At the 2023 ASCO Genitourinary Cancers Symposium, Scott Tagawa, MD, Weill Cornell Medicine, New York, NY, presents results from a phase 2 study evaluating ketoconazole, hydrocortisone, and anti-PSMA antibody J591 labeled with ¹⁷⁷Lu or ¹¹¹In for patients with high-risk non-metastatic castration-resistant prostate cancer.

Dr Tagawa stated, “Fewer patients with high-risk non-metastatic castration resistant prostate cancer developed metastasis at 18 months with Lutetium-177-radiolabeled J591 in combination with hydrocortisone and ketoconazole vs those that received Indium-111 J591.” Other secondary outcomes also favored Lutetium-177 in terms of efficacy.

Transcript:

Hi, my name is Scott Tagawa. I'm pleased to give an update on a study utilizing ketoconazole, hydrocortisone, and anti-PSMA antibody J591, radio-labeled with ¹⁷⁷Lutetium or ¹¹¹Indium, in patients with high risk, non-metastatic, castration-resistant prostate cancer, at the 2023 ASCO Genitourinary Cancers Symposium.

We know that patients that have primary therapy, such as surgery or radiation, will unfortunately often suffer a biochemical relapse, i.e. PSA going up after therapy, a quarter to a third of the time. We know that there is a fraction that are successfully salvaged and cured with local therapy, but local therapy doesn't cure everyone, particularly patients with micro-metastatic disease outside of the pelvis. We know that hormonal therapy can lower the PSAs, but most will have ultimate progression. We also know that the majority of prostate cancer cells express the cell surface antigen PSMA, and these can be targeted with small molecule antibodies.

Antibody J591 has been in humans for more than a couple of decades and has shown accurate targeting, and can be labeled with radionuclides. Lutetium-177 is a beta emitter, which is used for therapy, but also has some gamma emission, which is helpful for imaging. And Indium-111 is predominantly a gamma emitter for imaging, but also has some Auger effect for therapy. We hypothesize that, in patients with rapidly rising PSA following local therapy, despite surgical or medical castration, that anti-PSMA salvage radio-immunotherapy would be effective in terms of delaying time to metastatic disease.

Patients enrolled had what has been termed "non-metastatic" or "M0” castration-resistant prostate cancer at a serum testosterone less than 50. High-risk criteria was based on either a PSA doubling time less than 8 months, or an absolute PSA greater than 20, and no metastasis on conventional imaging, as defined by CT or MRI and bone scan. All patients had a renin period of ketaconazole-hydrocortisone. This was designed to up-regulate PSMA, and also radio-sensitize. And then, in a 2-to-1 randomization, received Lutetium-177 radio-labeled J591 or Indium-111 J591. Ketaconazole-hydrocortisone was subsequently continued per physician discretion, and regular imaging with CT, MRI and bone scan was performed every 6 months until PSA progression, and then every 3 months thereafter. The primary endpoint was 18-month metastasis-free survival, and a sample size of 55 patients was designed to give 80% power with an alpha of 10%, which determined an absolute difference of 80% versus 50% in terms of 18-month metastasis-free survival.

Patients enrolled had a median age of 68. Three quarters had a prior prostatectomy, about 1 in 5 had primary radiation, about 1 in 5 had salvage local therapy. The median baseline PSA was 8, and the median PSA doubling time was 3.0 months. The primary endpoint, in terms of intent-to-treat analysis, revealed that in the Lutetium-177 J591 arm, 50% developed metastasis by 18 months, whereas in the Indium-111 J591 arm, 76% had developed metastasis by 18 months, and the difference had a P value of 0.66. Secondary analyses were also in favor of Lutetium-177 versus Indium-111 in terms of efficacy, with biochemical progression-free survival of about 18.7 months versus 8.9 months, and a per protocol median metastasis-free survival of 23.8 months versus 20.8 months.

Confirmed 50% PSA reduction happened commonly in both arms of the trial, ketoconazole actually performed extraordinary well, with Lutetium-177 with ketoconazole, confirmed PSA-50 of 82%, and Indium-111 at 71%. PSA-90 or 90% reduction as best PSA, occurred in half of those receiving Lutetium-177 J591 with ketoconazole and hydrocortisone, and in 35% receiving Indium-111.

Not surprisingly, in terms of adverse events, there was more myelosuppression with Lutetium-177 J591, with more all-grade neutropenia and thrombocytopenia, as well as at least grade 3 neutropenia in 57% versus 11%. One patient in the Lutetium-177 arm had a febrile neutropenia episode, and 77% had grade 3 neutropenia versus 11%, with a quarter receiving platelet transfusion versus 6% with Indium-111. However, the non-hematologic toxicity was not worse with Lutetium-177, with more grade 3 adverse events actually with Indium-111 than Lutetium-177.

In summary, as hypothesized, fewer patients with high risk non-metastatic castration-resistant prostate cancer developed metastasis by 18 months with Lutetium-177 radio-labeled J591 in combination with hydrocortisone and ketoconazole, versus those that received Indium-111 radio-labeled J591. More patients had PSA declines with Lutetium-177 as well as, although the PSA control rate was quite good with anyone receiving ketoconazole in this patient population. There was more hematologic toxicity with Lutetium-177 than Indium-111, but not more non- hematologic toxicity.

This was a multi-center trial supported by the Department of Defense, a Prostate Cancer Young Investigator Award, and NIH funding as well. Investigators and their staff should be congratulated at multiple institutions around the country, and we'd especially like to thank the participants and their families. I'd also like to thank you for listening.

Source:

Tagawa ST, Thomas C, Adra N, et al. Randomized, double-blinded phase II study of ketoconazole (keto), hydrocortisone (HC), and anti-PSMA antibody J591 labeled with ¹⁷⁷Lu or ¹¹¹In in patients (pts) with high-risk non-metastatic (met) castration-resistant prostate cancer (M0 CRPC). Presented at 2023 ASCO Genitourinary Cancers Symposium; February 17-19; San Francisco, CA. Abstract LBA21