Published Date: December 2019
Prostate-specific membrane antigen (PSMA) is expressed 100 to 1,000 times more highly in prostatic adenocarcinoma than in benign prostate tissue, particularly in the setting of androgen deprivation.1 Around the world, we are seeing the rapid adoption of PSMA PET-CT/MRI, which is able to detect metastatic disease that is inapparent on conventional imaging (CT and bone scintigraphy).
It remains unclear, however, if the earlier detection of asymptomatic metastatic disease improves clinical outcomes for patients. Various questions and controversies also surround the emerging field of PSMA-based targeted therapies.
These topics received substantial attention at APCCC 2019, and I would like to highlight some clinical pearls here. A key point that was reiterated at APCCC 2019 was that PSMA-based imaging is not 100% sensitive for the detection of prostate cancer—it can produce false-negative results that lead to understaging. There are two main reasons for this. First, PSMA PET-CT/MRI does not reliably detect nodal metastases measuring <5 mm, as the volume of metastatic disease in these nodes is very low, and PET imaging is not equivalent to microscopy.2,3 Second, approximately 5% to 10% of prostate cancers do not express detectable amounts of PSMA, which means that patients may be negative on PSMA PET/CT but may be positive on FDG PET/CT, especially if they have more aggressive neuroendocrine differentiation.4-6 This leads me to conclude that various diagnostic radiopharmaceuticals such as PSMA, FDG, fluciclovine, and bombesin (to name a few) will play a role in the clinic depending on specific patient characteristics and disease states. With regard to theranostics, sequential imaging with multiple radiopharmaceuticals might become the standard of care to optimize patient selection for patients undergoing PSMA-targeted therapies.
Another question is how best to use PSMA-based imaging to detect oligometastatic disease, particularly given that we lack validated PSMA-based imaging endpoints from clinical trials, but also because there is no consensus on exactly how to define an oligometastatic state. At APCCC 2019, several experts (Piet Ost, Declan Murphy) stated that in their clinical experience, PSMA PET-CT/MRI frequently detects small metastases outside the prostate (often in the pelvic lymph nodes) in the settings of both hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). However, there is uncertainty about whether these lesions are driving metastatic progression.
Nonetheless, there appeared to be support for metastasis-directed therapy in the setting of biochemical recurrence, and data from the randomized Phase II ORIOLE trial7, which were presented after APCCC 2019 at the American Society for Radiation Oncology (ASTRO) 2019 meeting, provide some early indications that metastasis-directed therapy is beneficial for patients with biochemical recurrence. Some clinicians recommend local metastasis-directed therapy (either surgery or stereotactic body radiotherapy) for these lesions at initial diagnosis, but there are limited prospective data to support this practice8 and no published prospective data to support local treatment without concomitant systemic therapy in this setting. Likewise, there are no clear data demonstrating a positive impact for patients with CRPC. Because several systemic therapies are available that significantly postpone metastatic progression in patients with CRPC and rapid prostate-specific antigen (PSA) doubling times (indicative of low-volume metastatic disease),9-11 I do not recommend “hunting” for metastases by using next-generation imaging and then managing patients with CRPC with treatments that lack a solid evidence base.
The take-home point is that although next-generation PSMA-based imaging can detect low-volume metastatic disease, we do not know exactly how this affects clinical outcomes in our patients. Although there is growing evidence to support the use of next-generation imaging-guided metastasis-directed therapy in the setting of biochemical recurrence, there is a lack of convincing data demonstrating a positive impact among patients at initial diagnosis or in the setting of castration resistance.
Unfortunately, we have few prospective diagnostic trials to elucidate how the use of PSMA-based imaging affects treatment outcomes in advanced prostate cancer. Validating the clinical impact of a diagnostic exam is challenging, but innovative investigators have incorporated endpoints such as time to initiation of androgen deprivation therapy (ADT) and progression-free survival to demonstrate the value of next-generation imaging in patients with biochemical recurrence. Various prospective studies also remain in the pipeline. The prospective crossover ProPSMA study, which was highlighted at APCCC 2019,12 is a multicenter Phase III study of approximately 300 patients that evaluates the accuracy of PSMA PET/CT versus conventional imaging (CT of the abdomen/pelvis, and bone scintigraphy with SPECT/CT) for detecting nodal or distant metastatic disease. The study protocol includes measures to control for the quality of imaging, and imaging “accuracy” is pre-defined based on imaging criteria and histopathologic and clinical variables. The ProPSMA study also assesses the safety and cost of PSMA-based PET/CT, its impact on patient management, and the prognostic value of negative PSMA-PET/CT results. The results of this study will have a major impact on defining the value of PSMA-based diagnostics in the clinic.
Now let us move on to the therapeutic applications of PSMA-targeted ligands in CRPC, for which we have a limited but increasing amount of prospective data. In a single-center, Phase II trial of 30 men with progressive metastatic CRPC who had previously received standard taxane-based chemotherapy and androgen receptor pathway inhibitors, treatment with PSMA-targeted lutetium-177 (177Lu-PSMA-617) produced a >50% decline in PSA among 57% of patients.13 In an expanded 50-patient cohort of this study, 64% of patients achieved a PSA response, and 56% of patients with measurable soft tissue disease had an objective response according to RECIST 1.1 criteria.14 The most common treatment-related side effects of 177Lu-PSMA-617 included grade 1-2 dry mouth (66% of patients), transient grade 1-2 nausea (48% of patients), and grade 3-4 anemia and thrombocytopenia (in each case, 10% of patients). These results, which were discussed at APCCC 2019 and published this year, provide valuable data on the role of PSMA-targeted therapy in the advanced post-chemotherapy setting.
Larger studies in progress also were discussed at APCCC 2019. The international randomized Phase III VISION study evaluates radiographic progression-free survival and overall survival among patients receiving either 177Lu-PSMA-617 therapy plus best standard of care or best standard of care alone.15 The study design is similar to that of ALSYMPCA,16 which was the basis for the FDA approval of radium-223. The VISION study has fully accrued at approximately 750 patients, and we eagerly await results from this landmark trial.
In Australia, researchers also are conducting several important trials of PSMA-targeted therapies. The TheraP study compares 177Lu-PSMA-617 with cabazitaxel in approximately 200 patients with progressive, PSMA-avid metastatic CRPC who have previously received docetaxel.17 The primary endpoint is PSA response, and secondary endpoints include safety, pain response, and efficacy outcomes measures, such as radiographic progression-free survival, overall survival, and health-related quality of life. Initial results are expected in 2020. Australian investigators in Australia also are examining combination regimens with 177Lu-PSMA-617 for the treatment of metastatic CRPC. The Phase I/II PRINCE trial evaluates the safety and efficacy of 177Lu-PSMA-617 therapy plus the immune checkpoint inhibitor pembrolizumab in patients with metastatic CRPC.18 Primary endpoints are safety and PSA response, and results are expected in 2021. Additionally, the Phase I LuPARP trial assesses the pharmacokinetics and safety of 177Lu-PSMA-617 therapy plus the PARP inhibitor olaparib in approximately 52 patients with metastatic CRPC. Initial readouts are expected in 2022.
For the treatment of high-volume hormone-sensitive metastatic prostate cancer, the multicenter Phase II UpFrontPSMA trial compares triple-combination upfront therapy with 177Lu-PSMA-617, (ADT), and docetaxel (arm A) with standard-of-care docetaxel plus ADT (arm B).19 The target enrollment is 140 patients. Finally, for patients with high-risk localized prostate cancer, the LuTectomy study is evaluating the efficacy and safety of a single cycle of LuPSMA administered a few weeks prior to prostatectomy.20
Taken together, the results of these studies will start to address the current controversies and shed light on how best to use PSMA-based imaging and targeted therapy to achieve the best possible outcomes for patients with high-risk and advanced prostate cancer. Given the number of studies that currently are underway, we can expect even more extensive discussions of these topics at the next meeting of the APCCC, in 2021.
Written by: Philip Koo, MD, FACS, Division Chief of Diagnostic Imaging, Banner MD Anderson Cancer Center in Arizona, Gilbert, Arizona
1. Dorff T.B., Fanti S., Farolfi A., Reiter R.E., Sadun T.Y., Sartor O. The evolving role of prostate-specific membrane antigen–based diagnostics and therapeutics in prostate cancer. American Society of Clinical Oncology Educational Book. 2019:321-330.
2. Yaxley J.W., Raveenthiran S., Nouhaud F.X., Samartunga H., Yaxley A.J., Coughlin G., et al. Outcomes of primary lymph node staging of intermediate and high risk prostate cancer with 68ga-PSMA positron emission tomography/computerized tomography compared to histological correlation of pelvic lymph node pathology. J Urol. 2019;201:815-820.
3. van Leeuwen P.J., Emmett L., Ho B., Delprado W., Ting F., Nguyen Q., et al. Prospective evaluation of 68gallium-prostate-specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer. BJU Int. 2017;119:209-215.
4. Thang S.P., Violet J., Sandhu S., Iravani A., Akhurst T., Kong G., et al. Poor outcomes for patients with metastatic castration-resistant prostate cancer with low prostate-specific membrane antigen (PSMA) expression deemed ineligible for 177Lu-labelled PSMA radioligand therapy. Eur Urol Oncol. 2019;2:670-676.
6. Davis I. Pitfalls of PSMA PET/CT in APC imaging. Advanced Prostate Cancer Consensus Conference 2019; August 29, 2019; Basel, Switzerland. https://www.apccc.org/fileadmin/files/2019/apccc2019/slides/Session_1/Session_1_Talk_5_Davis.pdf.
7. Phillips R., Lim S.J., Shi W.Y., Antonarakis E.S., Rowe S., Gorin M., et al. Primary outcomes of a phase II randomized trial of observation versus stereotactic ablative radiation for oligometastatic prostate cancer (ORIOLE). International Journal of Radiation Oncology • Biology • Physics. 2019;105:681.
8. Zilli T., Ost P. Metastasis-directed therapy: A new standard for oligorecurrent prostate cancer? Oncotarget. 2018;9:34196-34197.
12. Hofman M., Murphy D.G., Williams S., Nzenza T., Herschtal A., Matera A., et al. The “propsma study” clinical trial protocol: A prospective randomized multi-center study of the impact of Ga-68 PSMA PET/CT imaging for staging high-risk prostate cancer prior to curative-intent surgery or radiotherapy. J Clin Oncol. 2019;37:TPS138-TPS138.
13. Hofman M.S., Violet J., Hicks R.J., Ferdinandus J., Thang S.P., Akhurst T., et al. 177Lu-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): A single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19:825-833.
14. Violet J., Sandhu S., Iravani A., Ferdinandus J., Thang S.P., Kong G., et al. Long term follow-up and outcomes of re-treatment in an expanded 50 patient single-center phase II prospective trial of lutetium-177 (177Lu) PSMA-617 theranostics in metastatic castrate-resistant prostate cancer. J Nucl Med. 2019.
15. Sartor A.O., Morris M.J., Krause B.J. Vision: An international, prospective, open-label, multicenter, randomized phase 3 study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37:TPS5099-TPS5099.
17. Hofman M.S., Emmett L., Violet J., A Y.Z., Lawrence N.J., Stockler M., et al. Therap: A randomized phase 2 trial of 177Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (clinical trial protocol ANZUP 1603). BJU Int. 2019;124 Suppl 1:5-13.
18. Victoria C.C. Prince : Phase Ib/II study of radionuclide 177lutetium-PSMA-617 therapy in combination with pembrolizumab for treatment of metastatic castration resistant prostate cancer (mCRPC).
19. Hofman M. PSMA-targeted therapies. Advanced Prostate Cancer Consensus Conference; August 30, 2019; Basel, Switzerland. https://www.apccc.org/fileadmin/files/2019/apccc2019/slides/Session_6/Session_6_Talk_6_Hofman.pdf
20. Peter MacCallium Cancer Centre. New radioactive treatment for advanced prostate cancer receives big funding boost. https://www.petermac.org/news/new-radioactive-treatment-advanced-prostate-cancer-receives-big-funding-boost. Published and last updated April 3, 2019. Accessed November 24, 2019.