LuPSMA vs cabazitaxel in metastatic castration-resistant prostate cancer progressing after docetaxel

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Published: 30 May 2020
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Prof Michael Hofman - Peter MacCallum Cancer Centre, Melbourne, Australia

Prof Michael Hofman speaks to ecancer about the preliminary results from the ANZUP TheraP trial, presented as part of the ASCO 2020 Virtual Meeting.

The randomised phase II is of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel.

Prof Hofman reports that the results suggest LuPSMA has higher efficacy and lower toxicity than cabazitaxel.

He discusses the next steps of the study and the potential impacts of this study along with other parallel trials.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

The results we are presenting at ASCO 2020 is the ANZUP therapy trial. This is a randomised phase II trial of lutetium-PSMA-617 compared to cabazitaxel chemotherapy in men with metastatic castration resistant prostate cancer. So this is really the first randomised controlled trial of this novel therapy, LuPSMA -617. It’s a radiolabelled small molecule that binds to prostate specific membrane antigen. This is expressed on the surface of prostate cancer cells and the molecule is a peptide-like molecule. We deliver it intravenously, like any other drug, it travels around the blood stream and binds with high affinity to prostate cancer cells and is then internalised. This is quite a novel means to deliver very high doses of beta radiation to sites of tumours. The lutetium-177 has a very short path length of only 1mm which means we get a lot of damage to cancer cells but much less damage to normal surrounding soft tissues. To date there has been just phase II data suggesting high efficacy and low toxicity of this novel treatment and this represents the first randomised data.

The therapy is a phase II randomised trial in 200 men performed at eleven sites around Australia. So men who had progressed after docetaxel who were potentially suitable for cabazitaxel were recruited. Men had progressive disease with a rising PSA and also a PSA over 20. They then underwent two types of PET scans – a PSMA and an FDG-PET scan. This allows us to assess whether all the sites of tumours had high PSMA expression. If that was the case they were randomised one-to-one either to six cycles of the experimental arm, LuPSMA -617 or up to ten cycles of cabazitaxel. The primary endpoint of the study was PSA response defined by a PSA reduction of over 50% compared to baseline.

The main results of the therapy trial were that the PSA response rate was much higher with lutetium compared to cabazitaxel. To quantify that there was 66% of men in the lutetium arm who had a PSA reduction of 50% or more compared to 37% of men in the cabazitaxel arm. So that’s a 29% absolute improvement favouring the LuPSMA arm which is really a large difference in this primary endpoint of efficacy.

We also looked at two key secondary endpoints, PSA progression free survival and adverse events. For the progression free survival analysis only 157 of the required 170 events have occurred to date so this is a preliminary analysis but nevertheless we show that LuPSMA delays progression with a hazard ratio of 0.69. With regards to adverse events we saw a lower rate of severe toxicity with LuPSMA, the experimental arm, compared to chemotherapy. We can quantify that by looking at the grade 3-4 toxicities and they occurred in 35% of men randomised to LuPSMA compared to 54% of men in the cabazitaxel arm. This tells us that not only was lutetium more effective but it also had less adverse events compared to cabazitaxel.

The summary of the therapy trial is that in men with progressive disease following docetaxel LuPSMA was more active than cabazitaxel with a higher PSA response rate, with relatively fewer grade 3-4 adverse events and a progression free survival favouring LuPSMA. Putting this all together, really LuPSMA now represents a new class of effective therapy for men with metastatic castration resistant prostate cancer.

We are awaiting longer follow-up of the men in this trial to more accurately define other events such as radiologic progression free survival and also overall survival. We have also looked at quality of life in both arms and that analysis is ongoing. So we hope to be able to report all of those endpoints by the end of this year. There’s a parallel trial that we’re not involved with but an industry trial called the VISION trial which is a phase III trial looking at LuPSMA. We also really await the results of that trial and we hope that these two trials together may lead to FDA registration of this agent and hopefully widespread global availability for men with prostate cancer in the future.

The results of this trial are very promising for LuPSMA and another aspect we would like to explore is using this treatment as an earlier phase of therapy rather than a last line therapy as we did in this study. So we have several studies ongoing in Australia looking at this. We have a study comparing LuPSMA to the combination of LuPSMA and enzalutamide, a study called the ENZA-p study. In our centre we’re also running a study called the UpFrontPSMA study where we’re giving LuPSMA to men with hormone sensitive rather than hormone castration resistant disease in an up-front setting and seeing how it performs in comparison to the current standard of care of docetaxel.

So, many more studies in this space and we really eagerly await the results.