The VISION Trial and Integration of PSMA-Targeted Therapy for Prostate Cancer

The VISION trial and how it will provide the basis for better models for integrating prostate-specific membrane antigen (PSMA) into the management of patients with advanced prostate cancer was discussed at last December’s 2021 Society of Urologic Oncology (SUO) annual meeting by  Michael J. Morris MD, Section Head of Prostate Cancer of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center, New York.

Medical oncology is in a state of transition as it switches from drugs that target hydroxyapatite, such as radium-223, to tumor-specific targeting therapies utilizing targets such as PSMA, Dr Morris noted. “Hopefully the realm of tumor-directed PSMA therapy will be more successful in terms of adoption into models for advanced disease than we saw with the bone-directed radiopharmaceutical therapies,” he remarked. Out of 2020 US market sales of $11.2 billion for prostate cancer drugs, bone metastases-targeting agents such as radium-223 accounted for only $0.3 billion, he noted.

Likely reasons for the poor adoption of bone-directed radiopharmaceutical therapies, Dr Morris suggested, include the limited therapeutic targets (bone dominant disease), the associated increase in risk for fragility fractures, as shown with radium-223 plus abiraterone in patients with early metastatic castrate-resistant prostate cancer (mCRPC) in the ERA 223 trial.¹ In addition, clinicians are reluctant to utilize these therapies as there is a lack of multidisciplinary patient management strategies to share care of the patient.

The Phase 3 VISION trial could change that trend, Dr Morris believes. The trial results were presented at the 2021 annual meeting of the American Society of Clinical Oncology (ASCO) and published shortly afterwards.² The trial enrolled patients with mCRPC who had progressed through at least one androgen-receptor-pathway inhibitor (ARPI) and either one or two taxane regimens. Patients had to have an ECOG performance status 0-2 and life expectancy of at least 6 months and PSMA-positive disease as documented by ⁶⁸Ga-PSMA-11 PET/CT scan. Patients were randomized 2:1 to either ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks × 6 cycles) plus protocol-permitted, physician-selected standard of care or standard of care alone. Primary endpoints of the trial were overall survival (OS) and radiographic progression free survival (rPFS).

As reported previously, the trial met both primary endpoints, with ¹⁷⁷Lu-PSMA-617 plus standard of care, with a 38% reduction in the risk of death (HR 0.62; median OS 15.3 vs 11.3 months) and a 60% reduction in rPFS (HR 0.40; median rPFS 8.7 vs 3.4 months), as well as a significant improvement in median time to first symptomatic skeletal events of 4.7 months (HR 0.50; median 11.5 months vs 6.8 months).

Further analysis of health-related quality of life (HRQoL) data from 581 patients presented at the 2021 ESMO annual meeting by Karim Fizazi, MD, PhD (University of Paris-Saclay, France)³ showed a 54% reduction in time to worsening of HRQoL with ¹⁷⁷Lu-PSMA-617 plus standard of care as measured by the Functional Assessment of Cancer Therapy – Prostate (FACT-P) scale. ¹⁷⁷Lu-PSMA-617 plus standard of care also resulted in a 55% reduction in time to worsening of pain intensity, as measured by the Brief Pain Inventory – Short Form (BPI-SF) scale.  “So this is truly the trifecta of impacting favorably how patients feel, how they function, and how they survive,” Dr Morris remarked.

All secondary endpoints of the VISION trial were met, Dr Morris noted, with a 46% rate of PSA decrease of at least 50% and 80% from baseline with ¹⁷⁷Lu-PSMA-617 plus standard of care compared with 7% with standard of care alone. Unusually in this population, Dr Morris added, 9.2% of patients with measurable disease at baseline who received ¹⁷⁷Lu-PSMA-617 had a radiographic complete response and 41.8% of these patients had a partial response. Overall, almost all patients who received ¹⁷⁷Lu-PSMA-617 had radiographically stable disease or better, he reported.

¹⁷⁷Lu-PSMA-617 is not without side effects, Dr Morris noted. Almost 40% of VISION patients experienced low grade xerostomia as a result of salivary gland expression of PSMA and nausea/vomiting (mostly low-grade nausea) secondary to the infusion. Hematologic toxicities included 12.9% and 7.9% of patients who experienced Grade ≥3 anemia and thrombocytopenia, respectively.

Looking at the future for optimizing the introduction of  ¹⁷⁷Lu-PSMA-617 and other radiopharmaceuticals into treatment of prostate cancer, Dr Morris explained that these therapies are currently focused in creating second, third- and fourth-line options. However, positive results from these trials will encourage exploration of the utilization of these therapies in earlier disease settings.

Two ongoing  clinical trials, PSMAfore (NCT04689828)⁴ and PSMAddition (NCT04720157)⁵ are  examining the role of ¹⁷⁷Lu-PSMA-617 in patients with earlier stage disease. PSMAfore is being carried out in mCRPC patients with disease progression after ARPI therapy and no prior taxane therapy. Patients are randomized 1:1 between 177Lu-PSMA-617 and a change in ARPI therapy plus standard of care in both arms. PSMAddition is focusing on patients with metastatic hormone sensitive prostate cancer (mHSPC) with no prior exposure to chemotherapy or hormonal therapy as well as identifiable disease on ⁶⁸Ga-PSMA-11 PET/CT scans. Patients are randomized 1:1 between ¹⁷⁷Lu-PSMA-617 plus standard of care (ARPI) or standard of care alone. The primary endpoint of both trials is rPFS and crossover into the ¹⁷⁷Lu-PSMA-617 arm is allowed.

Dr Morris noted that the advent of ⁶⁸Ga-PSMA-11 based imaging has allowed for identification of micro metastatic disease even earlier in the disease course, such as in patients with an asymptomatic rising PSA. Clinical trials to explore the nmCRPC and biochemically recurrent disease setting are being designed. He also advised significant caution due to a lack of long-term safety and toxicity data after radiopharmaceutical exposure. Data are also immature regarding administration of radiopharmaceutical monotherapy versus combination with ADT/ARPI therapy to increase PSMA expression and maximize dosimetry. Finally, Dr Morris explained that not every patient who would benefit from ¹⁷⁷Lu-PSMA-617 could be identified on ⁶⁸Ga-PSMA-11 scans and use of radiopharmaceuticals this early in the disease process may run the risk of overtreatment.

Dr Morris questioned whether PSMA imaging is necessary to identify which patients will benefit from ¹⁷⁷Lu-PSMA-617, citing the VISION trial, in which 12.6% (n=126/1003) of patients did not meet PSMA enrollment criteria.² Not having to obtain a diagnostic PSMA scan would reduce healthcare costs and may also indirectly decrease barriers to care for patients who otherwise could not afford such therapies, he maintained. In the TheraP trial,⁶ selection of participants using ⁶⁸Ga-PSMA-11 plus ¹⁸FDG PET/CT imaging led to higher PSMA therapeutic response rate by identifying patients who would most likely benefit from¹⁷⁷Lu-PSMA-617, Dr Morris asserted. He added that other biomarker candidates, including genomic markers and circulating tumor cells and DNA, have potential for identifying appropriate candidates for therapy.

Dr Morris concluded that the results of the VISION trial strongly indicate that ¹⁷⁷Lu-PSMA-617 should be incorporated into the armamentarium of treatments for use in patients with prostate cancer. (Based on the results of the VISION trial, the US Food and Drug Administration (FDA) designated ¹⁷⁷Lu-PSMA-617 as Breakthrough Therapy, and at the time of this presentation was expediting its development and regulatory review.⁷) In patients who have progressed after ARPI/chemotherapy, tumor-directed radioligand therapy achieves the trifecta of how patients feel, function, and survive, even in those with soft tissue disease, Dr Morris declared. ¹⁷⁷Lu-177-PSMA has opened the door to a new drug class for prostate cancer, new sequencing studies, and new combinations, he believes. However he also cautioned that the optimal “advanced” patient population has yet to be defined.

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.  

References

1. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:408-419. DOI: 1016/S1470-2045(18)30860-X
2. Sartor S, de Bono J, Chi KM, et al; VISION investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer, N Engl J Med. 2021;385(12):1091-1103. DOI: 1056/NEJMoa2107322
3. 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):S627-S628. Abstract 576MO. DOI:https://doi.org/10.1016/j.annonc.2021.08.1089
4. Morris MJ, Sartor O, Chi KN, et al. PSMAfore: A phase III study to compare 177Lu-PSMA-617 treatment with a change in androgen receptor pathway inhibitor in taxane-naïve patients with mCRPC Ann Oncol. 2021;32(Suppl):S675-S676. Abstract 648TiP. DOI: 1016/j.annonc.2021.08.1161
5. Tagawa ST, Sartor O, Saad F, et al. PSMAddition: A phase III trial to compare treatment with 177Lu-PSMA-617 plus standard of care (SOC) versus SOC alone in patients with metastatic hormone-sensitive prostate cancer. Ann Oncol. 2021; 32(Suppl):S673-S675. Abstract 647TiP. DOI: https://doi.org/10.1016/j.annonc.2021.08.1160
6. Hofman MS, Emmett L, Sandhu S, et al. [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomized, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804. DOI: 1016/s0140-6736(21)00237-3
7. FDA grants Priority Review for investigational targeted radioligand therapy 177Lu-PSMA-617 for patients with metastatic castration-resistant prostate cancer (mCRPC). Press release, Novartis. September 28, 2021. https://www.novartis.com/news/fda-grants-priority-review-investigational-targeted-radioligand-therapy-177lu-psma-617-patients-metastatic-castration-resistant-prostate-cancer-mcrp