This is an open label, prospective, trial that begins with a phase Ib safety run-in followed
by a phase II expansion cohort.
Drug combination rationale Radium-223 is a calcium-mimetic radiopharmaceutical that has been
approved for treatment of metastatic prostate cancer. Accumulating in areas of high bone
turnover, such as bony metastases, radium-223 emits high energy alpha radiation within a
narrow range thereby limiting toxicity (12). A pivotal phase III trial among patients with
mCRPC and symptomatic bony metastases led to the approval of radium-223 (13). When compared
to placebo, treatment with radium-223 resulted in an improved overall survival (OS) (3.6
months, HR 0.70, 95% CI 0.58 to 0.83). This benefit was accompanied by no clinically
significant difference in grade 3-4 adverse events between the two arms other than
cytopenias. Patients also experienced a significant improvement in quality of life measures
(14) with radium-223 compared to placebo.
Immunotherapy is a promising area of research in many areas of oncology. However, only
PROVENGE is currently approved in mCRPC, with ipilimumab, pembrolizumab, and nivolumab
previously demonstrating limited clinical efficacy. Beer et al evaluated ipilimumab
monotherapy versus placebo in asymptomatic or minimally symptomatic men with mCRPC (15).
Patients could not have visceral metastatic disease or prior chemotherapy. There was no
improvement in OS, the primary endpoint of this study, with ipilimumab over placebo. The
median OS was 28.7 months (95% CI, 24.5 to 32.5 months) for ipilimumab versus 29.7 months
(95% CI, 26.1 to 34.2 months) with placebo (HR 1.11; 95.87% CI, 0.88-1.39; P = .3667). There
was suggestion of some clinical response with the ipilimumab arm demonstrating more PSA
responses (23% vs 8%) and a longer median PFS (5.6 months vs 3.8 months). de Bono reported on
the clinical efficacy of single agent pembrolizumab in mCRPC patients (16). They evaluated
clinical activity based on the disease control rate (DCR), defined as no disease progression
(i.e. CR + PR + SD). Eleven percent of patients had DCR of 6 months or greater, median follow
up less than 12 months at the time of the study reporting. 19% of patients experienced any
degree of PSA decline and 11% of patients had a 50% reduction or greater to PSA as the best
response to therapy. Topalian et al evaluated the early safety and antitumor activity of
monotherapy nivolumab in the basket trial CA209-003. Of the 296 patients treated, 17 were
patients with CRPC. However, no objective responses (complete response or partial response)
were seen in this patient population (17). Overall the response rate is modest, demonstrating
some activity with immunotherapy but suggesting that combination therapy may be a more
attractive approach.
Recently the results of a prospective clinical trial of ipilimumab (CTLA-4 antagonist) and
nivolumab (PD-1 antagonist) combination was reported in metastatic castration-resistant
prostate cancer (18). 79 patients were treated and included patients who had previously
progressed on docetaxel (cohort 2) and those who were docetaxel naïve (cohort 1). The
objective response rate was 10% and 26% respectively. This therapy led to a significant
number of significant adverse events, with a grade 3-4 AE rate of 51% and 39% respectively. A
separate prospective pilot clinical trial in patients with high-risk disease as defined by
presence of AR-V7 expression was also recently reported. The objective response rate was 25%
in men with RECIST measurable disease and a 13% PSA response rate was observed overall (19).
These studies demonstrate the significant improvement in clinical activity of combination
immunotherapy over single-agent treatment in patients with metastatic castration-resistant
prostate cancer. Overall the responses are still low even with the combination of multiple
checkpoint inhibitors.
Many intrinsic mechanisms of resistance may account for this relative lack of efficacy
including minimal baseline immune infiltration within the tumor (20), presence of
immunosuppressive cells such as myeloid derived suppressor cells within the tumor
microenvironment (21), and low tumor mutation burden leading to a lack of significant
antigenicity (22).
External beam radiation therapy (EBRT) has been shown in preclinical models to alter the
tumor microenvironment and may work synergistically with PD-1 inhibition. EBRT plus PD-1
inhibition resulted in improved tumor control compared to either agent alone in murine models
(23). Alteration to PD-1 expression has also been observed with radium-223, suggesting
potential synergy of these two strategies (24). Promotion of antigen presentation and antigen
spreading may account for some of the beneficial effects of this combination in addition to
the observed immunomodulatory effects on T-lymphocyte populations (25). The combination of
EBRT plus checkpoint inhibitors has demonstrated promising efficacy in some early phase
clinical trials (26,27).
Kwon et al evaluated men with mCRPC who had progressed on docetaxel to receive radiation
therapy to a bone metastasis followed by randomization to ipilimumab or placebo (28). The
median OS was prolonged with ipilimumab (11.2 months vs 10.0 months). However, given high
toxicity early with ipilimumab, the primary endpoint was not statistically significant (HR
0.85; 95% CI 0.72-1.00; p=0.053). This benefit was even more evident in patients with good
risk disease (median OS 22.7 mo vs 15.8 mo; HR 0.62, 95% CI 0.45-0.86; p=0.0038). This
suggests that radiation therapy may provide added benefit to immunotherapy compared to
ipilimumab monotherapy, especially in patients with a more favorable biology such as in
patients lacking visceral metastasis (29) as will be tested in this clinical trial of
nivolumab plus radium-223.
T-regulatory cells (defined as CD4+/FOXP3+ T-cells) are immune suppressive. A higher
concentration in PBMCs and tumor infiltrating lymphocytes has been shown to correlate with an
increased risk of disease relapse in localized renal cell carcinoma (30). Additionally, it
also is associated with a worse prognosis in patients with metastatic melanoma (31). CD8+
T-cells are cytotoxic to tumor cells. A high level of CD8+ T-cells has recently been
associated with an increased response to immunotherapy in patients with metastatic renal cell
carcinoma (32). CD8+ and CD4+/FOXP3+ T-cell concentrations are associated with overall
prognosis in patients with metastatic melanoma (33). The concentration of CD8+ lymphocytes is
low in patients with prostate cancer (34). Animal models suggest that the combination of
radiation therapy and checkpoint inhibitors provides synergistic activity through the
alteration of the tumor microenvironment with increased CD8+ T-lymphocytes (35).
Radium-223 may overcome some of these mechanisms of resistance to single-agent checkpoint
inhibitor therapy though immunomodulatory effects of radiation therapy to the
microenvironment in addition to direct cytotoxicity of tumor cells leading to increased
antigen presentation. We hypothesize that radium-223 plus nivolumab will result in
significant, favorable tumor microenvironment alterations leading to significant clinical
activity in mCRPC.
Inclusion Criteria:
- Male subject aged ≥ 18 years.
- Histologically confirmed adenocarcinoma of the prostate.
- Diagnosis of metastatic, castration-resistant prostate cancer without evidence of
visceral metastasis.
- Symptomatic bone metastasis as determined by the treating physician.
- Castrate levels of testosterone as defined as < 50 ng/dL.
- ECOG Performance Status ≤ 2.
- Adequate organ function as defined as:
- Hematologic:
- White blood cell count (WBC) ≥ 2000/mm3
- Absolute neutrophil count (ANC) ≥ 1500/mm3
- Platelet count ≥ 100,000/mm3
- Hemoglobin ≥ 10g/dL
- Hepatic:
- Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless
there is a known history of Gilbert's syndrome.
- AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN
- Renal:
- Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula:
- Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)
- Highly effective contraception throughout the study and for at least 7 months after
last study treatment administration if the risk of conception exists.
- Recovery to baseline or ≤ Grade 1 CTCAE v 5.0 from toxicities related to any prior
treatments, unless AE(s) are clinically non-significant and/or stable on supportive
therapy as determined by the treating physician.
- Able to provide informed consent and willing to sign an approved consent form that
conforms to federal and institutional guidelines.
Exclusion Criteria:
- Active or prior autoimmune disease that might deteriorate when receiving an
immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo-or
hyperthyroid disease or other autoimmune diseases in the opinion of the treating
physician that is clinically insignificant or not requiring systemic immunosuppressive
treatment are eligible.
- Current use of immunosuppressive medication at the time of study enrollment, EXCEPT
for the following permitted steroids:
- Intranasal, inhaled, topical steroids, eye drops or local steroid injection (eg,
intra-articular injection);
- Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
equivalent;
- Steroids as premedication for hypersensitivity reactions (eg, computed tomography
(CT) scan premedication).
- Prior or concurrent malignancy (other than adenocarcinoma of the prostate).
--Note: Patients with prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial as approved by
the Principle Investigator.
- The subject has uncontrolled, significant intercurrent or recent illness that would
preclude safe study participation.
- Clinically significant cardiovascular disease: myocardial infarction (<6 months prior
to enrollment), unstable angina, congestive heart failure (> New York Heart
Association Classification Class IIB) or a serious cardiac arrhythmia requiring
medication.
- Known HIV infection with a detectable viral load at the time of screening.
--Note: Patients on effective antiretroviral therapy with an undetectable viral load
at the time of screening are eligible for this trial.
- Known chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with a
detectable viral load.
--Note: Patients with an undetectable HBV viral load are eligible. Patients with an
undetectable HCV viral load are eligible.
- Live attenuated vaccinations within 4 weeks of the first dose of radium-223 and while
on trial is prohibited.
- Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v5.0 Grade ≥ 3).
- Subjects taking prohibited medications as described in Section 6.4.1. A washout period
of prohibited medications for a period of at least 5 half-lives or as clinically
indicated should occur prior to the start of treatment.
