Analysis of novel immune checkpoint inhibitor combination strategies in metastatic prostate cancer: rationale and scientific hypotheses.
| Combination agents | Mechanism | Clinical phase | Trial ID | Indication | Primary endpoints | Scientific hypothesis & rationale for combination | Reference |
|---|---|---|---|---|---|---|---|
| Ipilimumab + nivolumab | Dual checkpoint blockade | II | NCT02985957 (CHECKMATE-650) | Metastatic CRPC | ORR and rPFS | Hypothesis: Concurrent CTLA-4 (priming) and PD-1 (effector) blockade can overcome the “cold” TME of mCRPC by promoting deeper T-cell infiltration and sustained activation, where single-agent therapy fails. | [43] |
| Ipilimumab + GVAX | Vaccination + immunotherapy | I | NCT01510288 | Metastatic CRPC | AE | Hypothesis: The GVAX vaccine provides a broad antigen source to prime and expand tumor-specific T-cells, which are then protected from exhaustion and inhibition by CTLA-4 blockade, creating a synergistic immune cycle. | [44] |
| Ipilimumab + nivolumab | Dual checkpoint blockade | II | NCT02601014 (STARVE-PC) | Metastatic CRPC with detectable AR-V7 transcript | PSA response | Hypothesis: AR-V7 positive tumors represent a more aggressive, treatment-resistant disease state that may harbor a distinct immune contexture, potentially making it more susceptible to intense dual immune checkpoint blockade. | [45] |
| Ipilimumab + nivolumab | Dual checkpoint blockade | II | NCT03061539 (NEPTUNES) | Metastatic CRPC with TMB | CRR | Hypothesis: High TMB generates more neoantigens, creating an intrinsically “hotter” TME. This pre-existing immune infiltration is predicted to be highly responsive to the powerful amplification provided by dual checkpoint inhibition. | [46] |
| Pembrolizumab + enzalutamide | Checkpoint blockade + ADT | 1b/II | NCT02861573 (KEYNOTE-365) | Metastatic CRPC | AE, PSA response, ORR | Hypothesis: Androgen receptor signaling inhibition can remodel the immunosuppressive TME and delay T-cell exhaustion. Combining it with PD-1 blockade may simultaneously remove suppressive signals (androgen & PD-1) to unleash a more potent anti-tumor response. | [47] |
| Pembrolizumab + enzalutamide | Checkpoint blockade + ADT | III | NCT03834493 (KEYNOTE-641) | Metastatic CRPC | OS and rPFS | Hypothesis: In a broad mCRPC population, the TME-remodeling effects of enzalutamide will convert a sufficient number of “cold” tumors to “hot”, allowing them to respond to PD-1 inhibition and thereby demonstrating a survival benefit at the population level (this primary hypothesis was not confirmed). | [48] |
| Nivolumab + CDX-301 + Poly-ICLC + SBRT | Immune activation + checkpoint + radiotherapy | I | NCT03835533 (PORTER) | Metastatic CRPC | CRR, 6-month DCR, rPFS, OS | Hypothesis: A multi-pronged “immunogenic primer” regimen—SBRT (in-situ vaccination), CDX-301 (dendritic cell expansion), and Poly-ICLC (TLR3 agonist)—will create a robust, inflamed TME that is then maintained and amplified by PD-1 blockade (nivolumab), overcoming profound immune ignorance. | [49] |
CRPC: castration-resistant prostate cancer; ORR: objective response rate; rPFS: radiographic progression-free survival; mCRPC: metastatic castration-resistant prostate cancer; AE: adverse event; PSA: prostate-specific antigen; AR-V7: androgen receptor splice variant 7; TMB: tumor mutational burden; CRR: composite response rate; ADT: androgen deprivation therapy; OS: overall survival; DCR: disease control rate; SBRT: stereotactic body radiotherapy; Poly-ICLC: polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose; CDX-301: Flt3 ligand; TME: tumor microenvironment; TLR3: Toll-like receptor 3. Adapted from Meng et al. [6] and Kim & Koo [5] with added strategic analysis (CC-BY).