Anti-PSMA antibody radiolabeled with 177Lu improves MFS in high-risk nmCRPC

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Published: 18 Feb 2023
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Prof Scott Tagawa - Weill Cornell Medicine, New York City, USA

Prof Scott Tagawa speaks to ecancer at ASCO GU 2023 about his talk on the randomised, double-blinded phase II study of ketoconazole, hydrocortisone, and anti-PSMA antibody J591 labeled with 177Lu or 111In in patients with high-risk non-metastatic castration-resistant prostate cancer.

He explains some of the endpoints for the study included median metastasis free survival, prostate-specific antigen response, overall survival, and toxicity.

Prof Tagawa outlines that the results showed anti-PSMA mAb J591 with ketoconazole/ hydrocortisone when radiolabelled with 177Lu lead to improved 18-month metastasis-free survival versus 111In. He concludes that this supports the development of anti-PSMA radioimmunotherapy for low volume advanced prostate cancer.

We performed a study of PSMA-targeted radioimmunotherapy in patients with high-risk, non-metastatic castration-resistant prostate cancer. By way of background, we know that following local primary therapy, for instance surgery, we know that a quarter to a third will have a biochemical relapse, meaning PSA goes up, we don’t see anything on the scans, and some of them we can cure with salvage radiation, i.e. we radiate the pelvis and the prostate bed, and some of them are cured. But many are not and that’s likely because of deposits of cancer outside of the pelvis that we can’t see. That we just know is a common phenomenon. But we also now know that these types of cancer probably express PSMA, and we know that we can target them with antibodies as well as small molecules. So, our hypothesis was that we will be able to decrease the chance, or at least delay the time until, metastatic disease, if we’re able to deliver radiation to all the sites, rather than just guessing and irradiating the pelvis.

The study enrolled patients with what we called high-risk non-metastatic prostate cancer. That was defined by having a rising PSA, either at a quick rate with a doubling time of less than eight months, and/or an absolute PSA of greater than 20, a serum testosterone less than 50, as well as no evidence of metastasis on conventional imaging, as defined by a CT and/or MRI, as well as a bone scan with no evidence of metastatic disease. 

These patients received a backbone of secondary hormonal manipulation with ketoconazole and hydrocortisone. That was designed to work on its own, as it’s a secondary hormonal therapy, but also increase PSMA expression, and lead to radiosensitization, and then they received an infusion of the antibody J591 which was radiolabelled either with indium-111 as the control arm, or lutetium-177 as a beta-emitter that is able to kill cells. They randomised it at 2:1 ratio, in favour of lutetium. Ketoconazole could be continued, and they were followed with regular imaging every six months, until PSA progression, and then every three months until the endpoint of overt metastasis on standard imaging. The primary endpoint of the study was 18 month metastasis-free survival, and the study was powered with a sample size of 55.

The primary endpoint was 18 month metastasis-free survival. In the intent to treat analysis there were fewer patients that had metastasis or died by 18 months, so at that 18 month mark, half the patients were alive without metastasis, having received lutetium J591, whereas only 24% were alive without metastasis, having received indium-111. 

During the conduct of the study two major shifts have occurred. Number one is we now have PSMA-PET imaging, so what we used to call non-metastatic or M0 CRPC, we now know most of the time we can actually see metastatic disease. It could be within the pelvis or outside the pelvis, but often outside the pelvis, that’s number one, so we wouldn’t call these non-metastatic. Number two, there are three androgen receptor signalling inhibitors that have been approved in this situation for more or less the same thing in terms of delaying time to metastasis as well as, as we now know, delaying time to death in terms of improving overall survival. So that has changed things, where we didn’t have any standard options and now we do.

That being said, this was really designed as a proof of concept study and I think that remains valid, so using one of these androgen receptor signalling inhibitors instead of the ketoconazole background, but still being able to target these small volume sites of disease that are PSMA-positive with a PSMA targeting agent – could be an antibody, could be a small molecule – with a radionuclide that’s able to treat. The smaller the disease burden, i.e. the more micrometastatic disease, I think it’s better for an alpha-emitter, and I think that the smaller volume is also probably better for an antibody versus a small molecule, but it just depends on the situation – is it PET positive, is it PET negative – but I think that the proof of concept was proven, and now I would like to be able to move this forward into an earlier disease setting and hopefully not just delay metastasis but maybe even cure some men.

This is a randomised phase II, not designed as a randomised phase III, but in concept we know that when we can see things, and we didn’t have PSMA-PET, but we can treat them, so in the true metastatic CRPC setting we now know we have a drug, lutetium-PSMA-617, it’s available in many places, a growing number of places, and it delays progression as well as delays death, so improves survival. So we know that is there. We are doing a number of different studies to move that earlier in the disease setting and this kind of a concept, doing it in combination with hormonal therapy, I think makes sense.