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Radionuclide Tx Wins in Third-Line Metastatic CRPC

— Early trial shows improved PFS, response rates versus cabazitaxel

MedpageToday

Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy reduced the risk of disease progression or death versus cabazitaxel (Jevtana) in men with previously treated metastatic castration-resistant prostate cancer (CRPC), and with fewer toxicities and better quality of life, a randomized phase II trial showed.

In the so-called TheraP study, which involved 200 patients with high PSMA expression and progressive disease following docetaxel, lutetium-177 PSMA-617 improved radiographic progression-free survival (PFS) over cabazitaxel (HR 0.63, 95% CI 0.46-0.86, P=0.0028), reported Michael Hofman, MBBS, of the Peter MacCallum Cancer Centre in Melbourne, Australia.

While median radiographic PFS was identical, at 5.1 months in each arm, 12-month rates were 19% with the PSMA-targeted radionuclide therapy versus 3% with cabazitaxel, according to findings presented at the virtual Genitourinary Cancers Symposium and published simultaneously in . Overall survival (OS) data were not mature.

"Lutetium PSMA-617 represents a new class of effective therapy for men with castration-resistant prostate cancer," said Hofman.

Lutetium-177 PSMA-617 is a small molecule that delivers high levels of beta-particle radiation to PSMA-expressing cells, Hofman explained, but low doses to normal tissue.

"A strength of the study is an active control arm using cabazitaxel -- a validated life-prolonging therapy reinforced with the publication of the CARD trial," he said.

Writing in an , Thomas Hope, MD, of the University of California San Francisco, and Jeremie Calais, MD, of the University of California Los Angeles, agreed.

"Cabazitaxel is an effective therapy for patients who have already received docetaxel," they noted, while adding that other PSMA-targeted radiopharmaceutical therapy trials are using weaker comparator arms, which may limit their interpretation.

Hope and Calais called attention to the PFS curves in TheraP, which only separated at 6 months, by which point the PSMA-targeted agent overtook cabazitaxel.

"This finding might be the most interesting aspect of this study and highlights two points. First, PSMA-targeted radiopharmaceutical therapy treatment is cumulative, unlike chemotherapy. Tumor cells receive doses of radioactivity every 6 weeks, and therefore the treatment effect might not be shown immediately," they wrote. "Second, a subpopulation of patients exist who have a prolonged benefit from PSMA-targeted radiopharmaceutical therapy, pushing out the tail of the PSMA-targeted radiopharmaceutical therapy progression-free survival curves."

As was previously reported, TheraP met its primary endpoint, with lutetium-177 PSMA-617 leading to a higher proportion of men seeing a 50% or greater reduction in prostate-specific antigen (PSA) levels from baseline compared with cabazitaxel (66% vs 37%; P<0.0001).

Objective response rates in the current study were doubled with the radiopharmaceutical therapy, at 49% compared with 24% with cabazitaxel. Men in the lutetium-177 PSMA-617 arm also had less pain following treatment, with 60% reporting improvements compared with 43% of those in the cabazitaxel arm (relative risk 1.4, 95% CI 0.9-2.2, P=0.10).

"Lutetium PSMA-617 was significantly more active than cabazitaxel with fewer grade 3/4 adverse events, and patient-reported outcomes in multiple domains favored lutetium PSMA," said Hofman.

Grade 3/4 toxicities occurred in 33% of patients treated with lutetium-177 PSMA-617 versus 53% with cabazitaxel, with the most common being neutropenia (4% vs 13%, respectively), thrombocytopenia (11% vs 0%), anemia (8% each), diarrhea (1% vs 5%), and fatigue (5% vs 4%).

On the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30), significant improvements with lutetium-177 PSMA-617 were seen in social functioning, fatigue, insomnia, and diarrhea, and all other measures trended in favor of the radionuclide group. There was also lower incidence of skin rash, sore hands/feet, altered taste, dizziness, urinary symptoms, and diarrhea with lutetium-177 PSMA-617.

The study also demonstrated improved deterioration-free survival (DFS) with lutetium-177 PSMA-617, which was defined as time to a ≥10 point deterioration in EORTC QLQ-C30 global health status, disease progression, death, or treatment discontinuation. At 6 months, DFS rates were 29% in the study arm versus 13% in the cabazitaxel arm. At 12 months, these rates were 21% versus 1%, respectively.

TheraP was an open-label, investigator-initiated phase II trial that from 2018 to 2019 randomized 200 men with metastatic CRPC who had previously been treated with docetaxel 1:1 to either lutetium-177 PSMA-617 (delivered intravenously every 6 weeks for up to six cycles, starting at 8.5 GBq and decreasing 0.5 GBq each cycle) or cabazitaxel (20 mg/m2 via IV for up to 10 cycles).

A paired diagnostic test involving PET-CT imaging with gallium-68Ga-PSMA-11 was used to exclude men who might not benefit from the treatment. Patients needed to have a PSMA SUVmax >20 at any site for inclusion, as well as no FDG-positive or PSMA-negative sites of disease. After screening 291 patients, 91 were excluded due to low PSMA expression (n=29), FDG-discordant disease (n=51), or other reasons (n=11). Fifteen patients dropped out in the cabazitaxel arm versus none in the study arm, a limitation of the study, Hofman noted.

Patients had a median age of 72 years, 91% had previously received androgen receptor-directed therapy (abiraterone [Zytiga], enzalutamide [Xtandi], or both), and about 95% of patients had an ECOG performance status score of 0 or 1.

PSA PFS showed a similar hazard ratio to the radiographic PFS analysis, as did per-protocol sensitivity analyses.

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    Ian Ingram is Managing Editor at ֱ and helps cover oncology for the site.

Disclosures

The study was funded by the Prostate Cancer Foundation of Australia, Australian Nuclear Science and Technology Organisation, the Distinguished Gentleman Ride, It's a Bloke Thing, and CAN4CANCER. Novartis supplied PSMA-617.

Hofman disclosed relationships with Endocyte, Janssen, Genzyme, and Ipsen. Co-authors reported various ties to industry.

Primary Source

Genitourinary Cancers Symposium

Hofman MS, et al "177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: Updated results including progression-free survival (PFS) and patient-reported outcomes (PROs) (TheraP ANZUP 1603)" GuCS 2021; Abstract 6.

Secondary Source

The Lancet

Hofman MS, et al "[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomised, open-label, phase 2 trial" Lancet 2021; DOI: 10.1016/S0140-6736(21)00237-3.

Additional Source

The Lancet

Hope TA, Calais J "PSMA-targeted radiopharmaceutical therapy in patients with metastatic castration-resistant prostate cancer" Lancet 2021; DOI: 10.1016/S0140-6736(21)00349-4.