PSMA Is Ready to Change Practice in mCRPC

Michael Hofman, MBBS, FRACP, FAANMS, FICIS

The emergence of diagnostic imaging and treatments that target prostate-specific membrane antigen (PSMA)–positive lesions has been heralded as a new chapter in metastatic castrationresistant prostate cancer (mCRPC). The improvement in detection and treatment associated with PSMA cannot be overstated, with many investigators describing the advancement as a global practice changer.

During the 28th Annual Prostate Cancer Foundation Scientific Retreat, Michael Hofman, MBBS, FRACP, FAANMS, FICIS, a nuclear medicine physician, physician-scientist, and director of the Prostate Cancer Theranostics and Imaging Centre of Excellence at the Peter MacCallum Cancer Centre in Melbourne, Australia, discussed the game-changing qualities of Gallium 68 PSMA-11 (Ga 68 PSMA-11) and lutetium Lu 177 (¹⁷⁷Lu) PSMA therapy, the latest theranostic approaches for advanced prostate cancer.¹

Traditionally, conventional imaging using CT and bone scans has demonstrated insuffi cient sensitivity when staging men with high-risk, localized prostate cancer. Ga 68 PSMA-11 is the first drug for positron emission tomography (PET) imaging of PSMA positive lesions in men with prostate cancer. The imaging drug is indicated for patients with suspected prostate cancer who are potentially curable by surgery or radiation therapy. Ga 68 PSMA-11 is also indicated for patients with suspected prostate cancer recurrence based on elevated serum prostate-specific antigen (PSA) levels. Ga 68 PSMA-11 is a radioactive diagnostic agent that is administered in the form of an intravenous injection.²

Novel imaging using PSMA PET–CT was shown to improve accuracy and affect management in a multicenter, 2-arm, randomized study (Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358).³

The primary outcome of this study was to determine the accuracy of first-line imaging for identifying either pelvic nodal or distant metastatic disease. Investigators demonstrated a 27 percentage-point greater accuracy for PSMA PET-CT (95% CI, 23-31) than that of conventional imaging: 92% vs 65% (P < .0001). Sensitivity and specificity also favored PSMA PET-CT at 85% vs 38% and 98% vs 91%, respectively.

For patients with pelvic nodal metastases, superiority of PSMA PET-CT was shown to be 91% in the area under the curve compared with traditional scans at 59% (32% absolute difference) and 95% vs 74% (22% absolute difference) for patients with distant metastases. Conventional imaging conferred management change less frequently, in 23 men vs 41 men (P = .008) who were scanned using PSMA PET-CT. Similarly, conventional imaging had more equivocal findings (23%) vs men who received PSMA PET-CT (7%). The investigators concluded that PSMA PET-CT provides superior accuracy to the combined findings of CT and bone scanning.

TheraP and VISION Trials

Turning to treatment, Hofman highlighted the TheraP trial (NCT03392428)⁴ and VISION trial (NCT03511664).⁵

In TheraP, men were randomly assigned 1:1 to ¹⁷⁷Lu-PSMA-617 (6.0-8.5 GBq) or cabazitaxel (Jevtana; 20 mg/m² ). The primary end point was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline.

The investigators reported that PSA responses were more frequent among men in the ¹⁷⁷LuPSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% [95% CI, 16%-42%; P < .0001]; and 66% vs 44% by treatment received; difference 23% [95% CI, 9%-37%; P = .0016]).

Grade 3/4 adverse events occurred in 32 (33%) of 98 men in the ¹⁷⁷Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to ¹⁷⁷Lu-PSMA-617. The investigators concluded that ¹⁷⁷Lu-PSMA-617 is a new, effective class of therapy and a potential alternative to cabazitaxel.

The VISION study was an open-label phase 3 trial evaluating ¹⁷⁷Lu-PSMA-617 in patients with mCRPC previously treated with at least 1 androgen receptor–pathway inhibitor and 1 or 2 taxane regimens who had PSMA-positive gallium 68–labeled PSMA-11 PET-computed tomographic scans.

Patients were randomly assigned to receive either ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for 4 to 6 cycles) plus protocol-permitted standard care or standard care alone. Standard care excluded chemotherapy, immunotherapy, radium 223 dichloride (Xofi go), and investigational drugs. The alternate primary end points were imaging-based progression-free survival (PFS) and overall survival (OS), which were powered for HRs of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events.

After a median follow-up of 20.9 months, PFS and OS both favored the combination treatment over the standard treatment. Specifically, median PFS for the combinational treatment was 8.7 months vs 3.4 months for standard care (HR, 0.40; 99.2% CI, 0.29-0.57; P < .001), and median OS was 15.3 months for the combination treatment vs 11.3 months for standard care (HR, 0.62; 95% CI, 0.52-0.74; P < .001).

“When we think about men with advanced castration-resistant prostate cancer who have received 3 or 4 lines of therapy, [there are] 2 things we can do—improve survival and improve quality of life,” Hofman said. “And lutetium [PSMA] does both of these.”

Regarding quality of life, the VISION trial reported on time to worsening pain. Investigators observed a delay in pain for men treated with ¹⁷⁷Lu-PSMA-617 of 14.3 months compared with 2.9 months for men in the standard-care arm. Regarding toxicities, Hofman noted that in the TheraP trial, half the cohort received ¹⁷⁷Lu-PSMA-617 and half received cabazitaxel and chemotherapy. As a result, chemotherapy-related adverse effects such as diarrhea, fatigue, hair loss, skin rash, and neuropathy were observed in patients who received cabazitaxel.

The FDA has accepted the new drug application for ¹⁷⁷Lu-PSMA-617 and granted it priority review for the treatment of mCRPC in the post androgen receptor pathway inhibition, post-taxane-based chemotherapy setting.6 The results from the VISION study previously led the FDA to grant breakthrough therapy designation to ¹⁷⁷Lu-PSMA-617 in July 2021. A decision on whether to approve ¹⁷⁷Lu-PSMA-617 for this indication will be made by the FDA in the first half of 2022.

Looking to the future, next-generation approaches are undergoing evaluation. In particular, Hofman emphasized improved imaging approaches, next-generation isotopes of ligands, and pharmacological mechanisms that can enhance therapy, either by combining with immunotherapy or by enhancing the effectiveness of radiotherapy. “We are prolonging life and improving quality of life. But we need to do even better,” Hofman concluded.

_REFERENCES:

_{1. Hofman M. LuPSMA: the newest treatment class for advanced prostate cancer. Presented at: 28th Annual Prostate Cancer Foundation Scientific Retreat; October 28-29, November 4-5, 2021; virtual. Accessed November 22, 2021.}

_{2. FDA Approves First PSMA-Targeted PET Imaging Drug for Men with Prostate Cancer. News release. December 1, 2020. https://bit. ly/3DJvy4Y}

_{3. Hofman MS, Lawrentschuk N, Francis RJ, et al; proPSMA Study Group Collaborators. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216. doi:10.1016/S0140-6736(20)30314-7}

_{4. Hofman MS, Emmett L, Sandhu S, et al; TheraP Trial Investigators; Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [ 177 Lu]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}

_{5. 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. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322}

_{6. FDA grants Priority Review for investigational targeted radioligand therapy 177Lu-PSMA-617 for patients with metastatic castration-resistant prostate cancer (mCRPC). News release. Accessed September 28, 2021. https://bit.ly/30M4VxC}