She began by highlighting the rationale and principles of combination therapies with immune checkpoint inhibition. The guiding rationale is to overcome primary or acquired resistance to these therapies. This may be accomplished in a number of approaches:
1. with the combination of two known effective therapies to achieve synergy: eg. combining traditional androgen deprivation therapy with luteinizing hormone-releasing hormone (LHRH) agonists with abiraterone acetate and prednisone.
2. with the combination of one treatment which is ineffective as monotherapy with one known to be effective to enhance its effectiveness: eg. the addition of anti-PD-1 therapy to enzalutamide.
3. with the combination of two treatments which are each ineffective as monotherapy with the hope that combinations will confer sensitivity to one or more of the agents: eg. the combination of anti-PD-1 and anti-CTLA4 agents.
As combination therapy, immune checkpoint inhibition has been combined with a number of known, effective, standard of care treatments for advanced prostate cancer including radiation therapy, radiopharmaceuticals, chemotherapy, and poly-ADP ribose polymerase (PARP) inhibitors, as well as other agents that are not as established in the treatment of patients with prostate cancer.
It is known, through prior studies of the abscopal effect, that radiotherapy is immunogenic. The rationale, therefore, is that radiotherapy would include the release of a tumor antigen which would then provide a substrate for the primed immune system.
However, to date, evidence has shown that the abscopal effect is rare, though combination therapy does appear safe.
In many other disease sites including lung cancer (small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) and breast cancer (triple-negative breast cancer (TNBC), combination therapy with chemotherapy and immune checkpoint inhibition has become standard of care. Mechanisms of action include a reduction in tumor burden, activation of an antigen cascade, reduction of myeloid-derived suppressor cells (MDSCs), reduction of T-regulatory cells, and restoration of Natural Killer (NK) cell effector function.
Recent data has demonstrated the role of PARP inhibitors in advanced prostate cancer, particularly in patients with DNA defect repair (DDR) mutations. There are three proposed mechanisms that Dr. Autio highlighted explaining why these agents may work in combination with immune checkpoint inhibitors:
1. DNA damage from PARP inhibition may increase the release of cytosolic DNA leading to activation of the cGAS-STING pathway with stimulation of interferon-gamma.
2. DNA damage from PARP inhibition leads to neo-antigen release, acting as a substrate for a primed immune system.
3. PARP inhibition, apart from DNA damage effects, leads to upregulation of PD-L1.
A phase II trial of Olaparib and durvalumab in patients with metastatic castrate-resistant prostate cancer (mCRPC) demonstrated promising radiographic/prostate specific antigen (PSA) responses (9 of 17 patients). Two of 3 responders had DNA damage response (DDR) mutations suggesting that these patients may derive the greatest benefit.
There is also a rationale for combining immune checkpoint inhibitors with anti-angiogenic agents. This has been demonstrated to be an effective strategy in renal cell carcinoma. The rationale is that tumor vasculature can create and endothelial immune cell barrier. Treatment may then alleviate immunosuppression and hypoxia and allow effector cell infiltration.
The phase Ib COSMIC-02 trial assessed the combination of cabozantinib and atezolizumab in patients with mCRPC and demonstrated an objective response rate of 32% with 10/34 patients having a PSA50 response.
There are further novel combinations of immunotherapeutic approaches with immune checkpoint inhibitors including cytokines, adenosine (which targets immunosuppressive pathways), vaccines, and bi-specific T cell engager (BiTE).
Numerous cytokines have been implicated including TGF-beta, IL23, IL6, and IL8. In particular, TGF-beta has been found in bone metastasis. These metastases release TGF-beta which, in combination with IL6, affects T-reg and T effector cell function. Combination therapy with immune checkpoint inhibitors and anti-TGF-beta agents promotes CD8 effect memory cell expansion and control of tumor growth.
An immune-suppressive tumor microenvironment is, as Dr. Autio explained, a common theme in the failure of single-agent immune checkpoint therapy. There are numerous approaches to address this including targeting TAM with CSF1r inhibition and targeting adenosine with anti-CD73 or anti-CD39 antibodies or with A2AR antagonists.
A phase Ia trial of the A2AR antagonist Ciforadenant +/- durvalumab demonstrated a complete response rate of 37.5% among patients with mCRPC.
The combination of vaccination with immune checkpoint inhibition is also promising. Sipuleucel-T set the precedent for cellular vaccines in advanced prostate cancer. Multiple ongoing trials are assessing immune checkpoint inhibitors plus vaccines to common tumor antigens such as PSA, PSMA, PSCA, and PAP.
Bi-specific T cell engagers (BiTE) are agents that bind CD3 T cells and PSMA expressing tumor cells to trigger a T-cell mediated tumor death. These agents are approved in hematologic malignancies (ALL) and are under investigation in combination with immune checkpoint inhibition for both efficacy and safety, with the main toxicity being cytokine release syndrome.
Moving forward, Dr. Autio highlighted that it will be important to understand what is unique about prostate cancer such that we can design rationale treatment approaches. Novel clinical trial designs with combinations of therapies are likely to be the next step – she highlighted the “PORTER” platform as an example.
As of 2020, most trials assessing immune checkpoint inhibitors in prostate cancer are in the advanced stages of disease (mCRPC) and are phase II designs assessing combination therapy.
Moving forward, she forecasts use in earlier disease states, in greater numbers of combinations including with chemotherapy, and using PSA directed approaches (radioligands, vaccines, bi-specifics, and CAR approaches).
Presented by: Karen A. Autio, MD, MSc, Medical Oncology Specialist at Memorial Sloan Kettering Cancer Center, New York City, New York
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, @WallisCJD on Twitter at the ASCO20 Virtual Education Program, #ASCO20, August 8-10, 2020