Prostate-Specific Membrane Antigen (PSMA)-Targeted Radioligand Therapies are Finally Arriving

Prostate-specific membrane antigen (PSMA) is a 750 amino acid type II transmembrane glycoprotein expressed in normal human prostate epithelium.  However, PSMA is overexpressed on virtually all prostate cancer cells.  Poorly differentiated, metastatic and castration-resistant prostate cancers harbor even higher expression.  Hence, not only is PSMA a potentially good target for diagnostic imaging but also for targeted therapy.  The field of PSMA PET imaging offers significant promise and is currently being utilized for detection and may off potential to direct oligometastatic disease ablation.  I will summarize the utilization of different PSMA PET imaging radiotracers and ongoing imaging trials in a future article.  For the purpose of this article, I will focus on therapeutic efforts with various PSMA-targeted radioligand therapy.

Early data with radiolabeled monoclonal antibodies that bind to the extracellular domain of PSMA showed some antitumor efficacy.  Specifically, the PSMA monoclonal antibody J591 had been radiolabelled with 90Yttrium or 177Lutetium in phase 1 and 2 trials.1-4  Unfortunately, these large molecules had poor permeability into solid tumors and cleared slowly from circulation, leading to myelosuppression and a narrow therapeutic index.

More recent attempts with radiolabeled small molecules targeted to PSMA have offered more promise.  These generally have more rapid tissue distribution and faster blood clearance.  For instance, the 177Lutetium-labeled DOTAGA-based PSMA ligand, 177Lu-DOTAGA-(I-y)fk(Sub-KuE) (177Lu-PSMA), more commonly known as I&T, led to a 80.4% (45 of 56 patients) PSA decline rate.5  There was a small, but a statistically significant reduction in erythrocyte and leukocyte counts, and mild reversible xerostomia occurred in 2 patients. 

Another small molecule, 177Lu-PSMA-617, is being used with many ongoing clinical trials.  A recently published, single-arm, single-center, phase 2 trial from Australia treated 30 men with metastatic castration-resistant prostate cancer who had variable lines of exposure to agents such as abiraterone, enzalutamide, docetaxel and/or cabazitaxel.6  Most patients (n=27) had received at least one line of previous therapy (87%).  Of the 30 treated patients, 17 (57%) achieved a PSA decline ≥50%.  Objective responses occurred in 14 (82%) of 17 patients with measurable disease.  Toxicities were generally mild with grade 1 dry mouth in 26 (87%) patients, grade 1/2 transient nausea in 15 (50%) patients and grade 1/2 fatigue in 15 (50%) patients.  However, grade 3/4  thrombocytopenia did occur in 4 (13%) patients.

131Iodine is another radiopharmaceutical that has been tagged to PSMA targeting small molecules.  A German compassionate use setting allowed treatment of 25 heavily pretreated patients with metastatic castration-resistant prostate cancer with 131Iodine-MIP-1095, another small molecule that binds to the extracellular domain of PSMA.7  Of the 25 treated patients, 61% achieved ≥50% PSA decline.  Of the 13 patients with bone pain, 11 (84.6%) had moderate or complete reduction in pain.  A phase 1 trial has recently completed accrual and additional studies are being planned.

Finally, alpha-emitting radiopharmaceuticals are being tagged to small molecules that target PSMA as well.  225Actinium-PSMA-617 activity has been recently reported after the treatment of 40 patients.8  Of the 38 patients who survived at least 8 weeks, 24 (63%) had ≥50% PSA decline and 33 (87%) had PSA decline of any degree.  Xerostomia was the main toxicity leading to treatment discontinuation in 4 patients.

In summary, there is clear activity with this class of agents in patients with metastatic castration-resistant prostate cancer.  The field has clearly moved towards using small molecules to target PSMA on prostate cancer.  However, establishing long-term efficacy and safety is important, and improvements in randomized control trials will be necessary to break this class of agents into the mainstream as a new standard of care.  Below, I highlight multiple ongoing clinical trials.

Clinical Trials with Radioligand therapy targeting PSMA

  • PRINCE trial – 177Lu-PSMA-617 with pembrolizumab (NCT03658447)
  • Testing two different doses of 177Lu-PSMA-617 (NCT03042312)
  • Randomized Phase 2 TheraP trial (ANZUP Protocol 1603) of 177Lu-PSMA-617 vs. cabazitaxel (NCT03392428)
  • Randomized Phase 3 VISION trial of 177Lu-PSMA-617 vs. Best Supportive Care (NCT03511664)

Written by: Evan Yu, MD

1. Vallabhajosula S et al.  Clin Cancer Res 2005; 11:7195S.
2. Milowsky MI et al.  J Clin Oncol 2004; 22:2522-31.
3. Bander NH et al.  J Clin Oncol 2005; 23:4591-601.
4. Tagawa S et al.  Clin Cancer Res 2013; 19:5182-91. 
5. Baum RP et al.  J Nucl Med 2016; 57:1006-13.
6. Hofman MS et al.  Lancet Oncol 2018; 19:825-33.
7. Zechmann CM et al.  Eur J Nucl Med Mol Imaging 2014; 41:1280-92.
8. Kratochwil C et al.  J Nucl Med 2018; 59:795-802.

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Watch: Nuclear Medicine and Lutetium 177 PSMA Therapies - Carmel Pezaro
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