As we counsel our patients about the importance of clinical research, there are two key messages to send. The first is that without clinical trials, we would not have access to the large number of life-prolonging therapies that we have for genitourinary cancers and others. That translates into more family trips, birthday parties, time spent with grandchildren and graduations attended. It translates into more time spent being productive at work, and net increase into societal wealth. These have meaningful impact. The second is that enrolling on a clinical trial is largely about altruism. The typical patient wants to receive a therapy that will help him/her. That is reasonable; however, the greatest reason to enroll in a clinical trial is that new knowledge will be gained regardless of the outcome.
Of course, there is potential for a patient to receive clinical benefit, but regardless of the patient outcome, the scientific/medical community and future patients will benefit by learning not only what works but also what doesn’t work. Additionally, a well-designed trial may also elucidate why something works or doesn’t work. Hence, as a clinician, we need to view a part of our role to educate patients about the favorable societal impact of participation in clinical research.
Unique to clinical research, the underlying goal is to improve how we treat or care for a real patient. To accomplish this, one must first recognize the clinical dilemmas that currently exist to be able to attack the problem. Hence, in this article, we propose to narrow down to what we view in our opinion are a couple key clinical questions that currently exist among the 4 main genitourinary malignancies: prostate, bladder/urothelial, renal and testicular germ cell cancers.
There are numerous clinical questions for a disease like prostate cancer. This is largely due to the fortunate fact that the natural history of the disease is very long, making it very challenging
to prove that any intervention is superior over any other or even no intervention. This is evident when considering the issues that surround early stages of prostate cancer such as prostate-specific antigen (PSA) screening, who to perform active surveillance on vs. local definitive therapy and the optimal local definitive treatment e.g. radical prostatectomy vs. external beam radiation therapy. However, it is reasonable to address some of the questions that affect people with more advanced stages of disease as outcome measures can be reached in acceptable time frames.
With the recent discovery that 23% of patients with metastatic castration resistant prostate cancer (mCRPC) harbor genetic alterations in DNA damage repair (DDR) genes e.g. BRCA2, BRCA1, ATM, etc,1 and the finding that 11.8% of patients with metastatic prostate cancer has germline alterations in DDR genes,2 clinical trials of PARP inhibition have moved from breast and ovarian cancer rapidly into prostate cancer. These trials generally require enrichment by selecting for patients with DDR alterations. Additionally, double-strand break inducing agents, such as platinum chemotherapy, can also result in impressive responses in these patients. Below are some ongoing trials in this area, but there remain many additional questions in this field. Some areas for future clinical trial exploration include testing PD-1/PD-L1 agents in patients with DDR, determining whether patients with DDR need to be treated early in the disease course with PARP inhibitors and/or platinum and studying mechanisms of resistance to PARP inhibitors and/or platinum. Many of these types of trials are listed below:
- NCT02952534: A Study of Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON2)
- NCT02975934: TRITON3: A Multicenter, Randomized, Open Label Phase 3 Study of Rucaparib Versus Physician's Choice of Therapy for Patients With Metastatic Castration Resistant Prostate Cancer Associated With Homologous Recombination Deficiency
- NCT02854436: A Phase 2 Efficacy and Safety Study of Niraparib in Men With Metastatic Castration-Resistant Prostate Cancer and DNA-Repair Anomalies
- NCT02924766: Niraparib + AR targeted therapy phase 2 for mCRPC (BEDIVERE trial)
- NCT03076203: Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)
- NCT02987543: Study of Olaparib (LynparzaTM) Versus Enzalutamide or Abiraterone Acetate in Men with Metastatic Castration- Resistant Prostate Cancer (PROfound Study)
- NCT03012321: Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients with Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects
- NCT03047135: Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis
- NCT02861573: Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365)
- NCT02598895: Docetaxel and Carboplatin in Treating Patients With Metastatic, Castration Resistant Prostate Cancer Containing Inactivated Genes in the BRCA 1/2 Pathway
- NCT02985021: A Phase 2 Study of Docetaxel and Carboplatin for Treatment of Patients With Metastatic, Castration Resistant Prostate Cancer and Germline or Somatic DNA Repair Deficiency
There are many small trials importing agents earlier to achieve androgen annihilation with undetectable PSA levels and PSA progression-free survival as early endpoints. There is also the EMBARK randomized control trial, a registration trial, evaluating metastasis-free survival with enzalutamide vs. placebo. This trial spans two disease states from BCR to M0 CRPC until patients develop mCRPC; it has the potential to redefine the standard of care for patients in this disease state.
- Randomized phase 3 of leuprolide vs. leuprolide + enzalutamide vs. enzalutamide (EMBARK trial) (NCT02319837)
- NCT03009981: A Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer
From 2004 onwards, targeted therapies directed at abrogating vascular endothelial growth factor (VEGF) mediated signaling have become a mainstay of therapy for metastatic RCC (mRCC). These agents include monoclonal antibodies with affinity for VEGF (e.g., bevacizumab) and small molecule tyrosine kinase inhibitors (TKIs) such as pazopanib, sunitinib and axitinib. Agents inhibiting downstream signaling through the mammalian target of rapamycin (mTOR), including everolimus and temsirolimus, have also demonstrated benefit in selected settings. 11
Over the past 2 years, a massive paradigm shift has occurred in the management of mRCC. Checkpoint inhibitors (specifically, nivolumab) were approved initially in the context of previously treated disease. The pivotal CheckMate 025 study compared nivolumab to everolimus in patients with prior VEGF-directed therapy and demonstrated benefits in overall survival (OS) and response rate (RR) with nivolumab12. Beyond checkpoint inhibitors, several novel TKIs have emerged with affinity for biologically relevant moieties outside of VEGF. These agents similarly had initial assessment in mRCC patients with prior exposure to VEGF-inhibitors. Cabozantinib, a VEGF-TKI with additional affinity for MET and AXL, demonstrated benefit in OS, RR and progression-free survival (PFS) relative to everolimus in the phase III METEOR trial.13 In a separate randomized phase II trial, the multikinase inhibitor lenvatinib, with affinity for fibroblast growth factor receptor (FGFR) as well as VEGF, was combined with everolimus. In comparison to everolimus monotherapy, the combination demonstrated an improvement in PFS and RR and a trend towards improved OS.14Although hard to envision, these studies evaluating second-line therapy have become somewhat obsolete given two recently reported first-line trials. The first study, Checkmate214, is a randomized, phase III study including treatment-naïve patients with mRCC. The study randomized patients to either nivolumab with ipilimumab or sunitinib, and demonstrated a significant benefit in OS and RR amongst patients with intermediate- and poor-risk disease.15 A second, smaller study, CABOSUN, compared cabozantinib to sunitinib and exclusively limited enrollment to patients with intermediate- and poor-risk disease. In this randomized, phase II study, a significant improvement in RR and PFS was observed, with a trend towards benefit in OS.16 While these two studies offer reasonable front-line options for advanced disease, there are a wealth of front-line clinical trials that have yet to report out which may add further to this armamentarium.
- NCT02811861: A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination With Everolimus or Pembrolizumab Versus Sunitinib Alone in First-Line Treatment of Subjects With Advanced Renal Cell Carcinoma.
- NCT02420821: A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma [IMmotion151]
- NCT02684006: A Phase 3, Multinational, Randomized, Open-label, Parallel-arm Study Of Avelumab (msb0010718c) In Combination With Axitinib (Inlyta(Registered)) Versus Sunitinib (Sutent(Registered)) Monotherapy In The First-line Treatment Of Patients With Advanced Renal Cell Carcinoma
- NCT02853331: A Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy as a First-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-426)
- NCT03024996: Adjuvant atezolizumab vs placebo in high-risk resected RCC
- NCT03142334: A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)
- NCT03138512: Adjuvant nivolumab/ipilimumab vs placebo in high-risk resected RCC
- NCT03055013: A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients With Localized Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC)
In advanced bladder cancer, cisplatin-based chemotherapy has long been cornerstone of treatment. Within the past several years, just as in mRCC, checkpoint inhibition has become incorporated into the treatment paradigm. For patients with prior platinum-based chemotherapy (either for metastatic disease or in the perioperative setting), two phase III trials have shown clinical benefit relative to standard chemotherapy. In KEYNOTE-045, patients were randomized to receive either pembrolizumab or cytotoxic chemotherapy until the time of progression or intolerable toxicity. Possible chemotherapy regimens included paclitaxel, docetaxel and vinflunine. Pembrolizumab led to an improvement in both RR and OS.20 A second trial, Imvigor-211, had an almost equivalent study design, examining atezolizumab as opposed to pembrolizumab. Although the study failed to meet its primary endpoint (an improvement in OS in a PD-L1-enriched population), there was a strong trend towards OS in the overall study population. Furthermore, atezolizumab appeared to clearly show benefit in OS as compared to regimens such as docetaxel and paclitaxel, most salient to U.S.-based practices.21
Three other single arm phase II studies have explored the benefit of checkpoint inhibition in patients with prior platinum-based therapies. These studies, assessing nivolumab22, durvalumab23 and avelumab24, have each shown largely similar RR and PFS data.
A clinical conundrum has been the management of patients with cisplatin-ineligible disease. A variety of carboplatin-based regimens have been attempted in this setting, and guidelines still incorporate carboplatin-gemcitabine as a reasonable choice in this setting, despite relatively poor PFS and OS associated with this doublet regimen. Two phase II studies have led to approvals for pembrolizumab and atezolizumab in this setting. Both studies show RRs above 20% and OS exceeding 1 year, therefore constituting a major development in this poor-prognosis subset of patients. 25,26
Moving forward in the front-line setting, several trials will take the bold step of combining chemotherapy with checkpoint inhibition or the even bolder step of juxtaposing immunotherapy alone against chemotherapy:
- NCT02807636: Study of Atezolizumab as Monotherapy and in Combination With Platinum-Based Chemotherapy in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma (IMvigor130)
- NCT03036098: A Phase 3, Open-label, Randomized Study of Nivolumab Combined With Ipilimumab, or With Standard of Care Chemotherapy, Versus Standard of Care Chemotherapy in Participants With Previously Untreated Unresectable or Metastatic Urothelial Cancer
- NCT02516241: Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer
- NCT02853305: A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab With or Without Platinum-Based Combination Chemotherapy Versus Chemotherapy in Subjects With Advanced or Metastatic Urothelial Carcinoma
- NCT02450331: A Study of Atezolizumab Versus Observation as Adjuvant Therapy in Participants With High-Risk Muscle-Invasive Urothelial Carcinoma (UC) After Surgical Resection (IMvigor010)
- NCT03244384: Phase III Randomized Adjuvant Study of MK-3475 (Pembrolizumab) in Muscle Invasive and Locally Advanced Urothelial Carcinoma (AMBASSADOR) Versus Observation
- NCT02632409: A Phase 3 Randomized, Double-blind, Multi-center Study of Adjuvant Nivolumab Versus Placebo in Subjects With High Risk Invasive Urothelial Carcinoma (CheckMate 274: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 274)
Testicular germ cell cancer is fortunately a disease where we have outstanding long-term outcomes. Hence, there is little ongoing clinical research. However, there are a couple of disease states where outcomes could be significantly improved with advancements in the field, and more clinical trials in these settings are needed.
For patients with refractory or relapsed germ cell tumor after initial cisplatin-based combination chemotherapy, it is yet uncertain how to achieve optimal outcomes. The debate centers around whether a patient should receive a salvage combination cisplatin chemotherapy regimen or whether high dose chemotherapy with autologous stem cell rescue27 should be introduced. Traditionally, transplant has been utilized in the 3rd line and attempts at introduction in the 1st line have not shown improved outcomes.28 The Alliance Cooperative Group in the United States is performing a large randomized trial in this setting testing standard dose TI-CE salvage chemotherapy vs. TI with high dose chemotherapy with stem cell transplant for patients in the 2nd line.
- NCT02375204: Standard dose salvage chemotherapy vs. high dose chemo- therapy with stem cell transplant
- NCT02689219: Brentuximab Vedotin in Relapsed/Refractory Germ Cell Tumors
- NCT02988843: Study of Brentuximab Vedotin And Bevacizumab in Refractory CD-30 Positive Germ Cell Tumors
- NCT03158064: Evaluating Immune Therapy, Duravalumab (MEDI4736) with Tremelimumab for Relapsed/Refractory Germ Cell Tumors
For each genitourinary cancer subtype (prostate, bladder, kidney and testicular), management strategies for both localized and advanced disease vary widely. However, as we review current clinical trial strategies, several themes emerge. First, there is an effort to interrogate the role of immunotherapy across each of these malignancies. At first glance, this may be somewhat surprising. Checkpoint inhibition has typically exerted the most potent effect in tumor types bearing a high mutational burden. With the exception of bladder cancer, genitourinary tumors tend to either demonstrate low or moderate mutational burden. In diseases such as prostate cancer or testicular cancer, it may be the rare patient with microsatellite instability that demonstrates a response to therapy, or a combination of therapies (e.g., PARP inhibition with checkpoint inhibition in prostate cancer) may be necessary to drive response. In diseases such as renal cell carcinoma, factors outside of mutational burden (for instance, the frequency of frameshift mutations) have been recently suggested to predict response to therapy.
Another pervasive theme across these studies is that many seek to add novel therapies to existing treatment modalities. In testicular cancer and bladder cancer, for instance, studies of checkpoint inhibition utilize a chemotherapy backbone. In prostate cancer, several combinations of already approved therapies (e.g., radium-223, enzalutamide or docetaxel) serve as the backbone of trials of PARP inhibitors. This is a pragmatic approach that may ultimately help resolve dilemmas in treatment sequencing.
Finally, it should be encouraging to see a trend towards exploring novel systemic therapies in earlier settings. In bladder and kidney cancer, studies of checkpoint inhibitors are now steadily accruing in patients with resected localized disease.
In prostate cancer, treatment strategies previously reserved for advanced disease are now moving into patients with high-risk localized disease and biochemical recurrence. As a field, we should continue to strive for better outcomes through clinical research by importing highly efficacious therapies earlier in the treatment paradigm.
Written by: By Evan Yu, MD and Sumanta Kumar Pal, MD.
- Robinson D, Van Allen EM, Wu YM, et al: Integrative clinical genomics of advanced prostate cancer. Cell 161:1215-1228, 2015
- Pritchard CC, Mateo J, Walsh MF, et al: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53, 2016
- Sweeney CJ, Chen Y-H, Carducci M, et al: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New England Journal of Medicine 373:737-746, 2015
- James ND, Sydes MR, Clarke NW, et al: Addition of docetaxel, zoledronic acid, or both to first-line long- term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387:1163-77, 2016
- Ryan CJ, Smith MR, Fizazi K, et al: Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 16:152-60, 2015
- James ND, de Bono JS, Spears MR, et al: Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. New England Journal of Medicine 377:338-351, 2017
- Crook JM, O’Callaghan CJ, Duncan G, et al: Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy. New England Journal of Medicine 367:895-903, 2012
- Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591-7, 1999
- Zagars GK, Pollack A: Kinetics of serum prostate-specific antigen after external beam radiation for clinically localized prostate cancer. Radiother Oncol 44:213-21, 1997
- D’Amico AV, Moul J, Carroll PR, et al: Prostate specific antigen doubling time as a surrogate end point for prostate cancer specific mortality following radical prostatectomy or radiation therapy. J Urol 172:S42-6; discussion S46-7, 2004
- Choueiri TK, Motzer RJ: Systemic Therapy for Metastatic Renal-Cell Carcinoma. New England Journal of Medicine 376:354-366, 2017
- Escudier B, Sharma P, McDermott DF, et al: CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma. Eur Urol 72:962-971, 2017
- Choueiri TK, Escudier B, Powles T, et al: Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 17:917- 927, 2016
- Motzer RJ, Hutson TE, Glen H, et al: Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 16:1473-82, 2015
- Hammers HJ, Plimack ER, Sternberg C, et al: CheckMate 214: A phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in patients with previously untreated metastatic renal cell carcinoma. Journal of Clinical Oncology 33:TPS4578-TPS4578, 2015
- Choueiri TK, Halabi S, Sanford BL, et al: Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients with Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 35:591-597, 2017
- Motzer RJ, Haas NB, Donskov F, et al: Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients with Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol:JCO2017735324, 2017
- Haas NB, Manola J, Uzzo RG, et al: Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 387:2008-16, 2016
- Ravaud A, Motzer RJ, Pandha HS, et al: Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 375:2246-2254, 2016
- Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 376:1015-1026, 2017
- Hoffman-Censits JH, Grivas P, Heijden MSVD, et al: IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC). Journal of Clinical Oncology 34:355-355, 2016
- Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. The Lancet Oncology 18:312-322
- Massard C, Gordon MS, Sharma S, et al: Safety and Efficacy of Durvalumab (MEDI4736), an Anti– Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients with Advanced Urothelial Bladder Cancer. Journal of Clinical Oncology 34:3119-3125, 2016
- Apolo AB, Infante JR, Balmanoukian A, et al: Avelumab, an Anti–Programmed Death-Ligand 1 Antibody, In Patients with Refractory Metastatic Urothelial Carcinoma: Results from a Multicenter, Phase Ib Study. Journal of Clinical Oncology 35:2117-2124, 2017
- Balar AV, Castellano D, O’Donnell PH, et al: First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. The Lancet Oncology 18:1483-1492, 2017
- Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. The Lancet 387:1909-1920
- Einhorn LH, Williams SD, Chamness A, et al: High-Dose Chemotherapy and Stem-Cell Rescue for Metastatic Germ-Cell Tumors. New England Journal of Medicine 357:340-348, 2007
- Motzer RJ, Nichols CJ, Margolin KA, et al: Phase III Randomized Trial of Conventional-Dose Chemotherapy with or without High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell Rescue As First-Line Treatment for Patients with Poor-Prognosis Metastatic Germ Cell Tumors. Journal of Clinical Oncology 25:247-256, 2007
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