Despite significant therapeutic advances and improved outcomes in all stages of prostate cancer (PCa) over recent years, metastatic castrate-resistant prostate cancer (mCRPC) remains a lethal disease. Chemotherapy and androgen receptor pathway inhibitors (ARPIs) have significantly improved survival in men with mCRPC, however there is inevitable progression and there remains substantial room for new and improved therapies.

Recent global developments in the field of imaging have revolutionized how we stage PCa. Prostate-specific membrane antigen (PSMA) is a 750-amino acid, type II transmembrane glycoprotein predominantly expressed on the cell membrane of prostate cancer cells and at extremely low levels in normal and non-prostate tissues. PSMA targeted imaging has demonstrated improved sensitivity and specificity of detection in early, recurrent, and advanced stages of PCa compared to standard of care (SOC) imaging such as CT and bone scan.^1,2 This disruptive technology has become the new SOC in parts of the world where readily available (such as Australia) and will undoubtedly become so in other areas such as Europe and the U.S. as availability increases.

An extension of the PSMA imaging revolution is through the development of PSMA-based theranostics. A theranostic is a combination of a diagnostic imaging target linked to a therapeutic payload such as chemotherapy or radionuclide. This is not a new concept and has been used widely in other cancer types such as thyroid and neuroendocrine tumors with great success. In the case of PSMA theranostics, combination of a small molecule or antibody targeting PSMA is linked to a radiopharmaceutical such as the beta emitter lutetium-177 (¹⁷⁷Lu). While initial small case series and phase 1 studies demonstrated promising results and striking images of resolution of tumors on PSMA imaging following treatment (see Figure), only recently have there been larger phase II and III studies confirming safety and efficacy. Two recent seminal studies into PSMA theranostics utilized the same target and payload, however they fundamentally differed in their design.^3,4

The TheraP trial, an open label, randomized phase II study led by the ANZUP collaborative trials group in Australia, compared ¹⁷⁷Lu-PSMA-617 to an active SOC control arm, cabazitaxel, in men with mCRPC.³ The primary endpoint of the study was a decrease in PSA ≥50% from baseline. Secondary endpoints included comparison of toxicity, PSA progression free survival, radiographic progression-free survival (RPFS), pain progression free survival and overall survival (OS). An active control arm was selected due to level I data demonstrating survival benefit using cabazitaxel in this setting and that this would be considered the next standard therapy in the cohort of men recruited for this study.^5,6 In this trial men were screened prior to enrollment based on ⁶⁸Ga-PSMA-11 PET CT and FDG PET CT imaging. Only men with PSMA avid disease and no discordant (PSMA negative but FDG positive) disease were included in the trial. This study in 200 men (99 in study arm and 101 in control arm) who had progressed following docetaxel chemotherapy and in 91% after further ARPIs, demonstrated superior efficacy for ¹⁷⁷Lu-PSMA-617 compared to cabazitaxel, with lower grade 3-4 toxicity and improved patient reported outcomes. The primary endpoint of decrease in PSA ≥50% from baseline was met in 66% of men in the ¹⁷⁷Lu-PSMA-617 arm compared to 37% of the cabazitaxel arm. PFS (PSA or radiographic) also favored the ¹⁷⁷Lu-PSMA-617 arm with a HR of 0.63. Overall survival data was presented this year at ASCO demonstrating no overall survival difference.

The US/European led VISION trial followed on as a larger phase III trial of ¹⁷⁷Lu-PSMA-617 + best supportive care vs best supportive care.⁴ Chemotherapy, immunotherapy, and systemic radioisotopes were specifically excluded, but hormonal therapy including ARPI was allowed as part of best supportive care. Eight hundred and thirty-one men who had previous ARPI therapy and 1-2 taxane based therapies with mCRPC and avid disease on ⁶⁸Ga-PSMA-11 PET CT imaging were randomized 2:1 as part of the trial. Primary endpoints were RPFS and OS and secondary endpoints were objective response rate, disease progression, and time to symptomatic skeletal events. Importantly, FDG PET CT was not utilized to assess for discordant disease. ¹⁷⁷Lu-PSMA-617+ best supportive care significantly prolonged both RPFS (8.7 months vs 3.4 months) and OS (median 15.3 months vs 11.3 months, HR 0.62) compared to best supportive care with all key secondary endpoints favoring ¹⁷⁷Lu-PSMA-617. Quality of life was comparable despite a higher grade ≥3 complication rate in the ¹⁷⁷Lu-PSMA-617 arm.

Both studies have clearly demonstrated that ¹⁷⁷Lu-PSMA-617 is a well-tolerated and efficacious therapy in heavily pre-treated men with mCRPC. Both demonstrated RPFS benefit, however the TheraP trial showed no OS benefit compared to cabazitaxel. This is most likely due to the use of cabazitaxel, an active control arm, with demonstrated life prolongation in this group of patients. Notably, ¹⁷⁷Lu-PSMA-617 did have a superior side effect profile compared to chemotherapy. The strict selection of men with no discordant disease in the TheraP trial is, however, different to those recruited to the VISION trial and could have enhanced efficacy compared to the less rigorously selected VISION cohort. The VISION trial does inform, however, that even with a more real-world selection using PSMA avidity alone, compared to supportive care, men do indeed gain RPFS and OS benefit with ¹⁷⁷Lu-PSMA-617 with low rates of complications.

The future role that PSMA theranostics will play in the PCa landscape continues to be defined. As with most of the new therapeutics introduced in PCa, there is significant interest in bringing this therapy earlier in the therapeutic timeline. As has been seen with ARPI and other therapies, the earlier these systemic therapies are introduced the more effective they are. Whether this holds true for ¹⁷⁷Lu-PSMA-617 is being investigated in various studies including the UpFront PSMA trial, which is investigating the role of combination docetaxel chemotherapy +/− ¹⁷⁷Lu-PSMA-617 in hormone sensitive metastatic prostate cancer.⁷ Multiple other combination trials with ¹⁷⁷Lu-PSMA-617 are also being investigated including radium 223, ARPIs, and immunotherapy. Toxicity and efficacy data from these various combinations are eagerly awaited. Finally, the optimal position for sequencing of this therapeutic option is also to be determined. Additional modifications of PSMA-based theranostics such, as alternative small molecules or antibodies and different radionuclide, are also being explored with next generation molecules utilizing higher powered alpha emitters such as actinium under investigation. The balancing of side effects such as xerostomia, hematological, and renal impairments with these alternative molecules will need to be carefully considered. For now, however, it appears that PSMA theranostics will provide another new effective weapon in the advanced prostate cancer armamentarium.