IMMUNOTHERAPY FOR PROSTATE CANCER

Immune checkpoint inhibitor monotherapy has so far had little success in the treatment of prostate cancer, in contrast to the clinical benefit seen in many other cancer types, including melanoma, as well as lung and kidney cancer combination therapy, which has now shown activity in advanced disease.

And so there is interest in the activity seen in advanced metastatic prostate cancerwith the combination of ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab(Opdivo, Bristol-Myers Squibb).

The data come from a phase 2 trial that were discussed here at the Genitourinary Cancers Symposium (GUCS) 2019.

"In a malignancy where immune checkpoint monotherapy has shown limited activity, nivolumab plus ipilimumab demonstrated antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC)," said study author Padmanee Sharma, MD, PhD, professor of Genitourinary Medical Oncology and Immunology at the University of Texas MD Anderson Cancer Center in Houston.

"Deep and durable object responses, as well as falls in prostate-specific antigen (PSA < 2 ng/mL) levels, we

re observed in a subgroup of patients," said Sharma, adding that the "preliminary data suggest that biomarkers have a role in identifying patients with mCRPC likely to respond to immunotherapy."

However, treatment tolerability was an issue.

Antitumor Activity Observed

The results come from the CheckMate 650 study, conducted in 90 patients with mCRPC who were divided into two cohorts based on previous treatment. Cohort 1 was comprised of symptomatic/minimally symptomatic patients who progressed after treatment with second-generation hormone therapy and had not received chemotherapy for mCRPC, and cohort 2 also included patients who had progressed after taxane-based chemotherapy.

A large proportion of patients (> 50%) had been previously treated with abiraterone(Zytiga, Janssen) or enzalutamide (Xtandi, Astellas).

Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, and then maintenance therapy with nivolumab 480 mg every 4 weeks.

The combination showed an objective response rate of 25% in cohort 1 and 10% in cohort 2. There were two complete responses in each cohort, and partial responses were observed in six patients in cohort 1 and one patient in cohort 2. Additionally, 13 patients achieved stable disease in cohort 1 and 11 patients in cohort 2.

Benefit was observed regardless of prior exposure to chemotherapy but appeared to be more pronounced in patients who had not received prior chemotherapy, Sharma commented.  

Median time to response was 1.9 months in the first cohort and 2.1 months in the second cohort.

However, disease progression was observed in 51.1% of patients in cohort 1 and 44.4% in cohort 2.

Median radiographic progression-free survival was 5.5 months in cohort 1 and 3.8 months in cohort 2, and overall survival was 19.0 and 15.2 months, respectively.

Mutational Tumor Burden and Outcomes

When looking at exploratory endpoints, the authors noted that a PSA response was observed in 17.6% of patients in cohort 1 and 10.0% of those in cohort 2. In the first cohort, five patients demonstrated a PSA < 0.2 ng/mL, as did two patients in the second cohort.

Of this patient subset, four from the first cohort and one from the second cohort also had an ongoing objective response, Sharma pointed out.

A biomarker analysis was conducted and results showed that higher tumor mutational burden was associated with response, and there was a significant association between higher tumor mutational burden and improved outcomes. High tumor mutational burden was associated with significantly longer radiographic progression-free survival  (7.4 vs 2.4 months; P < .0001).

A relationship was also observed between tumor mutational burden and PSA response. High versus low tumor mutational burden was associated with a higher PSA response (38.5% vs 0%) and achieving PSA < 0.2 ng/mL (30.8% vs 0%) in cohort 1, but the difference was less pronounced in cohort 2, at 14.3% vs 11.1% and 14.3% vs 0%, respectively.

When progression-free survival was evaluated by PD-L1 status, the median was 5.6 months for those with PD-L1 ≥ 1% and 3.9 months for those with PD-L1 < 1%.

High Discontinuation Rate

However, a drawback to combination ipilimumab and nivolumab is toxicity, which appears to affect patients with prostate cancer more than those with other cancer types.

In this study, almost all patients experienced treatment-related adverse events of any grade. Grade 3-5 events were experienced by 42.2% of patients in cohort 1 and 53.3% of patients in cohort 2. Adverse events also caused about a third of patients in cohort 1 and 2 to stop therapy (33.3% vs 35.6%, respectively).

The most common adverse events were diarrhea, fatigue, skin rash, nausea, and hypothyroidism, and there were four treatment-related deaths (two in each cohort).

Sharma commented that although the safety profile of both drugs was generally consistent with prior studies, the "dose/schedule optimization will be important for patients with mCRPC given the number of patients not completing all four combination doses and discontinuing study treatment due to toxicity."

During a discussion of the study, William Kevin Kelly, DO, professor of medical oncology at the Sidney Kimmel Cancer Center and Jefferson Health in Philadelphia, Pennsylvania, pointed out that the median duration of therapy didn't exceed 2.1 months.

"The thing that's dramatic about this is whether the drug was tolerable or not in this population," he said, as only a small percentage of patients in both cohorts actually received the four planned treatment cycles.

"Only a third of patients got to maintenance dose," he pointed out. "It was discontinued for toxicity by 50% in cohort 1 and 44% in cohort 2."

Kelly commented that other studies of this combination in patients with other types of cancer suggested better tolerability of the regimen. For example, in a renal cell carcinoma study, 79% of patients received all four treatments, and in a melanoma study, 50% of patients were able to tolerate the full regimen.

In contrast, only 33% of mCRPC patients in cohort 1 and 24% of those in cohort 2 received the planned four treatments.

"For some reason, prostate cancer patients are not tolerating therapy as well as the other populations," he said. "As I teach all my fellows, if we can't get the drug in, patients don't respond," he added.

The study was sponsored by Bristol-Myers Squibb. Sharma has reported financial relationships with Amgen, Astellas Pharma, AstraZeneca, BioAtla, Bristol-Myers Squibb, Constellation Pharmaceuticals, EMD Serono, Evelo, GlaxoSmithKline, Jounce Therapeutics, Kite Pharma, MSD, Neon Therapeutics, Oncolytics, and Pieris Pharmaceuticals. Several coauthors have also disclosed relationships with industry.

Genitourinary Cancers Symposium 2019. Presented February 14, 2019. Abstract 142