ESMO 2019: Invited Discussant (LBA51, LBA52, 848PD, 849PD and 855PD) – Immunotherapy in mCRPC, PSMA Radionuclide Therapy and an Update M0 STAMPEDE Data

Barcelona, Spain (  Dr. Cora Sternberg summarized the findings from several posters, including three immunotherapy phase 1 or 2 trials, a phase 2 trial of 177Lu-PSMA-617, and updated longer term data from the M0 standard of care + docetaxel STAMPEDE arm.

Prostate cancer is thought of as an immune-cold tumor. This is evidenced by a microenvironment containing low amounts of tumor-infiltrating lymphocyte and low rates of response to single agent immunotherapy agents. To date, Sipuleucel-T remains the only immunotherapy agent approved in prostate cancer based on the IMPACT study that showed an overall survival benefit for patients who received this drug1. Numerous efforts are underway to turn this “cold tumor” into an immunologically “hot tumor” using various drug combinations, three of which are summarized here.

Dr. Sternberg first discussed the findings of poster LBA51, a phase 2 Canadian trial looking at durvalumab (anti-PD-L1) versus the combination of durvalumab and tremelimumab (anti-CTLA4) in heavily pre-treated metastatic castration-resistant prostate cancer (mCRPC). 51% of patients in the final analyzed cohort had received prior chemotherapy and 72% had visceral metastatic disease. Due to lack of single agent activity, the durvalumab arm was closed early. In the combination arm, the ORR was 16%. Though numbers were limited, responders tended to have higher density of CD8+ T cells in their tumors. The combination was tolerated and may move forward in clinical trials.

Dr. Sternberg then reviewed data from LBA52, which presented an interim analysis of Arm B of the phase 2 Checkmate 9KD trial. In this trial, chemotherapy naïve mCRPC patients received nivolumab (anti-PD1) in combination with docetaxel. Of the 41 patients analyzed, 46% had a PSA response, and some decrease in PSA from baseline was seen in 78% of patients. Of the 19 patients in this cohort with measurable disease by imaging, the overall response rate was 37%, with 74% of patients having some decrease in the size of their lesions. The authors conducted correlative studies looking at the association of response with homologous repair deficiency status and tumor mutational burden. There was no clear association with tumor response and these analyzed factors. A phase III trial of this combination may be planned, but Dr. Sternberg emphasized the potential utility of utilizing molecular selection in further studies given prior difficulties with finding a benefit from docetaxel combination trials in mCRPC. This is a challenging issue as biomarkers for immunotherapy response in prostate cancers are unclear beyond perhaps microsatellite instability.

Dr. Sternberg then reviewed data from poster 848PD, a phase 2 study of adding pembrolizumab (anti-PD1) to enzalutamide in patients progressing on enzalutamide. This poster presented data from a 30-patient expansion cohort, and showed both a PSA response rate and overall response rate by imaging of approximately 20%. Of special interest in this poster were the correlative studies looking at single-cell transcriptomic sequencing of patients prior to immunotherapy. The authors identified lower abundance of a bacterial species Akkermansia muciniphilia and increased abundance of CD8+ exhausted T-cells in therapy responders. This raises provocative questions about potential biomarkers for immunotherapy response that need to be validated in larger cohorts of patients and could impact how providers think about antibiotic and probiotic therapy in these patients.

Next, the discussant reviewed poster 849PD, a phase 1/2 study of 177Lu-PSMA in heavily pre-treated mCRPC. This study differs from prior radionuclide-conjugated PSMA studies in that it delivered the total treatment dose in a hypofractionated manner, using just 2 doses spaced two weeks apart. This regimen was chosen based on lack of dose-limiting toxicities in the dose-escalation portion of the trial, and the potential to augment therapeutic effect by giving all the therapy up front. Despite not being selected for PSMA expression by advanced imaging techniques, over 60% of patients had a PSA response of greater than 50% and decrease in the number of prostate cancer circulating tumor cells detected. Treatment was well-tolerated, with cytopenias being the only grade 3 or greater toxicity. Of note, variables associated with response included the amount SUVmax of lesions on a PSMA-PET scan and prior chemotherapy.

The final poster reviewed was the longer-term update on the M0 docetaxel cohort from STAMPEDE. The STAMPEDE trial is well-known for its innovative trial design with numerous treatments arms that have been added and modified over time as treatment modalities and clinical knowledge has evolved. In this cohort, patients who were starting on long-term hormonal therapy but did not have evidence of metastatic disease were randomized to standard of care (androgen deprivation therapy with or without radiotherapy to the prostate) or standard of care and docetaxel. Despite earlier data supporting a failure-free survival benefit, there was no difference between the arms with regards to the important outcomes of metastatic progression-free survival and overall survival at this analysis timepoint. Though the combination was tolerated, there is no compelling evidence for adding docetaxel in this setting with regards to improving long term patient outcomes. 

Presented by: Cora Sternberg, MD, Clinical Director, Medical Oncologist at Weill Cornell Medicine, New York, USA, previously of Chief of the Department of Medical Oncology at the San Camillo-Forlanini Hospital in Rome, Italy, and as adjunct Professor of Oncology at La Sapienza University in Rome

References: Kantoff, Philip W. et al. 2010. "Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer". New England Journal of Medicine 363 (5): 411-422. Massachusetts Medical Society. doi:10.1056/nejmoa1001294.

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain