Does Atezolizumab Boost Survival With Chemotherapy in Small Cell or Neuroendocrine Carcinoma of the Prostate?

Lance C. Pagliaro, MD

A correlation between small cell or neuroendocrine carcinoma of the prostate and poor survival outcomes was revealed, despite treatment with the combination of the immunotherapy agent atezolizumab (Tecentriq) and chemotherapy, according to an institutional study conducted within the Mayo Clinic’s Division of Medical Oncology.

The exploration of this combination in prostate cancer was influenced by the survival benefit observed with atezolizumab and chemotherapy in patients with extensive-stage small cell lung cancer (SCLC). It is a common clinical practice to use regimens from the SCLC space to treat rare extrapulmonary small cell carcinoma, therefore oncologists at the Mayo Clinic sought to test the treatment strategy in their institution.

“Recent introduction of checkpoint inhibitor therapy for SCC of the prostate was based on extrapolation from studies in small-cell lung cancer. We wanted to review the outcomes for such patients who had received chemo-immunotherapy treatment at Mayo Clinic, the study lead Lance C. Pagliaro, MD, professor of oncology, Division of Medical Oncology, Department of Oncology at Mayo Clinic, told Targeted Oncology™ in an interview.

To investigate their theory, the investigators used an institutional database to find patients who were treated with immune checkpoint inhibitors like atezolizumab, pembrolizumab (Keytruda), nivolumab (Opdivo), and durvalumab (Imfinzi). From those search results, the investigators then narrowed the results to exclude patients who received immunotherapies other than atezolizumab, considering these patients were more likely to have had a platinum- and etoposide-based chemotherapy backbone. The second reason for isolating the data of patients treated with atezolizumab was that a significant heterogeneity in line of therapy and concomitant therapy administration was seen in the other populations.

The Kaplan-Meier method was used to determine the association between adding atezolizumab to standard chemotherapy and survival outcomes. A total of 7 men with small cell or neuroendocrine carcinoma of the prostate were identified from the data pool and of those patients, 6 received the combination of carboplatin, etoposide, and atezolizumab in the frontline setting. One patient received of carboplatin, and etoposide only and had a complete response for 7 months until disease progression. The population overall included 2 patients with de novo small cell/neuroendocrine pathology and 5 with transformation from a preexisting adenocarcinoma.

At a median follow-up of 6.5 months (range, 1.5-15.1), the median progression-free survival observed with firstline atezolizumab plus chemotherapy was 3.4 months (95% CI, 1.4 to not assessed [NA]). The median overall survival was 8.4 months (95% CI, 2.9-NA). Because 3 of the patients had died by the time data were censored, the median OS was not reached. Further, no patients experienced significant immune-related toxicities.

“Immunotherapy added to standard chemotherapy was well tolerated, but the responses were not better than we expected to see with chemotherapy alone,” explained Pagliaro.

Notably, a previously untreated patient was followed for 7.5 months and received 8 cycles of the combination. This patient was 73 years old with neuroendocrine pathology who at baseline was positive for keratin 9, synaptophysin, CD56, and INM1 on immunostains, a Gleason score of 5 + 5, and his prostate-specific antigen (PSA) was unknown. The patient also showed involvement in the pelvis, lymph nodes, and bones at the start of therapy. The patients had a 5.7-month PFS, which was longer than any other patient studied.

The patients who achieved the second longest PFS was patient 5. The 54-year-old patient had a diagnosis of high-grade neuroendocrine carcinoma that favored small cell snd was previously treated with androgen deprivation therapy and docetaxel. At baseline, tests for the patients were positive for pankeratin AE1/3, pankeratin OSCAR, synaptophysin, chromogranin, TTF1, and CDX2. His Gleason score was 4 + 5b, and his PSA was <.10 ng/ml at the time of biopsy. The patient also had a perirectal mass and liver involvement at baseline. After 5.4 months of follow-up, the patient had a 4.6-month PFS.

Of the patients who died during treatment, the longest OS was seen in a 58-year-old patient with SCC with positive synaptophysin, a Gleason score of 5 + 4b, and a PSA of <0.10 ng/ml. The patients showed involvement in the abdominopelvic lymph nodes and was previously treated with the hormone therapy agents, bicalutamide (Casodex), abiraterone acetate (Zytiga) plus prednisone and docetaxel chemotherapy. After 6 cycles of atezolizumab and standard chemotherapy, and 8.3 months of follow-up, the patient had a PFS of 4.2 months and an OS of 8.3 months.

Pagliaro stated that, “responses to the chemotherapy and checkpoint inhibitor combination are short-lived. The inclusion of a checkpoint inhibitor does not appear to prolong time to progression or death.”

Although the study hypothesis was not proven, by being the first to report outcomes of a study of patients with small cell or neuroendocrine carcinoma of the prostate who were treated with frontline immunotherapy and chemotherapy, the research Pagliaro et al may be explored further in a larger population of patients. For example, the combination may offer survival benefit to patients with other prostate cancer variants, according to Pagliaro et al.

“There are trials in progress that focus on small-cell or neuroendocrine cancers regardless of site like lung, prostate, or others and trials that focus on rare genitourinary cancers, among which are small cell and neuroendocrine types. The search for effective immunotherapy continues, as well as for targeted therapies and novel combinations. Whenever possible, we encourage patients with rare cancers to participate in clinical trials,” Pagliaro told Targeted Oncology™ during the interview.

_Reference:

_{Wee CE, Costello BA, Orme JJ, et al. Chemotherapy with atezolizumab for small cell or neuroendocrine carcinoma of the prostate: A single institution experience. Prostate. Published online ahead of print on July 12, 2021. doi: 10.1002/pros.24189}