PSMA-Directed Therapies and Diagnostics Expand Their Scope in Prostate Cancer

Michael J. Morris, MD

The December 2020 approval of the first agent for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA)–positive lesions in patients with prostate cancer, Gallium 68 PSMA-11 (Ga 68 PSMA-11), heralded an exciting new chapter in the diagnosis and treatment of metastatic castration-resistant prostate cancer (mCRPC). With the emergence of therapies that target PSMA, a cell surface transmembrane protein that is overexpressed in most prostate cancer cells, particularly in castration-resistant disease, the ability to detect and treat the disease has been transformed.

PSMA-Directed Therapeutics: Burgeoning Field

Imaging with Ga 68 PSMA-11 is being considered as a tool to guide targeted treatment.

“There’s a whole field of PSMA-directed therapeutics,” said Michael Morris, MD, clinical director of the Genitourinary Medical Oncology Service and prostate cancer section head, Memorial Sloan Kettering Cancer Center, New York City, New York, in an interview with Targeted Therapies in Oncology. “Many of those therapeutics are linked to a PSMA scan to identify patients who are most likely to respond to those therapeutics because you can establish the presence of the molecule that the therapeutic will be targeting. Most of the trials of PSMA-directed therapeutics utilize a PSMA scan prior to treatment to try to select for those patients who are likely to respond.”

PSMA-directed radioligands, immune therapies, and antibody-drug conjugates (ADCs) are undergoing evaluation. “Regardless [of whether the PSMA-directed] treatments are radioligand based, chemotherapy based, or immunology based, PSMA PET has the potential to [identify] those patient populations who are most likely to respond,” Morris said.

Radioligands

Daniel M. Geynisman, MD

The targeted radioligand lutetium-177–labeled PSMA-617 (LuPSMA) extended progression-free survival (PFS) and radiographic PFS compared with cabazitaxel (Jevtana) in the TheraP trial (NCT03392428), a phase 2 study of patients with mCRPC who had progressed on docetaxel. Findings were presented at the 2020 American Society of Clinical Oncology (ASCO) Genitourinary Cancers (GU) Symposium, held in February 2020. Data have since been published in Lancet.¹

“[LuPSMA] is a small molecule delivering high doses of β radiation to sites of tumors and very low doses to background normal tissues,” said Michael S. Hofman, MBBS, director of the Prostate Cancer Theranostics and Imaging Centre of Excellence and a nuclear medicine physician and physician-scientist at the Peter MacCallum Cancer Centre in Melbourne, Australia, who presented the data. “Lutetium has a 1-mm path length and 7-day half-life, ensuring high targeting of tumors.”

At a median follow-up of 18.4 months, the PFS rate at 1 year was significantly longer in patients randomized to LuPSMA versus cabazitaxel (19% vs 3%; HR, 0.60; 95% CI, 0.44-0.82; P= .001), with similar radiographic PFS findings (HR, 0.64; 95% CI, 0.46-0.88; P= .007). Median PFS, however, was 5.1 months in both arms, “demonstrating that the treatment effect was not constant with respect to time, with greater benefit emerging [after] 6 months,” he said.

The objective response rate (ORR) in the 78 patients with measurable disease at baseline was 49% in the LuPSMA arm versus 24% in the cabazitaxel arm (relative risk, 2.12; 95% CI, 1.10-4.08; P=.019). The proportion of patients with a reduction in prostate-specific antigen (PSA) of at least 50%, the primary end point of the study, was greater in the 177Lu-PSMA-617 arm compared with the cabazitaxel arm (66% vs 37%; difference, 29%; 95% CI, 16%-42%; P<.0001). Further, LuPSMA had a more favorable adverse event (AE) profile than cabazitaxel.

“The clinical impression is that LuPSMA is a favorable treatment option compared with cabazitaxel in men with high PSMA expression,” Hofman said. “In men with progressive disease following docetaxel, Lu-PSMA-617 was significantly more active than cabazitaxel with fewer grade 3 to 4 adverse events, and patient-reported outcomes in multiple domains favored Lu-PSMA. Accordingly, Lu-PSMA-617 represents a new class of effective therapy for men with castration-resistant prostate cancer.”

Recently, LuPSMA was reported to significantly improve radiographic PFS and overall survival (OS) versus standard of care in the ongoing phase 3 VISION study (NCT03511664) of patients with PSMA-positive mCRPC, according to a news release from Novartis, the treatment’s developer.2 The trial enrolled patients who had progressive disease following taxane-based chemotherapy and androgen receptor-directed therapy, as well as a positive Ga 68 PSMA-11 PET/CT scan. Few details were released; full results are expected to be announced at an upcoming medical meeting. Dry mouth was the most common treatment-related AE, occurring in 87% of patients.

Another trial, the open-label phase 2 ENZA-p study (NCT04419402) of LuPSMA in patients with mCRPC whose disease has progressed on androgen deprivation therapy, is randomizing participants to receive 160 mg/day enzalutamide (Xtandi), either alone or combined with 7.5 GBq of 177Lu-PSMA-617 on days 15 and 57.³

The objectives of the study are to measure the safety and activity of 177Lu-PSMA-617 and enzalutamide in patients with mCRPC who are at high risk of progressing on enzalutamide monotherapy and to determine potential prognostic and predictive biomarkers based on imaging, blood, and tissue samples.

The primary end point is PSA PFS. Secondary end points include radiographic PFS, PSA response rate, and clinical PFS and OS. Correlative studies include identification of prognostic and predictive biomarkers from Ga 68 PSMA-11 PET/CT, fluorine 18 ( 18F)-fludeoxyglucose PET/CT, circulating tumor cells, and circulating tumor DNA.

The multicenter, open-label, phase 2 ARROW study (NCT03939689) is randomizing patients with documented mCRPC to enzalutamide alone or combined with a novel, PSMA-targeted, small-molecule radioligand therapeutic (1095) that involves the iodine 131 isotope. This radioligand selectively binds to the extracellular domain of PSMA and delivers a targeted, lethal dose of radiation to prostate cancer cells.⁴

The primary objective is to determine the efficacy of I-131-1095 plus enzalutamide compared with enzalutamide alone, based on PSA response rate (confirmed PSA decline≥50%) according to Prostate Cancer Clinical Trials Working Group 3 criteria. Other objectives include ORR, PFS (defined as first occurrence of radiographic progression), duration of response, OS, and the safety and tolerability of I-131-1095 radioligand therapy.

Antibody-Drug Conjugates

Development of ADCs that target PSMA are ongoing, specifically MEDI3726 and PSMA ADC. For MEDI3726, pyrrolobenzodiazepine dimer toxin is conjugated to the antibody and monomethyl auristatin E is the toxin conjugate in PSMA ADC. In a phase 1 completed doseescalation study (NCT02991911), MEDI3726 was administered to 33 patients after failure of abiraterone (Zytiga) or enzalutamide with or without prior taxane-based therapy. The composite response rate across all doses was 6.1% (2/33), median PFS was 3.9 months, and median OS was 10.6 months.⁵

A phase 2 study (NCT01695044) of a PSMA ADC administered for up to 8 cycles was conducted in 119 patients with mCRPC who had progressed following abiraterone and/or enzalutamide therapy.⁶ Fourteen percent of all treated patients, including 21% of chemotherapy-naïve patients, had PSA declines of 50% or greater. Approximately three-fourths of all treated patients, including 89% of chemotherapy-naïve patients, had declines of at least 50% in circulating tumor cells.

Bi-Specific T-cell Engagers

PSMA-directed bispecific T-cell engagers (BiTEs) are still in early stages of investigation. In a first-in-human, multicenter, dose-escalation study, 16 patients with mCRPC refractory to standard therapy were treated with a PSMA/CD3 BiTE immune therapy known as pasotuxizumab at 1 of 5 doses (NCT01723475).⁷ Primary outcome measures included safety and tolerability, and secondary outcome measures included maximum drug concentration (BOX7 ). Investigators reported a dose-dependent decline in serum PSA level, with the 2 patients treated with the maximum dose of 80 µg/day experiencing a mean decline of 54.9%. Overall, 3 patients had a PSA decrease of 50% or more. One patient treated with 80 µg/day had complete regression of soft tissue metastases and marked regression of bone metastases by PSMA-PET/CT.

The effects of a half-life–extended PSMA/ CD3 BiTE, AMG 160, were investigated both alone and in combination with an anti–PD-1 antibody in a preclinical study. In human prostate cancer cells engineered to overexpress PD-L1, AMG 160 induced upregulation of PD-1 on T cells.⁸ Addition of the anti–PD-1 antibody increased the potency of cell killing compared with AMG 160 alone. In an ex vivo prostate tumor explant model, AMG 160 induced activation of autologous infiltrating T cells and cytokine production, effects that were enhanced by cotreatment with anti–PD-1. A phase 1 study of AMG 160 in patients with mCRPC is in progress (NCT03792841).⁹

CAR T-Cell Therapy

PSMA-directed adoptive cellular therapy also is undergoing investigation, with results from a phase 1 first-in-human study reported at ASCO GU 2021. Investigators led by Vivek Narayan, MD, MSCE, an assistant professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, studied transforming growth factor (TGF) β–insensitive PSMA-directed chimeric antigen receptor (CAR) T cells (CAR T-PSMA-TGF-β therapy) in 18 patients with mCRPC (NCT03089203)^.10

According to the investigators, the prostate cancer microenvironment is immunosuppressive, with high levels of TGF-β, which may limit the therapeutic potential of CAR T cells upon tumor infiltration. “Importantly, these immunosuppressive functions of TGFβ can be abrogated in T cells using a dominant negative TGFβ receptor (TGFβRdn), thereby enhancing antitumor immunity,” the investigators wrote.

A PSA decline occurred in 6 of 10 patients treated with CAR T-PSMA-TGF-β therapy across 2 dose cohorts. The PSA decline was 30% or greater in 4 of these patients, and 1 patient achieved a PSA level below 0.1 ng/mL.

Prior to that report, results from 2 phase 1 clinical trials of PSMA-targeted CAR T cells had been published. In a 2016 report, patients with prostate cancer received anti-PSMA CAR T cells combined with low-dose IL-2.¹¹ Two of 5 patients achieved partial responses, with PSA declines of 50% and 70%. A third patient had a minor response. Responses correlated inversely with engraftment and directly with plasma IL-2 levels. In an even earlier report from 2013, 2 of 7 patients with mCRPC who were treated with PSMA directed CAR T cells had a response, with 1 patient with stable scans lasting longer than 16 months (NCT01140373).¹²

PSMA-Based Imaging

The FDA has approved the use of Ga 68 PSMA-11 as a PET imaging agent in patients with suspected prostate cancer metastasis whose cancer is potentially curable by surgery or radiation therapy.¹³ Additionally, Ga 68 PSMA-11 PET is indicated for patients with suspected prostate cancer recurrence based on elevated serum PSA levels. The initial FDA approval limits its use to the 2 medical centers where pivotal trials were conducted: the University of California, Los Angeles, and the University of California San Francisco Medical Center.

As a 68 Ga-labeled, PSMA-targeted radiotracer, Ga 68 PSMA-11 is used with PET/CT and PET/MRI. Its applications include staging of intermediate- or high-risk prostate cancer or restaging in patients with PSA recurrence.

Technetium bone scans and conventional CT have been the foundations of imaging in prostate cancer detection, but both often miss disease that can be identified by the more sensitive Ga 68 PSMA-11 imaging, said Daniel Geynisman, MD, associate professor, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

“This test is much more sensitive [for picking] up spots of prostate cancer than traditional imaging. That [includes anything] from localized disease to locally advanced disease to metastatic disease,” he said in an interview with Targeted Therapies in Oncology. “It’s just a much more accurate and subtle way to pick up these lesions. It’s a major advancement in the field for diagnosis of prostate cancer, and then there are therapeutics that are associated with it, as well.”

PSMA imaging has been available globally for some time. In the United States, another tracer, radioisotope 18F, to be used with PET to identify PSMA-positive prostate cancer lesions is expected to be approved later this year. Use with other tracers in the United States is on the horizon, Morris said.

National approval for Ga 68 PSMA-11 also is expected later this year. For both of its FDAapproved indications in the United States, use of Ga 68 PSMA-11 PET will allow clinicians to devise a better treatment plan based on a more accurate understanding of the location of the disease. “Those are 2 circumstances under which understanding the distribution of disease is crucial to making the most intelligent decision about how best to treat your patient,” Geynisman said. The superior performance characteristics of PSMA imaging are especially apparent when PSA values are low.

If the United States follows the same pattern as other countries that already use PSMA imaging extensively, “it will replace standard bone scans and CT for your usual staging,” Morris said. “It’s a better scan than anything we have now; it identifies disease much more readily and much earlier than standard imaging, and so it will probably be transformative in terms of how prostate cancer [is] staged and, if [patients experience] relapse, how we understand where their disease is so we can treat them more accurately.”

Pivotal Trials: PSMA-Based Imaging

The 2 pivotal trials that led to the FDA approval of Ga 68 PSMA-11, NCT03368547 and NCT02940262, enrolled a combined 960 patients with prostate cancer who received 1 injection of Ga 68 PSMA-11.¹³

In the NCT03368547 trial, 325 patients with biopsy-proven prostate cancer who were being considered for prostatectomy with lymph node dissection underwent PET/CT or PET/MRI scans performed with Ga 68 PSMA-11. “Among the patients who proceeded to surgery, those with positive readings in the pelvic lymph nodes on Ga 68 PSMA-11 PET had a clinically important rate of metastatic cancer confirmed by surgical pathology,” according to an FDA news release.¹³

In the NCT02940262 trial, 635 patients who had rising serum PSA levels after prostate surgery and/or radiotherapy underwent a single Ga 68 PSMA-11 PET/CT or PET/MRI scan (FIGURE see page 3214). The scans showed that 74% of the patients had at least 1 positive lesion detected by Ga 68 PSMA-11 PET in at least 1 body region (bone, prostate bed, pelvic lymph node, or extrapelvic soft tissue). Local recurrence or metastasis of prostate cancer was confirmed in an estimated 91% of patients who also had correlative tissue pathology from biopsies, baseline or follow-up conventional imaging, and serial PSA levels available for comparison. “Thus, the second trial demonstrated that Ga 68 PSMA-11 PET can detect sites of disease in patients with biochemical evidence of recurrent prostate cancer,” according to the FDA.¹³

Regarding safety, investigators reported no serious AEs associated with Ga 68 PSMA11. Common treatment-related AEs were nausea, diarrhea, and dizziness. Image misinterpretation may occur because Ga 68 PSMA-11 may bind in other types of cancer, as well as certain nonmalignant processes.

One potential implication of using Ga 68 PSMA-11 PET/CT is recategorization of nonmetastatic CRPC.

“That whole category is basically going to disappear because if you do 1 of these PSMA tests, almost for sure you’re going to find disease in most people. You just haven’t been able to see it with the other tests,” Geynisman said.

OSPREY and CONDOR

The results of 2 pivotal clinical trials, OSPREY and CONDOR, support the use of PSMA-targeted 18F-DCFPyL PET/CT to stage prostate cancer.

In the OSPREY trial (NCT02981368), 385 participants with either high-risk prostate cancer planned for radical prostatectomy and pelvic lymph node dissection (cohort A; n=268) or with presumptive recurrent or metastatic prostate cancer based on radiologic findings (cohort B; n=117) underwent 18F-DCFPyL PET/CT scans.¹⁵

In cohort A, 18F-DCFPyL PET/CT had a specificity of 96% to 99%, a sensitivity of 31% to 42%, and a positive predictive value (PPV) of 78% to 91% in detecting disease in pelvic lymph nodes.

In cohort B, the sensitivity and PPV rates for detecting metastatic lesions were 93% to 99% and 81% to 88%, respectively.

CONDOR was a multicenter phase 3 study (NCT03739684) that enrolled patients with rising PSA after definitive therapy and negative or equivocal standard-of-care imaging, with the correct localization rate (CLR) as the primary end point. CLR is the percentage of patients with a 1:1 correspondence between at least 1 lesion identified by PyL–PET/CT and the composite standard of truth: pathology, correlative imaging, or PSA response. Among the 208 evaluable patients, 85% of whom underwent radical prostatectomy (either alone or with radiation), CLR values assessed by 3 blinded independent readers were 85.6%, 87.0%, and 84.8%.¹⁶

The FDA is reviewing the results of these trials and is scheduled to make an approval decision by May 28, 2021.

“This a rapidly evolving field,” Morris said. “A lot of these tracers that have been available outside the US will now be available nationally, pending approvals later this year.”

Initially, use of PSMA-based imaging may be confined to larger centers for technological reasons, Geynisman believes. “You have to be able to produce the actual ligand,” he said. “The center has to be able to make that, and it has to be a stable compound to be injected. Once it’s approved [nationally] and is able to be produced, it will probably be available all over. It’s like anything else, where initially it starts at major academic centers and then filters out.”

_References:

_{1. 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/S0140-6736(21)00237-3}

_{2. Novartis announces positive result of phase III study with radioligand therapy 177Lu-PSMA-617 in patients with advanced prostate cancer. News release. Novartis. March 23, 2021. Accessed March 23, 2021. https://bit.ly/3ce0zCQ}

_{3. Emmett L, Subramaniam S, Zhang AY, et al; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). ENZA-p: A randomized phase II trial using PSMA as a therapeutic agent and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901). J Clin Oncol. 2021;39(suppl 6):TPS177. doi:10.1200/JCO.2021.39.6_suppl.TPS177}

_{4. Sartor AO, Laidley D, Pouliot F, et al. A multicenter, randomized, controlled phase II study: efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW). J Clin Oncol. 2021; 39(suppl 6):TPS187. doi:10.1200/JCO.2021.39.6_suppl.TPS187}

_{5. De Bono JS, Fleming MT, Wang JSZ, et al. MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide. J Clin Oncol. 2021;38(suppl 6):99. doi:10.1200/JCO.2020.38.6_suppl.99}

_{6. Petrylak DP, Vogelzang NJ, Chatta K, et al. PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: efficacy and safety in open-label single-arm phase 2 study. Prostate. 2020;80(1):99-108. doi:10.1002/pros.23922}

_{7. Hummel HD, Kufer P, Grüllich C, et al. Phase I study of pasotuxizumab (AMG 212/BAY 2010112), a PSMA-targeting BiTE (bispecific T-cell engager) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(suppl 6):124. doi:10.1200/JCO.2020.38.6_suppl.124}

_{8. Paweletz AL, Li S, Bailis JM, Juan G. Combination of AMG 160, a PSMA/CD3half-life extended bispecific T-cell engager (HLE BiTE) immune therapy, with an anti-PD-1 antibody in prostate cancer (PCa). J Clin Oncol. 2020;38(suppl 6):155. doi:10.1200/JCO.2020.38.6_suppl.155}

_{9. Tran BT, Horvath L, Dorff TB, et al. Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(suppl 6):TPS261. doi:10.1200/JCO.2020.38.6_suppl.TPS261}

_{10. Narayan V, Gladney W, Plesa G, et al. A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer. J Clin Oncol. 2019;37(suppl 7):TPS347. doi: 10.1200/JCO.2019.37.7_suppl.TPS347}

_{11. Junghans RP, Ma Q, Rathore R, et al. Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate. 2016;76(14):1257-1270. doi:10.1002/pros.23214}

_{12. Slovin SF, Wang XY, Hullings M, et al. Chimeric antigen receptor (CAR+) modified T cells targeting prostate-specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC). J Clin Oncol. 2013;31(suppl 6):72. doi:10.1200/jco.2013.31.6_suppl.72}

_{13. FDA approves first PSMA-targeted PET imaging drug for men with prostate cancer. News release. FDA. December 1, 2020. Accessed April 14, 2021. https://bit.ly/2OOygSz}

_{14. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. JAMA Oncol. 2019;5(6):856-863. doi:10.1001/jamaoncol.2019.0096}

_{15. Pienta KJ, Gorin MA, Rowe SP, et al. A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate-specific membrane antigen PET/CT with 18F-DCFPYL in prostate cancer patients (OSPREY). J Urol. Published February 26, 2021. doi:10.1097/JU.0000000000001698}

_{16. Morris MJ, Rowe SP, Gorin MA, et al; CONDOR Study Group. Diagnostic performance of 18F-DCFPyL-PET/CT in men with biochemically recurrent prostate cancer: results from the CONDOR phase III, multicenter study. Clin Cancer Res. Published February 26, 2021. doi:10.1158/1078-0432.CCR-20-4573}