Imaging-Based Precision Medicine with 177Lu-PSMA-617 in Advanced Prostate Cancer – Who Will Benefit?

JEREMIE CALAIS, MD is Assistant Professor and Director of the Clinical Research Program of the Ahmanson Translational Theranostics Division of the Department of Molecular and Medical Pharmacology at UCLA. He is also a member of the Jonsson Comprehensive Cancer Center and the UCLA Institute of Urologic Oncology. Dr. Calais has established a clinical theranostics research program that combines academic investigator-initiated and industry-sponsored studies using targeted radionuclide imaging and therapy. The clinical research program focuses on translatable radiolabeled theranostic pairs that can be used and applied for diagnosis and therapy of cancer, and collaborates closely with clinical faculty across many departments at UCLA (urology, radiation oncology, radiology, medical oncology, oncologic surgery), and with multiple national and international institutions. Over the past five years, much of the program’s work has been focused on positron emission tomography (PET) imaging-based precision medicine in prostate cancer and how it can help patients and doctors.

177Lu-PSMA-617 in metastatic cancer-resistant prostate cancer

In June, the US Food and Drug Administration (FDA) granted breakthrough designation to lutetium-177 [177Lu]-PSMA-617, a novel targeted radioligand therapy, for the treatment of metastatic castration-resistant prostate cancer (mCRPC).2 177Lu-PSMA-617 delivers β-particle radiation emitted by lutetium-177 to cells positive for protein-specific membrane antigen (PSMA), a transmembrane protein that is highly expressed in prostate cancer and associated with reduced survival. The PSMA-617 ligand was developed specifically for imaging and radioligand therapy of prostate cancer.

The breakthrough therapy designation was based on the results of the phase 3 VISION trial, in which177Lu-PSMA-617 added to standard of care in over 800 previously treated patients with mCRPC prolonged radiographic progression-free survival by an average of 4 months and reduced mortality risk by 38% compared with standard of care plus placebo.3 177Lu-PSMA-617 was administered at a dose of 7.4 GBq every 6 weeks for 4-6 cycles. Standard of care excluded chemotherapy, immunotherapy, radium-223, and drugs under investigation at the time of the trial such as olaparib.

The VISION results, along with those from some smaller studies, indicate that 177Lu-PSMA-617 is “more than just a promising treatment,” according to Dr. Calais. “I’m sure that in the next years it will become standard of care for this patient population, which has previously been treated with chemotherapy,” he says. It has a good safety profile, especially compared with chemotherapy, and it has good antitumor efficacy, particularly if the patients who receive it are selected carefully, he stresses. He points out the importance of patient selection for this treatment and how it represents a transition to more precision medicine using imaging.

Selection of patients for treatment with 177Lu-PSMA-617

Usually, a patient is considered eligible to receive PSMA- targeted molecular therapy if the disease is PSMA-positive on PET-CT imaging, but this depends on how the selection criteria are defined, Dr. Calais points out. In the VISION trial, PSMA status of lesions was measured using gallium-68 [68Ga]-PSMA-11 PET-CT scanning, with PSMA-positivity defined as 68Ga-PSMA-11 uptake greater than that of liver parenchyma in one or more metastatic lesions and without any PSMA-negative lesion visible/measurable by CT (>1 cm for visceral metastatis, >2.5 cm for lymph nodes).3 In the Australian TheraP4 and LuPSMA5 trials, which also showed efficacy of 177Lu-PSMA-617 in patients with mCRPC, a dual-tracer approach was used to select patients with 68Ga- PSMA-11 PET-CT and 2-fluorine-18[18F]-2-deoxy-D-glucose (FDG) PET-CT, which allowed detection of more PSMA- negative lesions. FDG is a glycolytic PET tracer, so it would detect highly glycolytic, mostly aggressive lesions, Dr. Calais notes. In the TheraP trial, these “stringent eligibility criteria” resulted in 28% of men screened being ineligible because of discordant 68Ga-PSMA-11 PET-CT and 2-18F-FDG PET-CT imaging. In contrast, only 15% of patients screened for the VISION trial were considered ineligible.

“Of course, the more stringently you select the patients with very high PSMA uptake, low tumor volume, no FDG lesions, and no PSMA-negative lesions, the better they will respond compared with the controls, and you can have better response rates,” Dr. Calais says. “But it doesn’t answer the question of what you do with the other patients, and whether or not they would not benefit at all from treatment with a PSMA-targeting agent,” he cautions. “You may still have some treatment effect, even in patients considered PSMA-negative,” he maintains.6

As yet, there are no perfect criteria on baseline PET imaging for defining which patients will benefit from such treatment. “I think this will come, the more patients are treated with 177Lu-PSMA-617. “We’ll be able to analyze the imaging baseline characteristics of these patients and try to identify cohorts of very good responders or very poor responders. Maybe in future, we will do prospective trials with treatment algorithms based on the baseline PET imaging findings such as in lymphoma,” Dr. Calais suggests.

Using imaging data to determine benefit and prognosis

Dr. Calais stresses the importance of having data from patients with PSMA-negative lesions. “Only a very few studies report outcome of patients with PSMA-negative scans who were treated with LuPSMA. As expected, outcomes in these patients were worse than the ones that were highly positive.6 Multiple studies have shown that, the more uptake on the PSMA PET-CT scan, the fewer PSMA-negative lesions, the better the response to PSMA-targeted therapy.”7-10

Another improvement would be artificial intelligence-based automatic tools, Dr. Calais suggests. “PET-CT is a whole-body imaging modality. Usually, when we refer to standardized uptake value (SUV), we mean SUVmax, where we basically look at the highest uptake in one lesion among all the lesions. But with SUVmax, we’re not capturing the whole-body disease burden. Getting this assessment at the whole-body level in multi-metastatic patients can be a highly time-consuming task for the PET-CT reader.” With an automatic tool, with one click, it would be possible to have the whole-body tumor segmented and get an estimation of volume of the PSMA-expressing disease and the overall level of target expression. “That will give us the level of PSMA expression with SUVmean in the whole body, not only SUVmax. Some tools can also give even further definition of the amount of visceral, bone, and lymph node tumor volume, separately. That will help a lot to implement PSMA PET parameters to define prognosis and maybe even treatment algorithms based on it.” Dr. Calais noted that these tools are currently being developed by industry and academic researchers. “They are not yet ready for prime time, but I hope they will come soon because the best way to use the full potential of the PSMA PET-CT information is for these tools to be widely available and implemented,” he states.

References

  1. Dillard, R. Dr. Jeremie Calais on PET Imaging-Based Precision Medicine in Prostate Cancer. GU Oncology Now. August 20, 2021. https://www.docwirenews.com/gu-oncology-now/gu-oncology- now-videos/dr-jeremie-calais-on-pet-imaging-based-precision-medicine-in-prostate-cancer/
  2. Novartis receives FDA Breakthrough Therapy designation for investigational 177Lu- PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC). Novartis; News release, June 16, 2021. https://www.novartis.com/news/novartis- receives-fda-breakthrough-therapy-designation-investigational-177lu-psma-617-patients- metastatic-castration-resistant-prostate-cancer-mcrpc
  3. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. Published online June 23, 2021. DOI: 10.1016/S1470-2045(18)30198-0
  4. Hofman MS, Emmett L, Sandhu S, et al; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [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/S1470-2045(21)00274-6
  5. Hofman MS, Violet J, Hicks RJ, 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 DOI: http://dx.doi.org/10.1016/S1470-2045(18)30198-0
  6. Vlachostergios PJ, Niaz MJ, Skafida M, et al. Imaging expression of prostate-specific membrane antigen and response to PSMA-targeted β-emitting radionuclide therapies in metastatic castration-resistant prostate cancer. Prostate. 2021;81(5):279-285. DOI: 10.1002/pros.24104
  7. Seifert R, Seitzer K, Herrmann K,.et al. Analysis of PSMA expression and outcome in patients with advanced prostate cancer receiving 177Lu-PSMA-617 radioligand therapy. Theranostics. 2020;10(17):7812-7820. DOI: 10.7150/thno.47251
  8. Current K, Meyer C, Magyar CE, et al. Investigating PSMA-targeted radioligand therapy efficacy as a function of cellular PSMA levels and intratumoral PSMA heterogeneity. Clin Cancer Res. 2020;26(12):2946-2955. DOI: 10.1158/1078-0432.CCR-19-1485
  9. Gafita A, Calais J, Grogan TR, et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study. Lancet Oncol. 2021;22(8):1115-1125. DOI: 10.1016/S1470-2045(21)00274-6
  10. Ferdinandus J, Violet J, Sandhu S, et al. Prognostic biomarkers in men with metastatic castration-resistant prostate cancer receiving [177Lu]-PSMA-617. Eur J Nucl Med Mol Imaging. 2020;47(10):2322-2327. DOI: 10.1007/s00259-020-04723-z