A phase II clinical trial published in Annals of Oncology on September 16, 2024, has demonstrated promising results for dual immune checkpoint inhibitor therapy in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC). The INSPIRE trial, conducted at Radboud University Medical Center in the Netherlands, evaluated the efficacy and safety of combination nivolumab and ipilimumab in molecularly selected mCRPC patients.
The study, funded by Bristol Myers Squibb and the Radboud Oncology Fund, aimed to assess the potential of dual checkpoint inhibition in mCRPC patients with specific molecular profiles that may predict increased immunogenicity. These included mismatch repair deficiency (dMMR), high tumor mutational burden (hTMB), BRCA2 mutations (BRCAm), and biallelic CDK12 inactivation (CDK12i).
A total of 69 patients were enrolled between January 2021 and February 2024, with 65 patients included in the efficacy cohort (cohort A) and 4 patients in a separate cohort for those with prior immune checkpoint inhibitor monotherapy (cohort B). The median age of participants was 69 years. Inclusion criteria required patients to have progressive mCRPC and at least one of the specified molecular alterations. Patients were excluded if they had prior immune checkpoint inhibitor therapy (except for cohort B) or required chronic corticosteroid therapy above specified doses.
Treatment consisted of nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate at 6 months (DCR >6), with a target of surpassing 22%.
The results showed that the study met its primary endpoint, with a DCR >6 of 38% (95% CI 27-51%) in cohort A. Notably, efficacy varied significantly across molecular subgroups. Patients with dMMR demonstrated exceptional responses, with a DCR >6 of 81% (95% CI 58-95%) and a median progression-free survival (PFS) of 32.7 months. In contrast, the hTMB, BRCAm, and CDK12i subgroups showed more modest responses, with DCR >6 of 25%, 15%, and 19%, respectively.
The objective response rate in cohort A was 38% (95% CI 22-55%), with all responses being partial. Median PFS for the entire cohort A was 4.0 months (95% CI 3.5-12.0 months), while median overall survival was 19.9 months (95% CI 11.1 months-not reached).
Safety analysis revealed that 48% of patients experienced grade ≥3 treatment-related adverse events (TRAEs). The most common grade ≥3 TRAEs were diarrhea and elevated transaminases, each occurring in 10% of patients. Treatment discontinuation due to TRAEs occurred in 20% of patients, and there were two treatment-related deaths.
The study has several limitations, including its non-comparative design, single-institution nature, and relatively small sample sizes within each molecular subgroup. Additionally, the use of 6-month DCR as the primary endpoint, while pragmatic for including patients without RECIST-measurable disease, is not a conventional primary endpoint for mCRPC trials.
The authors concluded that dual immune checkpoint inhibition shows promising efficacy in molecularly selected mCRPC patients, particularly those with dMMR. They emphasized the need for early identification of dMMR patients to optimize treatment sequencing, suggesting that dual checkpoint inhibition may be most effective when administered before taxane chemotherapy in this subgroup.
The potential clinical impact of this study is significant, especially for patients with dMMR mCRPC. The exceptional efficacy observed in this subgroup may warrant consideration of early molecular testing and first-line use of dual checkpoint inhibition in dMMR mCRPC. However, the authors note that the considerable toxicity associated with the treatment regimen necessitates careful patient selection.
For patients with hTMB (without dMMR), BRCAm, or CDK12i, the modest efficacy observed suggests that these genomic alterations alone may not be sufficient to predict response to dual checkpoint inhibition. Further research is needed to identify additional biomarkers or combinations of markers that could better select patients likely to benefit from this approach.
The study also highlights the importance of optimizing the timing and duration of immune checkpoint inhibitor therapy in mCRPC. Exploratory analyses suggested that prior taxane treatment, presence of pain at baseline, and high alkaline phosphatase levels were associated with poorer outcomes, underscoring the potential benefit of earlier treatment with checkpoint inhibitors in suitable patients.
In conclusion, this phase II trial provides valuable insights into the use of dual checkpoint inhibition in molecularly selected mCRPC patients. While the results are particularly encouraging for dMMR patients, they also emphasize the need for further research to refine patient selection criteria and optimize treatment strategies for this challenging disease.
References
van Wilpe S, Kloots ISH, Slootbeek PHJ, et al. Ipilimumab with nivolumab in molecularly selected patients with castration-resistant prostate cancer: primary analysis of the phase II INSPIRE trial. Ann Oncol. 2024;35(12):1126-1137. doi:10.1016/j.annonc.2024.09.004
