The Phase III TRITON3 trial (NCT02975934) reported potentially practice-changing interim results, demonstrating improved radiographic progression-free survival (rPFS) with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring deleterious BRCA alterations. 1
Up to 25% of patients with metastatic prostate cancer have deleterious alterations in DNA damage response (DDR) genes, including BRCA1, BRCA2 and ATM. 2 Prostate cancers with DDR alterations may be particularly susceptible to targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), such as rucaparib. 2 Rucaparib was granted accelerated FDA approval for the treatment of BRCA1 or BRCA2 altered mCRPC based on the results of the single-arm Phase II TRITON2 trial (NCT02952534), demonstrating improved response and duration with rucaparib in the post-docetaxel setting. 3 TRITON3 was designed as a randomized Phase III study to confirm the efficacy of rucaparib in the pre-docetaxel setting. 4
The TRITON3 trial investigated rucaparib versus physicians choice in patients with chemotherapy-naïve mCRPC with BRCA1/2 or ATM alterations. As of August 25, 2022, 302 patients with deleterious genetic alterations in BRCA1/2 (n=302) or ATM (n=103), as well as disease progression after 1 prior second-generation androgen pathway inhibitor therapy (ARPI), were randomized 2:1 to receive rucaparib or physician’s choice, respectively. The primary endpoint was rPFS and overall-survival (OS) was a key secondary endpoint. In the BRCA subgroup, median rPFS was 11.2 months in patients treated with rucaparib versus 6.4 months in patients treated with physicians choice (HR, 0.50; 95% CI, 0.36-0.69; P <.001). In the intention-to-treat (ITT) population, rPFS was 10.2 months with rucaparib versus 6.4 months with physicians choice (HR, 0.61; 95% CI, 0.47-0.80; P <.001). In patients with ATM alterations, the median rPFS was 8.1 months with rucaparib versus 6.8 months with physician’s choice (HR, 0.95; 95% CI, 0.59-1.52; P =.84), a nonsignificant difference.
At the time of analysis, OS maturity was 54% in the BRCA subgroup and 59% in the ITT population. Median OS reached 24.3 months with rucaparib versus 20.8 months with physician’s choice in patients with BRCA alterations (HR, 0.81; 95% CI, 0.58-1.12; P = 0.21). In the ITT population, median OS was 23.6 months with rucaparib versus 20.9 months with physician’s choice (HR, 0.94; 95% CI, 0.72-1.23). No new safety signals were observed. Adverse effects (AE) led to treatment discontinuation for 15% of patients in the rucaparib arm compared with 22% of those in the physician’s choice group. The most common grade 3 or greater AEs in the rucaparib arm were anemia or decreased hemoglobin (24%), fatigue (7%), neutropenia (7%), thrombocytopenia or decreased platelet count (6%), and increased liver enzymes (5%).
Conclusively, TRITON3 met its primary endpoint of improved rPFS in the BRCA1/2 and ITT populations, however no significant benefit was observed in patients with ATM alterations. Although OS data demonstrated no statistical significance, the interim results suggest a trend towards improved OS with rucaparib.
An exploratory analysis of the Phase III IMvigor130 trial (NCT02807636) demonstrated that overall survival (OS) was not improved with atezolizumab compared to placebo plus platinum-based chemotherapy and gemcitabine in patients with untreated locally advanced or metastatic urothelial cancer (mUC). However, the results suggested a possible benefit with atezolizumab for patients with high PD-L1 expression (IC2/3), particularly in the cisplatin-ineligible population. 5
Two previous interim overall survival (OS) analyses from IMvigor130 demonstrated a non-significant OS benefit with atezolizumab monotherapy versus placebo plus platinum (investigator choice of carboplatin or cisplatin)/gemcitabine in patients with PD-L1-high mUC, as well as a favorable safety profile. Exploratory data showed clinical benefit with atezolizumab in cisplatin-ineligible patients with IC2/3 tumors.
Patients were randomized 1:1:1 to receive atezolizumab plus platinum/gemcitabine, atezolizumab monotherapy, or platinum/gemcitabine. OS was a primary endpoint, however, due to the statistical testing hierarchy, no formal comparison of OS in atezolizumab monotherapy versus platinum/gemcitabine was performed in the intention-to-treat (ITT) population and IC2/3 patients. Secondary endpoints included overall response rate (ORR) and duration of response (DOR), and safety. Subgroup analyses of OS in cisplatin-ineligible patients and disease control rate were exploratory.
As of the data cutoff in August 2022, the time since the last patient was randomized was 49 months. At this time, 19% of patients remained on study in the atezolizumab monotherapy arm versus 14% in the chemotherapy arm. Most study discontinuations in the atezolizumab and chemotherapy arms were due to death, at 73% and 74%, respectively.
OS data did not demonstrate a benefit in the ITT population. The 24-month OS rates were 34% with atezolizumab and 32% with platinum/gemcitabine. However, in patients with PD-L1 IC2/3, median OS was 27.5 months (95% CI, 17.7-49.4) with atezolizumab (n = 88) versus 16.7 months (95% CI, 10.0-26.1) with chemotherapy (n = 85) (HR, 0.70; 95% CI, 0.48-1.03).
In the cisplatin-ineligible IC2/3 subgroup, median OS was 18.6 months (95% CI, 14.0-49.4) with atezolizumab (n = 50) versus 10.0 months (95% CI, 7.4-18.1) with chemotherapy (n = 43; HR, 0.56; 95% CI, 0.34-0.91).
ORR was 24.2% with atezolizumab versus 44.4% with chemotherapy and median duration of response was 29.6 months versus 8.1 months, respectively. In cisplatin-ineligible IC2/3 patients, ORR was 40% with atezolizumab and 32.6% (14/43) with chemotherapy. Median duration of response was not evaluable with atezolizumab and was 6.2 months with chemotherapy.
No new safety signals were reported. Of safety-evaluable patients, 16% with atezolizumab and 80% with chemotherapy had a grade 3/4 treatment-related adverse event; 1% and 4%, respectively, had a grade 5 treatment-related adverse event. In cisplatin-ineligible IC2/3 patients, ORR was 32.6% with atezolizumab versus 40% with chemotherapy. Median duration of response was 6.2 months with atezolizumab and not evaluable with chemotherapy.
Overall, atezolizumab continued to demonstrate better tolerability compared to chemotherapy. The exploratory data supports the use of atezolizumab monotherapy for first-line cisplatin-ineligible IC2/3 metastatic urothelial carcinoma.
The Phase III COSMIC-313 trial (NCT03937219) has previously reported significantly improved progression-free survival (PFS) with the triplet regimen of cabozantinib plus nivolumab plus ipilimumab (C+N+I) versus a control regimen of placebo plus nivolumab plus ipilimumab (N+I) in first-line advanced or metastatic renal cell carcinoma (RCC) of International Metastatic RCC Database Consortium (IMDC) intermediate- or poor-risk. 6 Outcomes analyzed by IMDC group were presented at the ASCO GU Cancers Symposium 2023. 7
Cabozantinib inhibits tyrosine kinases including MET, VEGFR, and TAM kinases (TYRO3, AXL, MER) and may promote an immune-permissive environment, thereby enhancing response to checkpoint inhibitors. The combination of the PD-1 inhibitor, nivolumab, and the CTLA-4 inhibitor, ipilimumab, is a standard first-line treatment option for patients with intermediate- or poor-risk advanced RCC. Cabozantinib is approved alone or in combination with nivolumab in the same setting by the FDA and EMA. COSMIC-313 was designed to examine the effect of C+N+I on the duration of PFS versus nivolumab plus ipilimumab, and is the first study to use a standard of care immune-oncology doublet as a control. 8
The primary endpoint of COSMIC-313 was duration of progression-free survival (PFS) per RECIST 1.1 as determined by blinded independent radiology committee (BIRC), with the secondary endpoint being duration of overall survival (OS). 855 patients with intermediate- or poor-risk RCC according to IMDC criteria were enrolled. Patients were randomly assigned 1:1 to receive either C+N+I or N+I.
Overall, 75% of patients were IMDC intermediate-risk and 25% were poor-risk. In the PFS intention-to-treat (PITT) population, a 26% reduction in risk of progression or death was observed with the triplet regimen versus doublet group after 20.2 months follow-up.
In patients with intermediate-risk, PFS was significantly improved with the triplet therapy of C+N+I (HR 0.63, 95% CI 0.47–0.85). The objective response rate (ORR) was 45% in the intermediate-risk subgroup in patients treated with C+N+I versus 36% with N+I, and the disease control rate (DCR) was 88% and 74%, respectively. For poor-risk patients, no difference in PFS and ORR was apparent, although DCR was numerically higher with C+N+I. The ORR for the poor-risk subgroup was 37% with C+N+I and 38% with N+I, and the DCR was 79% and 68%, respectively.
Grade 3/4 treatment-related adverse events (TRAEs) occurred in 74% of patients treated with C+N+I versus 42% treated with N+I in the intermediate-risk group, compared to 67% versus 38%, respectively, for the poor-risk group. TRAEs led to discontinuation of all treatment components in 14% versus 5%, respectively, for the intermediate-risk group and 5% versus 4%, respectively, for the poor-risk group.
In conclusion, these results were consistent with the previously-reported primary analysis, demonstrating a PFS benefit with the triplet therapy in both the overall population and intermediate-risk subgroup. Notably, no PFS benefit was observed in the poor-risk subgroup. Follow-up for OS data is ongoing.
Written by Ellie Jackson
Edited by Helena Gibbon
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