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Even with New Treatment Advances for Metastatic Castration-Sensitive Prostate Cancer, There Is Still Opportunity to Bring in Radiopharmaceutical Therapy

I’ve recently focused on metastatic castration-sensitive prostate cancer (mCSPC) as a disease state undergoing significant novel therapeutic investigation.  With the PEACE-11 and ARASENS2 publications, the concept of triple combination therapy with androgen deprivation therapy (ADT), novel androgen pathway inhibitor, and docetaxel chemotherapy for front line treatment of patients with metastatic castration-sensitive prostate cancer is now ripe for digestion.  Beyond the triple combination therapy approach, there are yet many ongoing clinical trials for patients with this disease state.  I have recently concentrated on novel chemohormonal therapy, PD-1/PD-L1 antibody, and PARP inhibitor trials.3-5


The question is whether triple combination therapy is the absolute new standard of care.  Although I’m incredibly impressed by the data, and it is certainly a new standard of care, I’m hesitant to call it the only standard of care.  Not all populations are fit to receive docetaxel chemotherapy due to potential comorbidities or even patient desire, as some patients are concerned about the potential toxicities of chemotherapy.  We also must take a deep dive into the data from PEACE-1 and ARASENS.  In the PEACE-1 trial, eligibility for the trial mandated de novo, synchronous metastatic prostate cancer, and ADT with docetaxel and abiraterone was superior in overall survival compared to ADT with docetaxel in the high-volume disease subset of patients.  In the ARASENS trial, where ADT with docetaxel and darolutamide had superior overall survival compared to ADT with docetaxel, 86% of the patients in the trial had de novo, synchronous metastatic prostate cancer.  Hence, the populations enrolled on these two trials were clearly select populations with aggressive prostate cancer behavior.  Would this triple combination therapy approach lead to survival benefit for lower volume or lower risk metastatic prostate cancer patient populations?  Might there be other combinations that lead to similar or even better outcomes, yet less adverse events and better quality of life?  These are all unanswered questions, that we should continue to explore.  Now that we know a novel hormonal agent adds benefit to these select populations receiving ADT with docetaxel, an obvious question should also be asked.  Do we need the docetaxel?  We have not had a trial using ADT with a novel hormonal therapy with patients randomized to adding docetaxel vs. placebo/no intravenous therapy.

This month, I’m highlighting the concept of adding radiopharmaceutical agents to therapy for patients with mCSPC.  We’ve previously seen the alpha-particle emitting radiopharmaceutical, radium-223, offer an overall survival, symptomatic skeletal events, and quality of life benefits for patients with bone metastatic castration-resistant prostate cancer (mCRPC) and symptoms.6  However, a practical challenge is that radium-223 is often administered to heavily pre-treated patients very late in the mCRPC disease state, in a rather palliative setting.  On the contrary, the ALSYMPCA trial demographics were composed of ~40% of men who were not even on narcotic pain medications, and almost half the men on trial had not received docetaxel.  The danger of waiting late in the disease course is the higher likelihood of inability to administer the compound due to myelosuppresion either from previous chemotherapy or marrow involvement from prostate cancer spread.  Additionally, the development of visceral disease also may occur later in the disease course and immediately precludes a patient from receiving radium-223, as per the FDA label.  One key strategy to capture the potential benefits of radium-223 for our patients is to use the agent earlier in the disease course, for instance in mCSPC patient trials.

Another agent to consider in this earlier mCSPC disease state is 177Lu-PSMA-617, which recently received regulatory approval in the United States.7  The randomized, phase 3 VISION trial, showed clear overall survival benefit for patients who received 177Lu-PSMA-617 for 4-6 cycles in combination with best standard of care compared with best standard of care alone, in PSMA PET positive patients who received previous taxane chemotherapy and a novel hormonal agent.8  The TheraP trial, with more stringent PSMA PET eligibility criteria, has shown improved PSA response rate, composite progression-free survival, and tolerability over cabazitaxel in a similar, heavily pre-treated population.9  Although recent overall survival data presented at ASCO, looked rather similar between 177Lu-PSMA-617 and cabazitaxel from the TheraP trial, the other efficacy, and quality of life benefits of 177Lu-PSMA-617 for men with mCRPC are evident. 10  This may make 177Lu-PSMA-617 potentially an even better choice than docetaxel down the road in the mCSPC setting, but trials should be performed to prove this theory.

The radiopharmaceutical trials highlighted below for patients with mCSPC all offer strong rationale for our consideration of patient accrual.  They introduce radium-223 and 177Lu-PSMA-617 at a disease state that clearly requires treatment intensification, and now includes triple combination therapy for those populations with poor prognostic characteristics.  Yet, there is potential with radiopharmaceutical agents to offer outstanding efficacy, perhaps with less toxicity.  Following that line of logic, we should accrue fast and furious to these trials below.

Clinical Trials with Radiopharmaceuticals for Men with Metastatic Castration Sensitive Prostate Cancer

  • Randomized phase 2 trial of stereotactic body radiation therapy and radium-223 for oligorecurrent, non-castrate resistant prostate cancer (NCT05133440)
  • RAVENS – Phase 2 trial of stereotactic body radiation and radium-223 for oligometastatic prostate cancer (NCT04037358)
  • Phase 2 trial of stereotactic body radiation therapy with radium-223 and androgen deprivation therapy (NCT03361735)
  • PSMAddition – randomized phase 3 trial of 177Lu-PSMA-617 + standard of care vs. standard of care alone for metastatic castration-sensitive prostate cancer (NCT04720157)
  • UpFrontPSMA – randomized phase 2 trial of 177Lu-PSMA-617 followed by docetaxel vs. docetaxel alone for newly diagnosed high volume metastatic castration-sensitive prostate cancer (NCT04343885)
  • Bullseye – Phase 2 trial of 177Lu-PSMA-617 in oligometastatic hormone sensitive prostate cancer (NCT04443062)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References:

  1. Fizazi K, et al. "Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design."Lancet 2022; 399:1695-707.
  2. Smith MR, et al. "Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer." N Engl J Med 2022; 386:1132-42.
  3. Yu EY. "Metastatic Castration-Sensitive Prostate Cancer, The Advances Keep Coming With Chemohormonal Therapy." Urotoday Clinical Trials Portal. On-line: November 30, 2021.
  4. Yu EY. "Combination Strategies with PD-1/PD-L1 Inhibition for Patients with Metastatic Castration-Sensitive Prostate Cancer." Urotoday Clinical Trials Portal. On-line: January 3, 2022.
  5. Yu EY. "Can PARP Inhibitors Make It into the Metastatic Castration-Sensitive Prostate Cancer Disease State?" Urotoday Clinical Trials Portal. On-line: February 1, 2022.
  6. Parker C et al. "Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer." N Engl J Med 2013; 369:213-23.
  7. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-pluvicto-lutetium-lu-177-vipivotide-tetraxetan-treatment-adult#:~:text=On%20March%2023%2C%202022%2C%20the,pathway%20inhibition%20and%20taxane%2Dbased
  8. Sartor O, et al. "Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer." N Engl J Med 2021; 385:1091-103.
  9. Hofman MS, et al. "[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial." Lancet 2021; 397:797-804.
  10. Hofman MS, et al. "TheraP: 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel—Overall survival after median follow-up of 3 years (ANZUP 1603)." J Clin Oncol 40, 2022 (suppl 16, abstr 5000).