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American Society of Clinical Oncology Genitourinary Symposium 2019
This year’s Genitourinary Symposium, held at the ASCO meeting, took place in San Francisco from February 13 to 15, 2019, and hosted more than 1,500 oncology practitioners. We review below two key sessions on prostate cancer and two on renal cell carcinoma.
Results of a 50-Patient Single-Center Phase 2 Prospective Trial of Lutetium-177 PSMA-617 Theranostics in Metastatic Castrate-Resistant Prostate Cancer
- Michael Hofman, MD, Peter MacCallum Cancer Centre, Melbourne, Australia
Median overall survival (OS) results for lutetium-177 (177Lu)-PSMA-617 theranostics among 50 men with metastatic castration-resistant prostate cancer (mCRPC) support the strategy’s mechanism of action and the conduct of the ongoing TheraP and VISION randomized trials. Among included men, multiple lines of prior therapies had failed, Dr. Michael Hofman said in an ASCO-GU pre-meeting press webcast. Metastatic castration-resistant prostate cancer, he added, is a fatal disease, and new effective therapies are urgently needed.
[177Lu]-PSMA-617 is a radiolabeled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA). PSMA is over-expressed 100–1,000-fold in prostate cancers, with the expression further increased in metastatic and castration-resistant carcinomas. Through this affinity, LuPSMA delivers high doses of radiation, with a half-life of seven days, precisely to metastases while avoiding delivery of potentially hazardous radiation to normal cells. In addition, LuPSMA emits low levels of gamma rays, facilitating visualization with nuclear-medicine imaging and allowing clinicians to monitor tumor regression or progression.
Dr. Hofman had previously reported favorable activity with low toxicity in a 30-patient study in this population. The current report adds updated results including a 20-patient extension cohort. The included men (aged 50–87 years) had prostate-specific antigen (PSA) levels rapidly doubling (median 2.6 months) prior to enrollment. Most had previously been treated with docetaxel chemotherapy or antiandrogen therapy (abiraterone and/or enzalutamide), and 48% had also received second-line cabazitaxel chemotherapy.
Investigators administered up to four intravenous cycles of LuPSMA in an outpatient setting. Some responding patients who later progressed received further cycles of LuPSMA.
Among 32 of 50 men, PSA declined by 50% or more, and in 22 of 50 men, PSA declined by 80% or more, Dr. Hofman reported. Median OS was 13.3 months (95% CI, 10.5–18.0), and was significantly longer in those with PSA declines of 50% or more (18.0 vs. 8.7 months [P = 0.001]). Among LuPSMA responders, PSA values did not increase for a median of 6.9 months. In 9 of 14 men who received a median of two more cycles of LuPSMA after progression, PSA subsequently declined by 50% or more. Survival for this group was 33 months on average.
Nausea, fatigue, and dry mouth were the most common side effects (PSMA is present on salivary and tear gland cells). Serious anemia and thrombocytopenia were reported in 10% of men.
“In this trial, we treated men who would have otherwise been directed to palliative care,” said Dr. Hofman. “It’s exciting to see that LuPSMA can potentially offer benefits for many men with these very aggressive cancers, with few side effects and significant improvements in quality of life.”
Final Analysis of Phase 3 LATITUDE Study in Patients With Newly Diagnosed High-Risk Metastatic Castration-Naïve Prostate Cancer Treated With Abiraterone Acetate + Prednisone Added to Androgen Deprivation Therapy
- Karim Fizazi, MD, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France. Presented by Kim N. Chi, MD, British Columbia Cancer Agency, Vancouver, Canada.
Final analysis of the phase 3 LATITUDE study in patients with newly diagnosed high-risk metastatic, castration-naïve prostate cancer (NDx-HR mCNPC) confirms a significant overall survival (OS) advantage of combining abiraterone acetate plus prednisone (AA+P) with androgen deprivation therapy (ADT). The efficacy findings and adverse-event profiles, Dr. Kim Chi said in an oral presentation, are consistent with two prior interim analyses.
ADT had been the mainstay treatment of metastatic prostate cancer for more than 70 years until 2015, Dr. Chi noted, when ADT plus docetaxel became a treatment option that showed improved OS. Since 2017, based on earlier LATITUDE and STAMPEDE trial results demonstrating improved OS and quality of life, ADT + AA+P has been the standard of care.
LATITUDE investigators at 235 sites in 34 countries enrolled 1,199 NDx-HR mCNPC patients, randomizing them 1:1 to AA (1 g QD) + P (5 mg QD) + ADT or placebo + ADT. Included patients met two of three high-risk criteria (Gleason ≥ 8, ≥ 3 lesions on bone scan, and measurable visceral lesion). The co-primary efficacy endpoints were OS and radiographic progression-free survival (rPFS).
The median age was 67.5 years. Almost all patients (97.5%) met Gleason score and bone metastases criteria at diagnosis and screening. About 80% of participants met CHAARTED trial criteria for high-volume disease (presence of visceral metastases and/or ≥ four bone metastases, with at least one outside the vertebral column or pelvis).
The final analysis was conducted after a median follow-up of 51.8 months. Of 618 observed deaths, 275 (46%) occurred in the AA+P group and 343 (57%) occurred in the placebo group. Median OS in the AA+P group was 53.3 months and was 36.5 months in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.56–0.78]; P < 0.0001). The OS advantage, Dr. Chi pointed out, was generally consistent for the AA+P group across subgroups. Significant benefits for AA+P were also reported for a range of secondary endpoints: time to pain progression, time to skeletal-related event, time to chemotherapy initiation, time to subsequent prostate cancer therapy, and time from randomization to subsequent therapy/death. Particularly for time to pain progression, the AA+P benefit was substantial (47.4 months vs. 16.6 months for ADT + placebo; HR, 0.72; P = 0.0002). Also, OS in patients with high-volume disease was significantly longer for AA+P (49.7 months vs. 33.3 months; HR, 0.62; P = 0.0001). The AA+P advantage in low-volume disease was non-significant (P = 0.1242).
Dr. Chi noted that three treatment-related deaths were reported (0.5%) in both the AA+P and placebo groups. He concluded, “These findings thus reinforce the addition of AA+P to ADT as a standard of care for patients with newly diagnosed metastatic castrate-sensitive prostate cancer.”
Pembrolizumab Plus Axitinib Versus Sunitinib As First-line Therapy for Locally Advanced or Metastatic Renal Cell Carcinoma: Phase 3 KEYNOTE-426 Study
- Thomas Powles, MD, Professor of Urology Oncology at Barts Cancer Institute, London, England
In patients with previously untreated metastatic renal cell carcinoma (mRCC), overall survival (OS) and progression-free survival (PFS) were significantly longer for the combination of pembrolizumab and axitinib than for sunitinib, according to phase 3 KEYNOTE-426 study findings. Objective response rates were also higher for the combination, Dr. Thomas Powles said in an ASCO-GU pre-meeting press webcast.
Pembrolizumab is a PD-1 immune checkpoint inhibitor, and axitinib is an antiangiogenic agent. Separately, they have demonstrated first-line efficacy in mRCC, and in a phase 1b study, the combination of the two showed manageable safety and a high response rate (73%) in this population. Dr. Powles noted that axitinib was easier to combine with pembrolizumab than other angiogenic agents in the same class as sunitinib.
KEYNOTE-426 investigators enrolled 861 patients (median age, 62 years; 73% male) with untreated clear-cell mRCC and randomly assigned them to oral sunitinib once daily (50 mg for the first four weeks of each six-week cycle) or to combination therapy with pembrolizumab (200 mg intravenously every three weeks for up to 35 cycles) plus oral axitinib (twice a day). Treatment was continued until disease progression, high toxicity, or withdrawal from the study. The primary endpoints were OS and PFS.
At a median follow-up of 12.8 months, OS analysis for the pembrolizumab/axitinib combination showed risk of death to be reduced by 47% compared to sunitinib (hazard ratio [HR], 0.53; P < 0.0001). Twelve-month OS was 89.9% in the combination group and 78.3% in the sunitinib group. Neither risk status nor programmed death ligand 1( PD-L1) status affected OS, Dr. Powles noted.
Median PFS was 15.1 months in the combination group and 11.1 months in the sunitinib group (HR, 0.69; P = 0.0001).
Objective response rates were 59.3% and 35.7% in the combination and sunitinib groups, respectively; median response duration was not yet reached in the combination arm and was 15.2 months in the sunitinib arm.
Dr. Powles observed that treatment is ongoing in 59.0% of patients in the combination group and in 43.1% of the sunitinib group patients.
Serious treatment-related side-effect rates were 62.9% and 58.1% in the combination and sunitinib groups, respectively. Discontinuations attributed to side effects occurred at rates of 8.2% and 10.1%, respectively. In the combination group, 25.9% discontinued one or both of the therapies. Dr. Powles described the pembrolizumab/axitinib safety profile as “manageable.”
He commented, “Overall, we have not previously seen a renal cancer study which has improved response, progression-free survival, and overall survival. This is, therefore, a major step forward in renal cancer.”
Dr. Powles concluded, “Pembrolizumab plus axitinib should be a new standard therapy for first-line treatment of patients with mRCC.”
The ASCO GU press webcast moderator, Robert Dreicer, MD, stated: “Metastatic kidney cancer has very low survival rates and there have been few significant advances in treating this advanced form of the disease. These findings may help provide an important new option for patients.”
TIVO-3: A Phase 3, Randomized, Controlled, Multicenter, Open-label Study to Compare Tivozanib to Sorafenib in Subjects with Refractory Advanced Renal Cell Carcinoma
- Brian I. Rini, MD, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
In patients with refractory advanced renal cell carcinoma (RCC) in the TIVO-3 trial, tivozanib significantly improved progression-free survival (PFS) and overall response rate (ORR) compared to sorafenib. Also, Dr. Brian Rini said in an oral presentation, responses with tivozanib were more durable than the sorafenib responses.
Tivozanib is a potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3 with a long half-life. It is designed to optimize VEGFR blockade and minimize off-target toxicities, Dr. Rini said. In the phase 3 TIVO-1 study of tivozanib versus sorafenib, PFS for tivozanib was superior (11.9 vs. 9.1 months; hazard ratio [HR], 0.80; P = 0.04), as was ORR (33% vs. 23%). Overall survival (OS), however, was not longer for tivozanib (28.8 months vs. 29.3 months (HR, 1.25; P = 0.105). The finding, Dr. Rini speculated, was likely caused by an imbalance in the number of crossovers to active treatments. TIVO-3, he noted, was launched to confirm the PFS results in TIVO-1.
TIVO-3 investigators enrolled 350 patients with mRCC for whom two or three prior systemic regimens had failed (one among those being a VEGFR tyrosine kinase inhibitor), and randomized them 1:1 to tivozanib (1.5 mg orally, once daily for three weeks of a four-week cycle) or sorafenib (400 mg orally, twice daily continuously). Patients were treated until progression or unacceptable toxicity. The primary endpoint was PFS as assessed by the Independent Review Committee (IRC).
Dr. Rini reported that the median age was 63 years (72.5% male). Discontinuation rates were higher in the sorafenib group than the tivozanib group (92% vs. 79%), with disease progression being the most common cause (52% vs. 48%, respectively) and with adverse events being the cause more often in the sorafenib group (23% vs. 13%, respectively). More patients in the tivozanib group remained on study therapy (19% vs. 5%, respectively).
Median PFS was 5.6 months (95% CI; 5.3, 7.3) in the tivozanib group and 3.9 months in the sorafenib group (3.7, 5.6; HR, 0.73; P = 0.0165). One-year and two-year PFS was 28%/18% for tivozanib and 11%/5% for sorafenib. PFS favored tivozanib in all subgroups except those in the poor International mRCC Database Consortium risk category. A gradient of diminishing response from favorable-to-poor risk was observed.
ORR was significantly (P = 0.02) higher with tivozanib (18%) than with sorafenib (8%), as was duration of response probability at one and two years (71%/55% for tivozanib vs. 55%/0% for sorafenib). Also, a higher percentage of patients in the tivozanib group remain on study therapy (19% vs. 5%, respectively).
Adverse events leading to dose reductions were less common in the tivozanib group than the sorafenib group (24% vs. 38%), as were adverse events leading to dose interruptions (48% vs. 63%, respectively). Hypertension was the most common adverse event with tivozanib (grade 3–4, 20%). The incidence of off-target effects, such as hand–foot syndrome, diarrhea, and rash, was lower among tivozanib- than sorafenib-treated participants.
OS data remain immature, Dr. Rini said. He concluded, “Tivozanib significantly improves PFS and ORR compared to sorafenib in patients with treatment-refractory advanced RCC.”