of the study results, the FDA approved enzalutamide in August 2012 for use in patients with progressive mCRPC following a docetaxelbased chemotherapy regimen (Table 1). A phase III trial evaluating enzalutamide in the pre-chemotherapy setting was recently reported in a media release18 to significantly improve both OS (HR 0.7; P , 0.001) and radiographic PFS (HR 0.19; P , 0.001).6 46

Sipuleucel-T Prostate cancer cells express multiple prostate-organ and/or tumor-specific antigens, such as prostatic acid phosphatase (PAP), PSA, and prostate-specific membrane antigen (PSMA). Several approaches have been investigated to identify whether the patient’s own immune system can be harnessed to provide an immune-mediated destruction of tumor cells. Sipuleucel-T is an immunotherapy product designed to stimulate T-cell immunity to PAP. Patients have antigen-presenting cells, mostly dendritic cell precursors, harvested from peripheral blood by leukapheresis. The antigen-presenting cells are then washed and incubated with the appropriate target antigen, PA2024, which consists of PAP fused to human granulocyte macrophage colony-stimulating factor (GM-CSF).19 The activated cells are then infused back into the patients 2 to 3 days later. The infusions are repeated approximately every 2 weeks for a total of 3 treatments. Multiple trials have looked at the efficacy of sipuleucel-T.20–22 In the first randomized trial, patients with mCRPC were randomized to sipuleucel-T or placebo. Of note, patients with visceral metastases or cancer-related bone pain were excluded from study. The primary endpoint of time-to-progression benefit was not achieved, but there was a suggestion for improvement in OS.20,21 The follow-up Identification of Men With a Genetic Predisposition to Prostate Cancer (IMPACT) trial22 had a larger study population and was conducted with OS as the primary endpoint. Patients in IMPACT similarly had mCRPC that was either asymptomatic or minimally symptomatic. There was a statistically significant improvement in median OS (25.8 months vs 21.7 months) and 3-year OS (31.7% vs 23.0%) in the sipuleucel-T-treated group compared with placebo. Sipuleucel-T was generally well tolerated, with side effects mainly associated with infusion reaction, such



as chills, fever, nausea, and headache.22 Based on the study results, in April 2010, the FDA approved sipuleucel-T as a treatment option for patients with asymptomatic or minimally symptomatic men with mCRPC. Similar to previous trials, time to disease progression did not differ between study groups and changes in serum PSA levels were not often seen, which may have been due to delayed onset of antitumor responses, leading to extension of OS without early benefits.22


Radiopharmaceuticals Alpharadin is a calcium-mimetic radiopharmaceutical that accumulates in bones and emits alpha radiation from radium-223 decay, releasing relatively high energy with a narrow range (2 to 10 cells).23 Following promising results in a phase II trial,24 the phase III Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial was conducted in patients with mCRPC with symptomatic bone metastases who either had failed or were ineligible for docetaxel treatment.25 Patients received 6 doses of alpharadin 50 kBq/kg IV every 4 weeks. The trial revealed a significant 2.8-month median OS benefit with alpharadin treatment compared with the placebo arm (14 vs 11.2 months), which led to FDA approval of the agent.25 Moreover, trial data for the toxicity profile appeared excellent with grades 3–4 neutropenia in 1.8% of patients and thrombocytopenia in 4% of patients. Based on the data, alpharadin may replace the use of samarium and strontinum, both of which have demonstrated palliative benefits without an extension of patient survival.

Emerging Treatment Agents for mCRPC and Key Ongoing Trials

Many other novel agents of different classes are u ndergoing vigorous investigation. Ipilumimab, a lymphocytecheckpoint inhibitor, which is already approved for the treatment of patients with metastatic melanoma, is undergoing phase III investigation in both pre-chemotherapy and post-chemotherapy settings.26,27 Ipilumimab binds to cytotoxic T lymphocyte antigen-4 molecule (CTLA4) receptors on T cells, causing an augmented immune response of T cells to foreign antigens and self-antigens.26 The postdocetaxel phase III study demonstrated activity for ipilimumab in mCRPC, and although overall survival was not statistically significant, ipilimumab appeared most active in patients with lower disease burden (no visceral disease and favorable laboratory parameters).27 Hence, results from the pre-docetaxel trial are eagerly awaited. A poxvirus-based vaccine targeting PSA (Prostvac-VF) has shown promise

in phase II studies and is currently being evaluated in a phase III trial as well.28 Recently, cabozantinib, an orally bioavailable tyrosine kinase inhibitor (TKI) that targets MET and vascular endothelial growth factor (VEGF) receptor 2, demonstrated a reduction of soft-tissue lesions (72% at 12 weeks), improvement in PFS, and improved QoL markers. Further prospective phase III trial evaluation is ongoing to confirm efficacy.29 Tasquinimod, an oral quinoline-3-carboxamide derivative with both antiangiogenic and immunomodulatory properties, demonstrated an improvement in median PFS (7.6 vs 3.3 months) in a phase II trial30 that led to an ongoing placebo-controlled phase III trial in chemo-naïve patients. In general, targeted systemic agents used in combination with docetaxel have failed to demonstrate benefit, including bevacizumab, aflibercept, lenalidomide, GVAX allogeneiccell line-based vaccine, and calcitriol analog.6,31,32 Custirsen (OGX-011) is an anti-sense oligonucleotide that targets clusterin, a chaperone, stress-induced protein, which may be responsible for resistance to docetaxel. In a randomized phase II trial, weekly IV custirsen plus docetaxel extended patient median survival compared with docetaxel alone (23.8 vs 16.9 months).33 Based on such promising data, phase III trials are evaluating custirsen in combination with docetaxel or cabazitaxel.6 Additionally, other androgen-synthesis inhibitors (eg, TAK-70034) and AR inhibitors (eg, ARN-50935) are undergoing investigation. Unfortunately, TAK-700 did not extend patient survival in a post-docetaxel, placebocontrolled, phase III trial, although post-trial therapy may have confounded these results.36

Renal Cell Carcinoma Therapy Until 2005

The mainstay of systemic therapy for advanced clear cell RCC were the cytokines interferon (IFN)-α and high-dose interleukin (IL)-2.37–39 With IFN-α, a demonstrated extension of median OS of ∼1 year was seen in patients, whereas treatment with high-dose IL-2 yielded durable complete remissions and durable, long-term remission in ∼7% of selected patients. High-dose IL-2 is associated with significant acute toxicities due to capillary leak syndrome, including mortality in ∼3% of patients, pulmonary edema, hypotension, and cardiac arrhythmias; therefore, only select young patients without significant comorbidities should be offered treatment with high-dose IL-2. Two randomized controlled trials have demonstrated a survival benefit for cytoreductive nephrectomy (nephrectomy in the setting of metastatic disease) in patients receiving IFN-α.40


Mooney et al

In the context of IFN therapy, the following prognostic factors have been identified: low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and time from initial RCC diagnosis to start of IFN-α therapy of , 1 year.41 Those patients with 0 (favorable risk), 1–2 (intermediate risk), and $ 3 factors (poor risk) demonstrated a median OS of 30 months, 14 months, and 5 months, respectively.


Advances in Understanding the Role of Angiogenesis in Tumorigenesis of Clear Cell RCC

Somatic loss of the Von Hippel Lindau (VHL) tumor suppressor gene has been recognized to upregulate angiogene sis, mediated by amplified hypoxia inducible factor (HIF), a transcription factor that induces production of multiple proangiogenic molecules, including VEGF.42 Indeed, VHL, when altered at the germline level, engenders other angiogenic tumors in addition to RCC (such as retinal angiomas, cerebellar hemangioblastoma, and pheochromocytoma). In addition, a role for the Akt/mammalian target of rapamycin (mTOR) signaling pathway in the tumor cell has become recognized, which also promotes angiogenesis. The recognition of a role for MET signaling in papillary RCC has led to recent clinical trials evaluating MET inhibitors in this subset of patients.43,44

Advances in Systemic Therapy for RCC Since 2005

Multiple VEGF and mTOR inhibitors have supplanted cytoki nes as the cornerstone of RCC therapy. Vascular endothelial

growth factor inhibitors include the VEGF-receptor TKIs sunitinib, pazopanib, sorafenib and axitinib, and the monoclonal antibody, bevacizumab; mTOR inhibitors include temsirolimus and everolimus (Table 2).

Vascular Endothelial Growth Factor Inhibitors In patients ineligible for high-dose IL-2, first-line therapy includes 1 of the VEGF-receptor TKIs, sunitinib or pazopanib, or the VEGF-inhibiting monoclonal antibody, bevacizumab (Table 3), in combination with IFN-α, which extended the median PFS to 8 to 11 months in phase III trials that enrolled primarily good- and intermediate-risk patients with RCC.45–48 Data from a recent randomized, double-blind, phase II trial showed that treatment with pazopanib was preferred by 70% of patients, sunitinib by 22% of patients, and 8% of patients had no preference.49 Moreover, patients on pazopanib had fewer dose reductions (13% vs 20%) and interruptions (6% vs 12%) compared with patients taking sunitinib. The results of a phase III trial comparing pazopanib and sunitinib in therapy-naïve patients demonstrated the non-inferiority of pazopanib for PFS, the primary endpoint (median 8.4 vs 9.5 months). Moreover, median survival in both arms was comparable and was . 2 years (28.4 vs 29.3 months).50 Pazopanib was associated with a lower incidence of handfoot syndrome, fatigue, and mucositis, whereas incidence of liver enzyme abnormalities was higher. Quality of life scores favored pazopanib. The data suggest that pazopanib should be preferred for first-line therapy. Axitinib, another potent VEGF receptor TKI, has demonstrated an extension in PFS following previous sunitinib treatment or use of other agents and is approved for second-line therapy in patients

Table 2. Phase III Trials of Agents for Advanced RCC Line of Therapy

Eligibility

Standard Group

Experimental Group

Median PFS (months) (experimental vs standard, P value)

First-line

Therapy-naïve Therapy-naïve Therapy-naïve Therapy-naïve Therapy-naïve or post-cytokine Therapy-naïve or post-cytokine Therapy-naïve Therapy-naïve

IFN Sunitinib IFN Placebo-IFN Placebo Sorafenib Sorafenib IFN

Sunitinib Pazopanib Bevacizumab-IFN Bevacizumab-IFN Pazopanib Tivozanib Axitinib Temsirolimus

Second-line

Post-cytokine Post-1 prior therapy (cytokine, VEGF or mTOR inhibitor) Post-VEGF inhibitor Post-VEGF inhibitor

Placebo Sorafenib

Sorafenib Axitinib

11 vs 5 (, 0.001)92 8.4 vs 9.5 (NS)50 8.5 vs 5.2 (, 0.0001)93 10.2 vs 5.4 (0.0001)94 9.2 vs 4.2 (, 0.001)46 11.9 vs 9.1 (0.042)60 NS 95 Median survival 10.9 vs 7.3 (0.008)55 5.5. vs 2.8 (, 0.01)96 6.7 vs 4.7 (, 0.0001)51

Placebo Sorafenib

Everolimus Temsirolimus

4.9 vs 1.9 (, 0.001)57 4.3 vs 3.9 (0.19)58

Abbreviations: IFN, interferon; mTOR, mammalian target of rapamycin; NS, not significant; PFS, progression-free survival; VEGF, vascular endothelial growth factor.

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Table 3. Management of Advanced RCC Setting

Patientsa

Primary Therapy

Other Options

First-line

Good or intermediate risk

Pazopanib Bevacizumab + IFN Sunitinib Temsirolimus

High-dose IL-2 Sorafenib Observation Sunitinib Pazopanib Sunitinib Bevacizumab + IFN Temsirolimus Other VEGF inhibitors Temsirolimus VEGF inhibitors Trial Different TKI Rechallenge TKI

Poor risk Second-line

Post-cytokine

Post-VEGF inhibitor


Third-line

Post-mTOR inhibitor Post-TKI→TKI Post-mTOR→TKI or Post-TKI→mTOR

Sorafenib Pazopanib Axitinib Everolimus Axitinib Trial Everolimus Trial

a Patients with 0, 1–2, and $ 3 of the following factors are defined as having good-, intermediate-, or poor-risk disease: low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and time from initial RCC diagnosis to start of IFN-α therapy of < 1 year. Abbreviations: IFN, interferon; IL-2, interleukin-2; mTOR, mammalian target of rapamycin inhibitor; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

with RCC.51 Sorafenib is not a preferred first-line option as a randomized, phase II trial demonstrated similar median PFS as with IFN-α treatment (∼5.7 months), in contrast to the post-IFN setting, where sorafenib demonstrated an extension of PFS.41,52 The combination of bevacizumab and IFN has the disadvantage of being a parenteral regimen. All of the VEGF-targeting TKIs have been associated to some extent with fatigue, hypertension, cardiac toxicities, hand-foot skin reaction, hypothyroidism, and arterial thrombotic events. The mTOR inhibitors have unique metabolic adverse effects, including hyperglycemia, hyperlipidemia, and interstitial pneumonitis. Intriguingly, multiple trials have demonstrated a potential link between toxicities and efficacy, suggesting that toxicity may represent pharmacodynamic activity of the drug.53,54

Mammalian Target of Rapamycin Inhibitors The mTOR inhibitor, temsirolimus (administered as a weekly IV infusion) extended median OS compared with IFN in a trial devoted to patients with poor-risk disease.55 Unlike all of the other randomized phase III trials, the mTOR-inhibitor trial included patients with non-clear cell RCC.55 Furthermore, patients with non-clear cell RCC exhibited better hazard ratios for prolonged survival with temsirolimus treatment. Everolimus is an oral mTOR inhibitor that extended patient median PFS after treatment failure with sunitinib, sorafenib, or both.56,57 The median PFS was 4.9 months with everolimus treatment compared with 1.9 months with placebo (HR 0.33; P , 0.001). Median OS was similar in both groups (14.8 vs 14.4 months), but was confounded by 80% of patients in the placebo arm crossing over to everolimus therapy. The choice

between everolimus or axitinib for second-line therapy following other TKIs is empiric and depends on patient and physician choice (Table 3). However, one recent phase III trial did not demonstrate a significant difference in PFS, the primary endpoint, between temsirolimus and sorafenib use, although patient survival was significantly longer with sorafenib.58 Sequencing of everolimus and sunitinib has recently been evaluated in a randomized phase II trial of untreated patients to sequential everolimus followed by sunitinib at progression compared to sequential sunitinib followed by everolimus at progression.59 The non-inferiority of firstline everolimus could not be demonstrated since median PFS was 10.7 months for patients treated with first-line sunitinib, compared with 7.8 months for patients treated with first-line everolimus, suggesting that the treatment paradigm for renal cell carcinoma remains sunitinib followed by everolimus. Moreover, in order to refine therapy for non-clear cell RCC, a randomized phase II trial will compare sunitinib and everolimus as first-line therapy.59

Emerging Agents and Ongoing Trials Another novel and potent VEGF receptor TKI, tivozanib, extended PFS in a phase III trial (Table 2).60 Tivozanib demonstrated significant improvement in median PFS (11.9 vs 9.1 months; P = 0.04) compared with sorafenib as first-line or post-cytokine therapy. In treatment-naïve patients, the median PFS was 12.7 months. However, for a number of reasons beyond the scope of our review, the FDA denied approval of tivozanib for treatment of RCC. T-cell checkpoint inhibitors are exhibiting promising activity. Both PD-1 and CTLA-4 inhibitors have exhibited promising activity.61 Based



Mooney et al

on encouraging durability of responses with BMS-936558, a PD-1 inhibitor, a phase III trial is comparing it with everolimus following use of VEGF inhibitors.62 Additionally, other biologic agents, such as Met inhibitors, are emerging. Although multiple tumor tissue, host-based germline, and plasma-based factors appear prognostic and/or predictive, none have been validated and are not available for general treatment in the clinic. Combinations of sunitinib and other targeted agents have been overly toxic (eg, bevacizumab, IFN, temsirolimus, everolimus) in investigational studies.63–66 The combination of bevacizumab with either temsirolimus or everolimus did not improve PFS.67,68 Finally, the role of cytoreductive nephrectomy in metastatic disease and VEGF and mTOR inhibitors in the adjuvant setting following surgical resection of localized high-risk disease is not established and is undergoing vigorous investigation in phase III trials.69,70

Urothelial Carcinoma Current Systemic Therapy for Urothelial Carcinoma

In patients with urothelial carcinoma, cisplatin-based combination chemotherapy regimens, including methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), dose-dense MVAC (DD MVAC), and gemcitabine and cisplatin (GC) appear to have similar activity.71–73 The 5-year OS rate is 4% to 20%, with a median OS of 12 to 15 months. Use of GC is generally preferred because of its favorable toxicity profile. The addition of weekly paclitaxel to GC did not demonstrate a statistically significant improvement in OS (15.8 vs 12.7 months; P = 0.10).74 Renal dysfunction, poor performance status, and other comorbidities often preclude use of cisplatin-based therapy.75,76 Carboplatin-based regimens have been employed in patients with urothelial carcinoma but appear to yield suboptimal outcomes.77 The median survival for patients treated with second-line therapy, such as taxanes, pemetrexed, and other agents, is only 6 to 9 months and there are no commercially approved agents available in the United States.78 Cisplatin-based neoadjuvant chemotherapy provides a modest improvement in OS compared with radical cystectomy alone.79–81 Pathologic complete remission following neoadjuvant chemotherapy (ie, no residual tumor in cystectomy specimen) appears to be an excellent intermediate endpoint translating to improved long-term outcomes, suggesting that novel combination regimens may be expeditiously developed by exploiting this endpoint.82 Conversely, strong data to support adjuvant chemotherapy do not exist, although it is frequently offered to

50

patients who are cisplatin-eligible within 3 months of radical cystectomy, who have extravesical or node-positive disease.

Molecular Biology of Urothelial Carcinoma

The key molecular drivers of advanced urothelial carcinoma are unclear. Recently, 5 molecular subtypes of bladder cancer have been described based on gene expression profiling of 308 localized or regionally metastatic tumor samples.83 Molecular classification is based on differing expression of cell cycle genes, receptor tyrosine kinases, particularly fibroblast growth factor receptor (FGFR)3, ERBB2, and epidermal growth factor receptors (EGFRs), cytokeratins, and cell adhesion genes with different mutation frequency of FGFR3, PIK3CA, and TP53. These 5 subtypes, urobasal A, genomically unstable, urobasal B, squamous cell carcinoma (SCC)-like, and heterogeneous infiltrated class of tumors are independent of pathologic grading and validated in 3 publically available datasets. Very importantly, these subtypes were significantly associated with different patient survival rates, where urobasal A was associated with good survival; genomically unstable and the infiltrated group were associated with intermediate survival; and urobasal B and SCC-like were associated with the worst survival outcomes.83,84 The molecular subtypes cut across pathologic classification, and susceptibility to specific drugs appeared more likely to be associated with molecular than pathologic information.

Ongoing Investigation of Novel Agents for Treatment of Urothelial Carcinoma

Poor understanding of major molecular drivers of advanced urothelial carcinoma may explain lack of therapeutic advances in disease management for . 2 decades. A novel microtubule antagonist vinca alkaloid, vinflunine, has been approved for use in several countries (but not in the United States) based on a phase III trial comparing best supportive care (BSC) with or without vinflunine.85 Vinflunine binds relatively weakly to tubulin, which has been hypothesized to translate to less neurotoxicity. Although the difference in OS was not statistically significant by intention-to-treat analysis, multivariate Cox analysis, adjusting for prognostic factors, showed a statistically significant effect on OS (P = 0.036), reducing the risk of patient mortality by 23% (HR 0.77; 95% CI, 0.61–0.98). In the eligible study population (n = 357), median OS was significantly longer for vinflunine plus BSC compared with BSC alone (6.9 vs 4.3 months; P = 0.040). Overall response rate, disease control, and PFS favored vinflunine plus BSC. The modest activity of vinflunine



suggests that more rational development of second-line systemic therapy is warranted, with a better selection of patients likely to respond. Recent trials data indicate promising activity for nanoparticle-albumin-bound (nab) paclitaxel and pazopanib as salvage therapy, and further investigation is planned.86,87 Moreover, subsets of patients with advanced urothelial carcinoma may demonstrate dramatic responses to biologic agents, as seen with everolimus (mTOR inhibitor) in patients with tumors bearing TSC1 mutations.88


Conclusions

Dramatic advances have occurred in the realm of systemic therapy for advanced CRPC and clear cell RCC in the last few years. Advances have been fueled by a better understanding of the molecular biology of the malignancies. Urothelial carcinoma has not seen major therapeutic advances for . 2 decades, since the establishment of cisplatin-based multiagent combination chemotherapy regimens as first-line therapy, although GC chemotherapy may represent a less toxic regimen with efficacy similar to MVAC therapy. Additionally, our review has not focused on testicular germ cell tumors, which are highly responsive to and generally curable with cisplatin-based combination chemotherapy.89 However, an understanding of the biology of cisplatin-refractory disease is necessary to salvage all patients with recurrent testicular germ cell tumors.90 Similarly, other less common urologic malignancies, such as penile and urethral cancer, are beyond the scope of our review, and a better understanding of the molecular biology is warranted to yield treatment advances for these malignancies. It is particularly challenging to develop agents for rare malignancies, given the difficulties of accrual to trials and lack of strong commercial motives for industry. Supportive care advances have facilitated palliative benefits, such as with denosumab, a RANKL-inhibiting monoclonal antibody, which was shown to provide an ∼18% benefit in time to first skeletal-related event compared with zoledronic acid in patients with advanced malignancies and bone metastasis.91 The discovery of molecular biomarkers that are predictive for benefit from specific agents remains of paramount importance. Examples of such biomarkers used in the clinic are present in the setting of trastuzumab and lapatinib for ERBB2 expressing breast cancer; tamoxifen and aromatase inhibitors for estrogen receptor expressing breast cancer; and vemurafenib for B-Raf V600E mutation expressing melanoma. At this time, there are no b iomarkers to practice individualized systemic therapy for u rologic malignancies. Further advances will arrive based on

ultidisciplinary research and cooperation between basic m and clinical scientists.

Conflict of Interest Statement

David Mooney, MD, Ravikumar Paluri, MD, MPH, Amitkumar Mehta, MD, and Jatinder Goyal, MD, disclose no conflicts of interest. Guru Sonpavde, MD, receives research support from Novartis, Pfizer, BMS, Celgene, Bellicum Pharmaceuticals, Sanofi-Aventis; and is a speaker or advisory board member for Novartis, Pfizer, GSK, Astellas, Dendreon, Janssen, Sanofi-Aventis, and Amgen.

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Malignancies in systemic lupus erythematosus: a 2015 update.

Treatment of bone metastases in urologic malignancies.

Systemic therapy of non-colorectal gastrointestinal malignancies in the elderly.

Advances in systemic therapy for advanced pancreatobiliary malignancies.

[Management of symptomatic bone metastases in urologic malignancies].

Tumour markers in gastrointestinal malignancies: an update.

Mycology - an update Part 3: Dermatomycoses: topical and systemic therapy.

Systemic therapy for advanced hepatocellular carcinoma: an update.

Update on systemic therapy for advance prostate cancer.

Systemic antibiotics for prophylaxis in urologic surgery: a critical review.

Reporting quality of abstracts in phase III clinical trials of systemic therapy in metastatic solid malignancies.

[Systemic sclerosis - an update].

Applications of spectroscopy in diagnosis, staging, and treatment of urologic malignancies.

The status, limitation and improvement of adoptive cellular immunotherapy in advanced urologic malignancies.

Targeted therapy in gastrointestinal malignancies.

Update on juvenile systemic sclerosis.

Liquid biopsy: a step forward towards precision medicine in urologic malignancies.

Long Non-coding RNAs in Urologic Malignancies: Functional Roles and Clinical Translation.

Update on the treatment of HIV-associated hematologic malignancies.

Tumor Growth Mitigating Effects of Valproic Acid in Systemic Malignancies.

Effect of perioperative blood transfusion on mortality for major urologic malignancies.

Systemic complications of status epilepticus--An update.

Cold atmospheric plasma in orthopaedic and urologic tumor therapy.

Update on systemic therapy of advanced non-small-cell lung cancer.