Glutamate carboxypeptidase II, better known as PSMA (prostate-specific membrane antigen) has been shown in recent years to be a viable diagnostic and therapeutic target in the management of advanced prostate cancer. PSMA is expressed in prostate cancer cells on the luminal surface. As prostate cancer and the malignancy process unfolds, however, there is a transition to expression of PSMA in the extracellular compartment as well as upregulation of PSMA expression by 100- to 1000-fold.1 In 2021, the VISION trial results exploring the utility of PSMA-targeted radiotherapy in patients with advanced prostate cancer were released, demonstrating many clear benefits for this patient population. Specifically, the trial compared results in patients with progressive metastatic castration-resistant prostate cancer (mCRPC) that was refractory to chemotherapy, or second-generation androgen-receptor (AR) inhibitors who received lutetium-177‒PSMA-617 (177Lu-PSMA) therapy plus standard of care (SOC) with patients who received SOC alone.
Patients in the 177Lu-PSMA treatment arm received benefits in overall survival (OS; 15.3 vs 11.3 months), radiographic progression-free survival (rPFS; 8.7 vs 3.4 months), and time to first symptomatic skeletal event (11.5 vs 6.8 months) compared with those in the SOC-only arm.2 In addition to these clinically promising results, analyses presented at the European Society for Medical Oncology Congress 2021 (ESMO 2021) showed that use of 177Lu-PSMA therapy prolonged time to worsening of health-related quality of life (9.7 vs 2.4 months) and delayed time to worsening pain (14.3 vs 2.9 months).3 With these promising results, and more in mind, several presentations at the 2022 ASCO Genitourinary Cancers Symposium (ASCO GU 2022) were delivered on the topic of targeted radiotherapy for patients with prostate cancer using PSMA and other agents.
Dr Sandhu Gives Radiotherapy Review
Dr Shahneen Sandhu, associate professor at the Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia, delivered the first lecture, “Targeting Prostate-Specific Membrane Antigen: Lutetium and the Next Wave of Novel Radiopharmaceuticals.” She began her discussion by reviewing PSMA and its pro-proliferative function, which occurs through activation of Pi3K and the Akt/mTOR pathways. She remarked that high PSMA expression has been shown to be associated with worse patient outcomes. Dr Sandhu also defined the field of PSMA “theranostics” as the combination of the PSMA molecule with varying radioactive compounds for both diagnostic and therapeutic purposes, such as gadolinium-68 for diagnosis and lutetium-177 for delivery of beta radiation to prostate cancer cells.
Dr Sandhu reviewed the randomized trials that have been completed to date in the PSMA theranostics sphere. The TheraP trial of 177Lu-PSMA versus cabazitaxel4 demonstrated that in patients with mCRPC, PFS (progression-free survival) at 12 months was significantly improved in patients randomized to the 177Lu-PSMA arm (19% vs 3%). Moreover, patients in this group experienced greater declines in PSA (PSA response) compared to their counterparts who received cabazitaxel. Overall, Dr Sandhu remarked that the TheraP trial demonstrated a significant delay in progression of disease, representing an advantage with 177Lu-PSMA treatment (hazard ratio, 0.63).
Dr Sandhu also reviewed the results of the VISION trial (described above). She presented an additional subset analysis of the patients in VISION which demonstrated that the benefit of 177Lu-PSMA therapy was most significant in patients receiving second-generation androgen pathway inhibitors as part of the SOC. Dr Sandhu theorized that the mechanism for this effect was due to upregulation of PSMA receptors by these AR inhibitors, allowing for a greater radiotherapeutic effect.
Next, Dr Sandhu discussed fluorodeoxyglucose‒positron emission tomography (FDG-PET) and PSMA PET in patient selection for PSMA theranostics. She offered an example of a patient whose disease was categorized by PET/computed tomography as largely PSMA-negative. However, further probing with FDG revealed large-volume metastatic disease. Based on this observation, Dr Sandhu remarked that despite some appreciable benefit to the patient, such tumors usually cannot be treated with PSMA-targeted radiotherapeutic compounds. She emphasized that in such cases, dosimetry is crucial for determining patient-specific dosing based on tumor volume, rather than using prespecified doses.
Dr Sandhu then moved on to comment on techniques in development for improving response rates to 177Lu-PSMA therapy. There are several biological mechanisms under current review that can be altered to theoretically enhance the response rate of radiopharmaceuticals. She remarked that such variables include the number of receptors on the cancer cell, radiation dosing, power and range of the radioactive decay of the payload (ie, range of beta emission), and radiation sensitivity of the cancer cell. She highlighted these points by describing the clinical scenario of tumor volume. Currently, patients receive the same dose of 177Lu-PSMA regardless of baseline tumor volume. Dr Sandhu explained that a variable such as baseline tumor volume should be used to personalize treatment by creating a dose and fractionation specific to the patient to, theoretically, improve outcomes.
In the final segment of her radiopharmaceuticals review, Dr Sandhu noted 3 ways to optimize the results of these drugs in patients with advanced prostate cancer: augmenting therapy with immunotherapy, techniques to upregulate PSMA using second-generation AR blockade, and augmenting the effect of radiopharmaceuticals with other types of therapy.
Dr Sandhu commented on the results of ENZA-p,5 a phase 2 trial investigating the utility of 177Lu-PSMA therapy in the setting of enzalutamide therapy. She remarked on the concept of phenotype adjustment. In this approach, enzalutamide therapy results in upregulation of PSMA receptors, which in turn allows for more targets for 177Lu-PSMA radiotherapy (and radiation delivery), and subsequently downregulate and facilitate phenotype adjustments that enable enzalutamide to function more effectively. In theory, this process should create a cyclical feedback loop.
Radiopharmaceuticals in Immunotherapy
In discussing methods to enhance cell death, Dr Sandhu remarked that beta-emitting radiopharmaceuticals such as 177Lu-PSMA have been shown to produce fewer double-strand DNA breaks (required for cell death) and higher collateral cell damage compared with alpha-emitting agents. She described augmenting beta-emitting radiopharmaceuticals with other medications. The first mechanism for accomplishing this may involve the use of polyADP-ribose polymerase (PARP) inhibitors. PARP protein is important in a multitude of DNA-repair pathways, specifically involving base excision repair. In theory, inhibition of PARP should allow for accumulation of single-strand breaks (SSB) in DNA.6 Use of 177Lu-PSMA results in accumulation of SSBs.
Dr Sandhu explained that 177Lu-PSMA, in combination with PARP therapy, would increase the rate of SSBs translating into double-stranded breaks. A phase 1 clinical trial investigating the combination of an olaparib (PARP inhibitor) and 177Lu-PSMA combination therapy in patients with mCRPC is currently under way.7 In a similar vein, Dr Sandhu discussed NOX66, a radiosensitizer that is a potent inhibitor of both S1P receptors and the protein kinase B‒resistance axis. She reviewed the phase 1 trial results in which combination NOX66 and 177Lu-PSMA resulted in a PSA PFS of 7.5 months.8
Dr Sandhu then considered the utility of immunotherapy in PSMA-targeted therapy. She explained that radiopharmaceuticals play an integral role in enhancing the immunogenicity of a given tumor, providing the rationale for augmenting care with immunotherapy. She noted that several trials including the combination of 177Lu-PSMA and pembrolizumab are under active investigation to explore this topic.
In her concluding remarks, Dr Sandhu discussed terbium-161‒PSMA-617 (161Tb-PSMA), a future radiopharmaceutical under investigation in a trial comparison with 177Lu-PSMA. She explained that 161Tb-PSMA has characteristics similar to 177Lu-PSMA, including similar half-life, energy emission, and pharmacokinetics. However,161Tb-PSMA has emission characteristics that make it preferable for small-volume disease, and its use in preclinical studies has demonstrated reduced tumor growth and reduced cell viability. Clinical trials to investigate 161Tb-PSMA are in the planning phase.
Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.
- Jones W, Griffiths K, Barata PC, Paller CJ. PSMA theranostics: review of the current status of PSMA-targeted imaging and radioligand therapy. Cancers (Basel). 2020;12(6):1367. Doi: 10.3390/cancers12061367
- Morris MJ, De Bono JS, Chi KN, et al; on behalf of the VISION Investigators. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(18 suppl): abstract LBA4. doi: 10.1200/JCO.2021.39.15_suppl.LBA4
- Fizazi, K, Herrmann K, Krause BJ, et al. Health-related quality of life (HRQoL), pain and safety outcomes in the phase III VISION study of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Ann Oncol.2021;32(suppl 5):S627-S628. Abstract 576MO. doi: 10.1016/j.annonc.2021.08.1089
- Hofman MS, Emmett L, Sandhu S, 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(10276):797-804. doi: 10.1016/S0140-6736(21)00237-3
- Emmett L, Subramaniam S, Joshua AM, et al. ENZA-p trial protocol: a randomized phase II trial using prostate-specific membrane antigen as a therapeutic target and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901). BJU Int. 2021;128(5):642-651. doi: 10.1111/bju.15491
- Chen A. PARP inhibitors: its role in treatment of cancer. Chin J Cancer. 2011;30(7):463-471. doi: 10.5732/cjc.011.10111
- gov website. 177Lu-PSMA-617 Therapy and Olaparib in Patients with Metastatic Castration Resistant Prostate Cancer (LuPARP). NCT identifier: NCT03874884. https://www.clinicaltrials.gov/ct2/show/NCT03874884. Accessed February 24, 2022.
- Kiknavelidze K, Shavdia M, Chikhladze N, et al. NOX66 as Monotherapy, and in Combination with Carboplatin, in Patients With Refractory Solid Tumors: Phase Ia/b Study. Curr Ther Res Clin Exp. 2021;94:100631. Published 2021 Mar 28. doi: 10.1016/j.curtheres.2021.100631