The Importance of Clinical Trials for Genitourinary Malignancies - Evan Yu and Sumanta Kumar Pal

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.

PROSTATE CANCER

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:

With 6 regulatory approved agents for mCRPC, the press release of the positive PROSPER and SPARTAN trials of enzalutamide and apalutamide, respectively, for M0 CRPC, and the recent trial data supporting the use of docetaxel3,4 and abiraterone5,6 for metastatic hormone-sensitive prostate cancer, the next obvious disease state to study known efficacious therapies is the biochemically-recurrent (BCR) setting after local definitive therapy. There is significant heterogeneity of outcomes for people in this disease state, with median survival of approximately a decade.7 Patients with a long time to BCR with a long PSA doubling time may not require aggressive intervention.8,9 However, we recognize that those with a short PSA doubling time have poor outcomes.10

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.

RENAL CELL CARCINOMA (RCC)

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.

Beyond advance disease, there is renewed interest in the setting of localized disease. Two studies evaluating adjuvant VEGF-TKIs, PROTECT and ASSURE, have produced resoundingly negative results. PROTECT compared pazopanib to placebo, while ASSURE compared sunitinib monotherapy and sorafenib monotherapy to placebo.17,18 A third trial, S-TRAC, showed a modest gain in disease-free survival (DFS) with sunitinib versus placebo in the adjuvant setting, but despite an associated FDA approval, it is anticipated that utilization of this regimen will be low on account of toxicities associated with the agent. Furthermore, the study has shown no evidence of OS benefit to date.19 Four trials evaluating adjuvant checkpoint inhibition will hopefully skew the risk/bene t ratio in a more positive direction. These studies are as follows:

BLADDER CANCER

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:

There are also efforts to move systemic therapy to the setting of muscle-invasive and non-muscle invasive setting. Studies of adjuvant nivolumab and atezolizumab are well underway, and a cooperative-group sponsored study assessing adjuvant pembrolizumab has just launched:

TESTICULAR CANCER

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.

The other major clinical dilemma is how best to improve outcomes for patients who have relapsed after stem cell transplant, where there are no remaining curative treatment options. This is a disease state where many more clinical trials need to be developed. There are currently a couple ongoing trials exploring Brentuximab vedotin as embryonal carcinoma expresses CD30. There have also been isolated case reports of the activity of checkpoint inhibitors for patients with resistant germ cell tumors,29,30 and as a result, there is an ongoing prospective trial testing combination checkpoint inhibitors. Some trials available for advanced, refractory/relapsed germ cell tumors are listed below:

CONCLUSIONS/FUTURE DIRECTIONS

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.

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