Expert Expands on Evolving Treatment Strategies for Prostate and Urothelial Cancers

Tanya Dorff, MD

As the landscape of genitourinary cancers continues to evolve, clinical trials determine better strategies for treatment of patients with these diseases.

In prostate cancer, advancements in the field have shown that treatments are more effective when used earlier, but combination therapy has yet to be proven beneficial. On the other hand, experts in treating urothelial cancer expect new agents in combination regimens will likely become standard care.

During a virtual presentation organized by the Medical Oncology Association of Southern California, Tanya Dorff, MD, associate clinical professor of medicine and head of the Genitourinary Cancer Program at the City of Hope, discussed evolving practices in prostate and urothelial cancers as well as highlighted controversies in the treatment landscape such as the role of combination therapy in prostate cancer.

Outlining Standard of Care

The standard of care for patients with metastatic hormone-sensitive prostate cancer (mHSPC) has long been established as androgen deprivation therapy (ADT). However, many clinical trials are now challenging the role of ADT monotherapy by combining the therapy with other agents to improve upon survival.

The addition of docetaxel chemotherapy to ADT with prednisolone led to a significant improvement in overall survival (OS) compared with ADT alone in the STAMPEDE trial (HR, 0.78; 95% CI, 0.66-0.93;P= .006). In patients with metastases, survival was also improved (HR, 0.82; 95% CI, 0.48-1.40;P= .475). However, toxicities must be considered with this regimen due to the rate of grade 5 adverse events (AEs), which occurred in 4 out of 592 patients in the docetaxel-treated arm.¹

Based on data from the LATITUDE trial, the early addition of abiraterone (Zytiga) to ADT and prednisone in patients with mHSPC improved survival compared with placebo (HR, 0.62; 95% CI, 0.51-0.76;P<.001).²

During parallel enrollment to the cohorts adding either abiraterone or docetaxel to standard-of-care therapy in mHSPC, data from the STAMPEDE trial suggest that there is little difference in terms of OS between the 2 agents.³There is no clear guidance on selecting the most appropriate agent to combine with ADT in patients with mHSPC, but physicians can evaluate the toxicity profiles associated with the drugs, patient characteristics, and the financial toxicity to select the appropriate agent for their patients.

Subsequently apalutamide (Erleada; TITAN) and enzalutamide (Xtandi; ENZAMET) were also shown to improve survival when added to ADT for mHSPC further confirming the importance of up-front intensification.^4,5

Many of these therapies have also been proven efficacious in patients with castration-resistant prostate cancer (mCRPC).

In the COU-AA-301 trial, abiraterone led to a median OS of 14.8 months versus 10.9 months with placebo in the post-docetaxel setting for patients with mCRPC (HR, 0.65; 95% CI, 0.54-0.77;P<.001).⁶The agent also led to an improvement in radiographic progression-free survival (rPFS) of 16.5 vs 8.2 months in the pre-docetaxel setting (HR, 0.52; 95% CI, 0.45-0.61;P<.0001).⁷

Enzalutamide has efficacy in both pre- and post-chemotherapy settings, with the agent leading to a median OS of 18.4 months versus 13.6 months with placebo (HR, 0.63; 95% CI, 0.53-0.75; P<.001) in the post-docetaxel setting in the phase III AFFIRM trial.⁸ Patients who were chemotherapy naive and received enzalutamide treatment in the PREVAIL trial also demonstrated improvement in median OS, at 32.4 months versus 30.2 months (HR, 0.71; 95% CI, 0.60-0.84; P<.001), respectively, further demonstrating the benefit of earlier treatment in prostate cancer.⁹

The a emitter radium-223 dichloride (rad223) produced a median OS of 14.9 months versus 11.3 months with placebo in the ALSYMPCA trial (HR, 0.70; 95% CI, 0.58-0.83;P<.001).¹⁰

Sipuleucel-T, an immunotherapeutic agent, also had an improved median OS compared with placebo in the IMPACT trial, in which the median was 23.2 months versus 18.9 with placebo (P= .001).¹¹

Dorff went on to explain that for now, combination therapy for prostate cancer has yet to be proven effective or more beneficial than single-agent therapy.

In the Alliance A031201 clinical trial, enzalutamide was evaluated alone or in combination with abiraterone plus prednisone as a treatment of patients with mCRPC. However, survival was not prolonged with the combination in this patient population compared with enzalutamide alone. The combination also led to more toxicity than the monotherapy.¹²

In the randomized, open-label phase III EORTC 1333/PEACE III trial, investigators evaluated enzalutamide with or without rad223 in patients with mCRPC. This trial demonstrated excess risk of fracture with the combination, although adding in bone supporting agents nearly eliminated the increased risk. Dorff concluded by stating it has not been reported whether there is an advantage for the combination versus enzalutamide alone.¹³

New Agents on the Scene

PARP inhibitors are entering the treatment landscape for patients with prostate cancer. In a phase II trial of patients with mCRPC, olaparib (Lynparza) showed a high response rate in patients with defects in DNA-repair genes who were no longer responding to standard treatments.¹⁴

Additionally, data from the randomized phase II TOPARP-B trial evaluating olaparib in patients with mCRPC with DNA damage repair alterations demonstrated an objective response rate (ORR) of 54% at a dose of 400 mg twice daily. The highest ORRs were observed in patients harboring mutations inBRCA1/2(80%),PALB2(57%),ATM(37%), andCDK12(25%).¹⁵

The phase III PROFOUND trial also compared results for olaparib versus physician&rsquo;s choice of therapy in a 2:1 randomized open-label study. Patients with mCRPC were divided into 2 cohorts, including cohort A with BRCA1/2 or ATM mutations and cohort B with all other alterations. In cohort A, the rPFS was 7.39 months versus 3.55 months with the PARP inhibitor versus physician&rsquo;s choice, respectively (HR, 0.34; 95% CI, 0.25-0.47; P<.0001). The median OS was 18.50 months with olaparib versus 15.11 months, with a hazard ratio of 0.64 (95% CI, 0.43-0.97; P = 0.0173). OS benefit was seen despite >80% crossover on the study.¹⁶

Other PARP inhibitors—such as niraparib (Zejula), rucaparib (Rubraca), and talazoparib (Talzenna)&mdash;are also under evaluation in the setting of patients with mCRPC.

Checkpoint blockade may also make its way into the armamentarium of physicians who treat prostate cancer in patients with microsatellite instability. The phase II KEYNOTE-199 evaluated the role of pembrolizumab (Keytruda), a PD-1 inhibitor, as treatment of patients with mCRPC.

In cohort 1, which included PD-L1—positive tumors, patients experienced an ORR of 5% (95% CI, 2%-11%), and in cohort 2, with PD-L1&ndash;negative tumors, there was an ORR of 3% (95% CI, <1%-10%). The disease control rate was 22% (95% CI, 15%-30%) in cohort 1 and 24% (95% CI, 14%-36%) in cohort 2. These response rates do not warrant use of this agent in an unselected mCRPC population, although the treatment appeared to be well-tolerated with an acceptable safety profile.¹⁷

Clinical Trials Underway in Prostate Cancer

Going forward, the phase III KEYNOTE-991 will be enrolling patients at sites across the US to evaluate the role for immune checkpoint inhibitors as treatment of patients with mHSPC. Patients will be stratified by prior docetaxel for mHSPC and high-volume disease. In arm 1, patients are treated with pembrolizumab plus enzalutamide and ADT, while patients in arm 2 will receive placebo with enzalutamide and ADT. The primary end points are rPFS and OS.

The role of the radiopharmaceutical 117-Lu-PSMA is also under evaluation for the treatment of patients with prostate cancer. In a study in Australia, 50 patients received a median of 3 doses of 117-Lu-PSMA, and 22 patients (45%) had a prostate-specific antigen (PSA) decline of more than 50%. The main AEs included fatigue and nausea in this trial.¹⁸

In a German study, 52 patients were treated with this therapy as well, and 81% had any decline in PSA at 2 months, while 44% had a decline of more than 50%. The median OS was 60 weeks, or 13.8 months.¹⁹

VISION (NCT03511664), a randomized phase III clinical trial, is currently evaluating the role of 117-Lu-PSMA-617 in this setting; the trial has now completed accrual. The primary end points are rPFS, RECIST response, and time to a first symptomatic skeletal event. Investigators will also determine the safety and tolerability of the drug in this population.

Although it is not far along in the development process, chimeric antigen receptor (CAR) T-cell therapy is a newer approach to treating patients with mCRPC that is currently under evaluation. In a phase I study, patients are being treated across 4 arms, which include varying doses of prostate stem cell antigen—targeting CAR T cells. The primary end points are all toxicities and dose-limiting toxicities. Secondary end points include persistence/expansion of CAR T cells and response. PSMA-targeting CAR T-cells are also beginning enrollment of patients with mCRPC.

Updates to the Urothelial Cancer Treatment Landscape

For patients with urothelial cancer, major changes are underway in the treatment landscape. Immune checkpoint inhibitors are available in the frontline setting for patients who are cisplatin ineligible and have high PD-L1 expression and in the second-line setting following platinum chemotherapy.

Erdafitinib (Balversa), an FGFR inhibitor, is available in the third-line setting for patients harboringFGFR3orFGFR4alterations. This agent led to an objective response in 40% of patients with 3% complete responses (CRs) and 37% partial responses (PRs). Additionally, 39% of patients achieved stable disease, and 18% had progressive disease. The median time to response was 1.4 months, and the median duration of time to first response was 5.6 months (95% CI, 4.2-7.2).²⁰

In terms of responses per independent radiologic assessment, 34 patients had an objective response, including 3 CRs and 31 PRs. Investigators noted responses in 5 of 12 patients who previously did not receive chemotherapy (42%), 35 of 87 patients who progressed or relapsed after prior chemotherapy (40%), and 13 of 22 who received prior immunotherapy (59%).²⁰

Most patients who received 8 mg QD of this agent had tumor shrinkage. Seventy-five out of 99 patients had reduction in the sum of target lesion diameters (76%). In terms of toxicities, the most common AEs included hyperphosphatemia (73%), nail events (52%), non-CSR ocular events (52%), and skin events (49%). The most common grade 3 or greater AE was nail events in 14 of the 99 patients (14%).²⁰

Treatment-related AEs (TRAEs) included hyperphosphatemia (73%), stomatitis (55%), dry mouth (43%), diarrhea (37%), dysgeusia (35%), dry skin (32%), alopecia (27%), decreased appetite (25%), hand-foot syndrome (22%), and fatigue (21%). The most common grade 3 or greater TRAEs included stomatitis (9%), hand-foot syndrome (5%), diarrhea (4%) hyperphosphatemia (2%), and fatigue (2%).²⁰

Enfortumab vedotin (EV), an antibody drug conjugate, is also FDA-approved in the post-platinum and/or -immune checkpoint inhibitor setting. In the EV-201 study 44% of the 125 metastatic urothelial cancer patients had objective partial response by RECIST criteria with median duration of response 7.6 months. Preliminary evidence suggests high response rates when EV is combined with pembrolizumab.²¹

In the EV-302 trial, enfortumab vedotin will be evaluated as first-line treatment of urothelial cancer (NCT04223856). In arms A and C patients will receive enfortumab vedotin on days 1 and 8 with pembrolizumab on day 1. In arm C, patients will also receive cisplatin/carboplatin on day 1. In arm B, patients will receive gemcitabine on days 1 and 8 plus cisplatin/carboplatin on day 1.

In this clinical trial, patients are stratified by cisplatin eligibility, liver metastases, and PD-L1 expression. Scans occur every 9 weeks from the start of randomization for 18 months, then every 12 weeks thereafter. Investigators will evaluate survival, subsequent anticancer therapy, and patient-reported outcomes.

City of Hope, where Dorff practices, among other sites in the US is currently enrolling for a number of different clinical trials for the treatment of patients with urothelial cancer, as well as mCRPC and mHSPC. These trials are evaluating new and novel therapeutic options to improve survival in patients with these diseases.

References

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