ASCO 2022: Discussant: Familiar Faces and New Directions for Prostate Cancer

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a discussant presentation by Dr. Bradley Carthon discussing familiar faces and new directions for prostate cancer. Dr. Carthon started his presentation by highlighting the complexity of the prostate cancer treatment landscape:

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Indeed, we are currently seeing unprecedented median overall survival, with the most recent reporting of the SWOG-1216 trial noting a 70.2 month survival in the control arm. However, despite these treatment advances in advanced prostate cancer, it remains a relatively “cold” tumor with regards to immunotherapy, with modest results for pembrolizumab in KEYNOTE-199, nivolumab + ipilimumab followed by nivolumab in CheckMate 650, and atezolizumab in combination with Radium-223 in men with mCRPC:

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For this discussant presentation, Dr. Carthon discussed three abstracts including “Targeting B7-H3 in prostate cancer: Phase 2 trial in localized prostate cancer using the anti-B7-H3 antibody enoblituzumab, with biomarker correlatives” presented by Dr. Eugene Shenderov, “A phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/r) in patients with mCRPC” presented by Dr. Ulka Vaishampayan, and “PRINCE: Phase I trial of 177Lu-PSMA-617 in combination with pembrolizumab in patients with mCRPC” presented by Dr. Shahneen Sandhu.

Dr. Carthon notes that the mechanism of enoblituzumab is via antibody-dependent cellular cytotoxicity, as it is an IgG1 humanized antibody with increased affinity for activity CD16A and decreased affinity for inhibitory CD32B. Additionally, it may also reduce negative immunoregulatory signals by blocking the B7-H3 molecule on tumor cells. The hypothesis of the study by Dr. Shenderov was that neoadjuvant enoblituzumab treatment in patients with high-risk localized prostate cancer will lead to reduced biochemical recurrence following prostatectomy, by modulating T cell immunity in the tumor microenvironment and also direct tumor killing via antibody-dependent cellular cytotoxicity. This was a phase 2 single-arm biomarker-rich neoadjuvant trial of men with operable intermediate- and high-risk localized prostate cancer (Grade Groups 3-5) that were enrolled to evaluate the safety, anti-tumor efficacy, and immunogenicity of enoblituzumab when given prior to prostatectomy. Patients received enoblituzumab (15 mg/kg IV weekly x 6) prior to surgery. Prostate glands were removed 2 weeks after the last dose, and were examined for pathologic and immunologic endpoints:

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This was a truly high-risk population, with 50% of patients Gleason group 5 at biopsy, 71.9% of patients T3+ at initial diagnosis, and 71.9% of patients classified as very-high risk localized prostate cancer. As follows are the most common adverse events:

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Treatment with enoblituzumab resulted in pre-prostatectomy PSA declines of >10% in 31% of patients (95% CI 16-50%), PSA0 at 1 year post-op in 66% of men (95% CI 47-81%), median time to PSA recurrence not reached (median follow-up of 30 months), and Gleason group upgrade in 13% of patients, no change in 37%, and downgrade in 50% of patients. The author’s conclusions from this study were:

  • A total of 32 patients were enrolled, with no surgical delays secondary to adverse events
  • In a population with high risk disease, PSA0 at 1 year post-operatively was seen in 66% of men (95% CI 47-81)
  • Grade Group changes were significantly associated with enoblituzumab treatment (p = 0.023)
  • TCR sequencing showed focused peripheral expansion of tumor associated T-cell clones that correlated with PSA0 at 1 year
  • Levels of IL-2, IL-36b, IL-17, and soluble 4-1BB (CD137) were found to increase, while levels of IL-15, and IL-6 were found to decrease
  • This first-in-human application of B7-H3 targeted immunotherapy is feasible, generally safe, and appears to enhance clinical outcomes

Dr. Carthon notes that the strengths of this study include its neoadjuvant approach, tissue for correlatives, TCR and cytokine studies, notable downstaging, and the very high-risk population. The limitations include the small sample size, six weeks of treatment, and the potential difference in biology between CPSC and CRPC. Dr. Carthon emphasized that this data may have implications on future clinical trials and combination therapy.

Dr. Carthon then discussed the phase II randomized study of oral docetaxel + ritonavir in patients with mCRPC. Docetaxel has proven efficacy in prostate cancer and in other disease states, but it is associated with neurological and hematological adverse events, skin and nail changes, and infusion reactions. The MI8MDP trial tested oral docetaxel + ritonavir versus IV docetaxel with the following trial design:

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Patients were well balanced, including with respect to visceral disease at baseline, median PSA, prior enzalutamide therapy, and prior abiraterone therapy. The median time to rPFS was not reached in both arms of the trial:

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The overall response rate for ModraDoc006/ritonavir was 38.9% (95% CI 17.3, 64.3) compared to 28.6% (95% CI 8.4, 58.1; p = 0.712) for IV docetaxel, and the PSA response rate was 48.3% (95% CI 29.4, 67.5) for ModraDoc006/ritonavir compared to 50.0% (95% CI 30.6, 69.4; p = 1.0) for IV docetaxel. Maximum tumor size reduction was comparable between the two arms: 

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With regards to safety, ModraDoc006/ritonavir was better tolerated with 0% of all grades neutropenia and anemia, as compared to 26% (19% ≥G3) and 16% respectively on IV docetaxel. Neuropathy was significantly reduced at 9.7% grade 1 only on ModraDoc006/ritonavir vs 9.7% grade 1 and 19.4% grade 2 on IV docetaxel, whereas alopecia was reduced to 16.1% grade 1 and 6.5% grade 2 on ModraDoc006/ritonavir vs. 22.6% grade 1 and 19.4% grade 2 on IV docetaxel. GI toxicities were broadly comparable with diarrhea 32% (3% ≥ grade 3) vs 29%, nausea 29% vs 13% and stomatitis 3% (grade 3) vs 13% (3% ≥ grade 3), respectively. The author’s conclusions from this study were as follows:

  • There were mild grade 1 GI toxicities, with much improved hematological parameters, reductions in alopecia and neuropathy, and elimination of infusion reactions
  • There was a similar effect between oral and IV docetaxel on rPFS, response rate, and PSA response
  • ModraDoc006/ritonavir is a possible future alternative therapeutic option

Dr. Carthon notes that the strengths of this study were the decreased hematological adverse events, reduced infusion reactions, reduced infectious risk, and similar efficacy to IV formulation. The limitations are the GI specific adverse effects, the cost and potential difficulty availability, bioavailability problems, and efficacy in different disease states, with an unknown effect of ritonavir with doublet/triplet therapy. There are clinical implications for this data including in future trials, other disease states, combination therapy, and the effect of ritonavir.

To conclude, Dr. Carthon discussed the PRINCE phase I trial of 177Lu-PSMA-617 in combination with pembrolizumab for men with mCRPC. In this trial, mCRPC patients with high PSMA expression (SUVmax ≥ 20 in an index lesion, SUVmax > 10 for all lesions ≥ 10mm), and no FDG positive/PSMA negative lesions on paired baseline PET/CT screening, received up to 6 cycles of 177Lu-PSMA-617 (starting at 8.5 GBq, reducing by 0.5 GBq with each cycle) every 6 weeks in conjunction with 200mg of pembrolizumab every 3 weeks for up to 2 years. The study schema is as follows:

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The median follow-up was 16 months, over which time the 50% PSA response rate was 76% (28/37 [95% CI 59-88]) and 7/10 (70%) patients with RECIST-measurable disease had a partial response:

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The median rPFS was 11.2 months (95% CI: 5.1-14.1), median PSA-PFS was 8.2 months (95% CI: 5.1-11.2), and median OS was 17.8 months (95% CI:13.4-not estimable). The 12-month rPFS and OS was 38% (95% CI: 22-54) and 83% (95% CI: 67-92), respectively. Common (≥10%) treatment-related adverse events were mainly grade 1-2, including xerostomia (78%), fatigue (43%), pruritus (27%), nausea (27%), rash (24%), diarrhea (14%), anorexia (16%), thrombocytopenia (16%), elevated ALT (11%), arthralgia (11%) and a flare in bone pain (11%). Hematologic treatment-related adverse events included grade 2-3 anemia (8%), grade 1-2 thrombocytopenia (16%), and grade 1 neutropenia (3%). Grade 3 immune-related adverse events occurred in 10 (27%) patients with no dominant manifestation. Dr. Carthon emphasized that the PSA response rate of 76% in the PRINCE trial compares favorably to the VISION1 trial (46%) and may suggest a positive combinatorial effect of 177Lu-PSMA-617 and pembrolizumab: 

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The author’s conclusions from this trial included:

  • The primary endpoint of PSA response rate was 76%, median rPFS was 11.2 months, the 12-month rPFS was 38%, median OS was 17.8 months, and the 12-month OS rate was 83%
  • Adverse events were similar to those of single agents
  • Translational studies for mechanisms and the tumor microenvironment are ongoing

Dr. Carthon highlighted that the strengths of the study included the robust PSA response rate, a well-tolerated combination therapy, and an unselected IO biomarker patient population. Limitations of the trial include the mechanism and correlates, cost and availability, refining the best endpoints (OS? MFS? rPFS?), and the modest sample size and follow-up. Dr. Carthon notes several clinical implications including the need for larger trials, candidate selection, and approved individual agents. Several ongoing larger trials are testing combination therapy:

  • Australia: 177Lu-PSMA Therapy versus 177Lu-PSMA in Combination with Ipilimumab + Nivolumab for men with mCRPC (ANZUP2001) (NCT05150236)
  • USCF: 177Lu-PSMA-617 and Pembrolizumab in Treating Patients with Metastatic Castration-Resistant Prostate Cancer (NCT03805594) 

Presented by: Bradley C. Carthon, MD, PhD, Emory University Hospital Midtown, Atlanta, GA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022. 

References:

  1. Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
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