NOVEL THERAPIES FOR UROLOGICAL CANCERS

Attendees gathered at the 2020 Genitourinary Cancers Symposium in San Francisco to hear the latest news about treating patients with cancers of the prostate, bladder, kidneys, and testicles. In addition to the comprehensive coverage of the meeting in The ASCO Post, here are some brief highlights related to prostate, bladder, and kidney cancers.

Radium-223 Plus Sipuleucel-T in Metastatic Prostate Cancer

The combination of radium-223 and sipuleucel-T produced unanticipated and somewhat perplexing results in a study of patients with metastatic castration-resistant prostate cancer.¹ Although several key clinical outcomes were improved with the combination vs sipuleucel-T alone, immune responses (ie, systemic T-cell proliferation) were superior with single-agent sipuleucel-T vs the combination.

Systemic T-cell proliferation, as measured by PA2024 antigen in the blood, increased by 7% at 6 weeks with the combination vs 25.3% with sipuleucel-T monotherapy (P = .0071). However, time to radiographic/clinical disease progression, prostate-specific antigen (PSA) response, and alkaline phosphatase response all improved significantly with the combination vs sipuleucel-T alone.

The investigators hypothesized that radium-223 and sipuleucel-T would enhance the vaccine’s ability to induce immune response and lead to improved outcomes. “The clinical results provided evidence of synergistic activity with the two drugs, but the immune response data were the exact opposite of what we had anticipated, and we don’t have an explanation for that. We intend to continue analyzing the results to try to get some insight into that,” said lead author Catherine H. Marshall, MD, MPH, Assistant Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore.

The study enrolled 32 patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer and randomly assigned them to sipuleucel-T alone or in combination with radium-223. Eligible patients had serologic or radiologic disease progression, absolute PSA level ≥ 2 ng/mL, and Eastern Cooperative Oncology Group COG status of 0 to 1. Prior treatment with abiraterone acetate or enzalutamide was allowed.

The primary endpoint was PA2024-specific T-cell proliferation in peripheral blood at 6 weeks. PA2024-specific T-cell proliferation remained significantly higher with sipuleucel-T monotherapy at 14 weeks vs the combination and decreased thereafter, until the proliferation index was similar in the two groups at week 26. PA2024-specific proliferation remained similar in the two groups throughout follow-up. None of the other immune-response measures differed significantly between the two groups at any time during follow-up.

The time to radiographic/clinical disease progression tripled with the combination (9.3 vs 3.1 months), representing a 74% reduction (P = .0011). Five patients achieved PSA responses with the combination vs none with monotherapy (P = .04). One patient randomly assigned to single-agent sipuleucel-T had an alkaline phosphatase response compared with nine patients in the combination group (P = .01). Adverse event rates were similar between the two groups.

Metastasis-Directed Therapy for Oligometastatic Recurrent Prostate Cancer

Treating oligometastatic recurrence of prostate cancer led to a fourfold improvement in the percentage of patients alive without the need for androgen-deprivation therapy at 5 years, in a phase II screening trial.² The estimated 5-year androgen-deprivation therapy–free survival rate (the primary endpoint) was 34% for treated patients vs 8% for the active surveillance group, a significant difference correlating with a hazard ratio of 0.57 in favor of treatment (P = .06).

Metastasis-directed treatment (ie, surgical removal of metastases or sterotactic body radiotherapy for metastases) led to better androgen-deprivation therapy–free survival regardless of PSA doubling time or lymph node involvement. Immediate treatment also delayed the time to development of castration-resistant prostate cancer, although the difference did not reach statistical significance. Overall survival rates were between 80% and 90% in both groups.

Although these results are supportive of immediate treatment of oligometastatic disease (ie, one to three extracranial metastatic lesions), they are not definitive. This was a phase II screening trial. “This trial was designed to show what we should be doing in a phase III trial,” said lead author Piet Ost, MD, of Ghent University, Belgium.

The analysis focused on 62 patients enrolled in the Belgium-based, multicenter STOMP trial. All patients had asymptomatic or minimally symptomatic oligorecurrent prostate cancer. Patients were treated according to the European guidelines in place in 2012 when the trial was initiated, so the control arm underwent observation. In the intervention arm, patients received immediate metastasis-directed treatment. In both groups, treatment continued until development of symptomatic local or polymetastatic disease progression, when androgen-deprivation therapy was initiated.

The median follow-up was 5.3 years. The 5-year overall survival was high in both groups, as was prostate cancer–specific survival. Six of 14 total deaths resulted from prostate cancer, Dr. Ost said.

Neoadjuvant Nivolumab Plus Chemotherapy in Muscle-Invasive 
Bladder Cancer

The combination of neoadjuvant nivolumab plus gemcitabine/cisplatin chemotherapy led to a pathologic non–muscle invasive rate of 66% and a pathologic complete response rate of 49% in patients with muscle-invasive bladder cancer, in the phase II BLASST-1 trial.³ No new safety concerns were raised, and patients proceeded to cystectomy without complications. The pathologic complete response rate in this trial was more favorable than that associated with cisplatin-based chemotherapy regimens, which is about 30%. The phase III ENERGIZE trial will evaluate this combination further.

“The results [of BLASST-1] are encouraging, and long-term follow-up will further confirm safety,” said presenting author Shilpa Gupta, MD, of Cleveland Clinic Taussig Cancer Institute.

Shilpa Gupta, MD

Andrea Necchi, MD

BLASST-1 trial discussant, Andrea Necchi, MD, of Fondazione Istituto dei Tumori, Milan, Italy, explained this is one of several trials evaluating neoadjuvant immunotherapy plus chemotherapy before radical cystectomy. “It is good that a phase III trial will be conducted for this combination, which has the potential for a paradigm shift,” Dr. Necchi stated.

BLASST-1 included 41 patients with nonmetastatic muscle-invasive bladder cancer treated with the combination of checkpoint inhibitor plus gemcitabine/cisplatin. All patients were physically fit, cisplatin-eligible, and candidates for radical cystectomy.

Patients received four cycles of gemcitabine/cisplatin, and a fixed dose of nivolumab was added on day 8 of each cycle. Patients underwent cystectomy at 6 to 8 weeks after completion of systemic therapy. The primary endpoint (downstaging to a non–muscle invasive state) was met in 27 patients (66%). 

“The majority of adverse events were attributed to chemotherapy. Most of the hematologic toxicities were consistent with what we see with gemcitabine and cisplatin. Most of them were grade 1 or 2 anemia, neutropenia, and thrombocytopenia,” Dr. Gupta said. Immune-related adverse events consisted of rash in one patient, hypothyroidism in one patient, inflamed lymph nodes in two patients, and Guillain-Barré syndrome in one patient.

Correlative analyses are continuing to determine predictors of response and resistance to chemoimmunotherapy.

Sacituzumab Govitecan in Metastatic Bladder Cancer

The antibody-drug conjugate sacituzumab govitecan yielded encouraging preliminary results in previously treated patients with metastatic bladder cancer, including those who had received anti–programmed cell death protein 1 (PD-1) therapy. Sacituzumab govitecan links a TROP-2 targeting monoclonal antibody to an active metabolite of irinotecan, a chemotherapy approved for use in colorectal cancer.

Scott Tagawa, MD

In a study of 45 patients who received sacituzumab govitecan (IMMU-132) in the second- or later-line setting, 31.1% responded overall, including 4 of 17 patients previously treated with anti–PD-1 therapy, according to lead author Scott Tagawa, MD, of Weill Cornell Medicine, New York.⁴Responses with sacituzumab govitecan were also seen in patients with liver metastases (5 of 15), and overall there were two complete responses. Median progression-free survival and overall survival were 7.3 and 16.3 months, respectively. Among responders, the median duration of response was 12.9 months.

Toxicity included any-grade diarrhea (69%), nausea (67%), fatigue (58%), and neutropenia (51%) as the most common adverse events. The most common grade 3 adverse events included neutropenia (22%), anemia (13%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%); grade 4 neutropenia occurred in 14% of patients. “There was a relatively low rate of treatment discontinuation due to adverse events, none due to neutropenia, and there were no treatment-related deaths,” Dr. Tagawa said.

Better treatment options are needed for patients who do not respond to anti–PD-1 therapy or who experience disease progression on immunotherapy. “We believe the activity in this modest subset of patients deserves further study,” he added. The phase II TROPHY-U-01 study will evaluate sacituzumab govitecan in patients whose disease has failed to respond to either platinum-based agents or PD-1 inhibitors.

Sitravatinib Plus Nivolumab in Renal Cell Carcinoma

Nivolumab plus the multitargeted tyrosine kinase inhibitor sitravatinib showed promising results in pretreated patients with metastatic clear cell renal cell carcinoma and improved progression-free survival and disease control compared with historic controls receiving nivolumab alone, according to a single-arm phase II trial.⁵ Objective responses were observed in 15 of 38 patients (39%) who experienced disease progression on up to two prior lines of antiangiogenic therapy. Clinical benefit (defined as best response of stable disease, partial response, or complete response) was seen in 35 of 38 patients (92%). The median progression-free survival was 10.3 months. Historical objective response rates in this setting are 25% with nivolumab, 17% to 21% with cabozantinib, and 3% to 5% with everolimus.

Pavlos Msaouel, MD

Lead author Pavlos Msaouel, MD, of MD Anderson Cancer Center, Houston, said: “Responses tended to be durable. With a median follow-up of 17.7 months, the median overall survival has not been reached, and currently 30 of 38 patients are alive. The combination has an acceptable safety profile.”

The study included 40 patients to date. During the dose-­escalation phase, four different dose levels of sitravatinib (60, 80, 120, and 150 mg/d) were combined with standard-dose nivolumab. Sitravatinib was given alone for 2 weeks, and nivolumab was added on day 15. Patients were treated and evaluated every 6 weeks during the first year and then every 12 weeks until progressive disease or toxicity.

The dose of 120 mg/d of sitravatinib in combination with nivolumab is being explored moving forward and in other tumor types, in addition to renal cell carcinoma, including refractory urothelial carcinoma, non–small cell lung cancer, and head and neck cancer.

The most commonly reported adverse events were diarrhea (29 patients, none due to immune-related colitis), fatigue (27 patients), and elevated alanine aminotransferase levels (23 patients). There was one treatment-related grade 5 event in a patient who developed nivolumab-related myasthenia gravis. A total of 21 patients required dose reductions due to toxicities, 15 of which occurred within 12 weeks of starting treatment.

Daniel Geynisman, MD

Study discussant Daniel Geynisman, MD, of Fox Chase Cancer Center, Philadelphia, agreed that the response rates in the trial were quite good, but he questioned whether sitravatinib is an improvement over cabozantinib. “Sitravatinib is very active in renal cell carcinoma but has a lot of overlap with the targets of cabozantinib. How different is this drug from cabozantinib? If the answer is ‘not much,’ then what is the added value?” Dr. Geynisman said.

Other tyrosine kinase inhibitors—such as tivozantinib, axitinib, and lenvatinib—have been studied in combination with a checkpoint inhibitor in metastatic renal cell carcinoma. “There is a hint in studies that, no matter what tyrosine kinase inhibitor you combine with a checkpoint inhibitor, you get responses in disease control rate in the second line [in renal cell carcinoma],” Dr. Geynisman continued. “We need more data on this combination in the post–checkpoint inhibitor space and as front-line treatment. Ongoing trials should provide some answers,” he added.