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A New Approach to Identifying Patients Who May Benefit from PSMA-Targeted Therapy
On the horizon: A liquid biopsy of circulating tumor cells to help predict which men will benefit from PSMA-targeting treatment

I have metastatic castrate-resistant prostate cancer (mCRPC).  Could I benefit from PSMA-targeted radioligand therapy?

This is a good question.  Not all men with mCRPC are helped by PSMA-targeting therapy, and the reason for this is that not all mCRPC prostate cancers are alike.  They are heterogeneous; that is, they are made up of many different types of cells, and this variety makes them harder to kill.  For example, androgen deprivation therapy (ADT) and androgen receptor (AR)-targeting drugs (such as abiraterone and enzalutamide) can kill prostate cancer cells that are controlled by male hormones. But the drugs are powerless against other prostate cancer cells that don’t need male hormones to grow.  And treatment that targets PSMA (prostate-specific membrane antigen, a protein that sits on the surface of prostate cancer cells) is not effective against cancer cells that don’t make much – or any – PSMA.

So:  who is most likely to benefit?  A “liquid biopsy,” currently under investigation, may soon be able to help.  But wait – what’s a liquid biopsy?  It does much of what a traditional biopsy does.  In a traditional biopsy, a pathologist studies cells and tissue taken from the primary tumor or metastatic site.  In a liquid biopsy, the same thing happens – except what is studied are individual cancer cells that have left the original tumor and migrated into the bloodstream, hitching a ride to future sites of metastasis.  These are called circulating tumor cells (CTCs).

Now, a new PCF-funded study has shown that it is possible to detect PSMA on CTCs in men with mCRPC – and to predict who may be helped, and who may not likely be helped, by PSMA-targeting radioligand therapy.  “We were motivated to do this study because so many men want to know about PSMA lutetium,” says Duke University medical oncologist Andrew Armstrong, M.D., MSc.  He is lead investigator of the study, published March 2023 in Clinical Cancer Research.

Identifying Patients for “Smart-Bomb” Therapy

Lutetium-177-PSMA-617 (PluvictoTM), approved by the FDA in 2022, delivers beta-particle radiation to PSMA-expressing cells.   “It is the only FDA-approved therapy that came out in 2022 that was life-prolonging,” continues Armstrong, who describes it to his patients as a “smart bomb.”  Today, “we are using that smart-bomb therapy, and we require PSMA PET scans to determine eligibility for this medicine.”  Only men who have PSMA-positive PET scans are considered good candidates for PSMA-Lutetium-177; even so, “not all patients respond equally.  About half the patients respond really well, and half have more limited responses.  Of those who respond well, about 20 percent “have extremely long responses.”

Armstrong and colleagues developed the CTC test used in the study “to ideally and eventually complement, rather than replace, the PSMA PET imaging,” he says, “to tell us more about what’s going on inside the patient with the cells that are disseminating and forming new metastases.  There’s a lot of heterogeneity of PSMA expression in advanced prostate cancer.  Under the microscope, we can see PSMA-positive and -negative cells coexisting – the cells that lack PSMA and those that have it, side by side.”

PSMA-positive circulating tumor cells in a liquid biopsy sample.

In the study, investigators analyzed men with mCRPC who participated in the PCF-funded PROPHECY trial, and were treated either with abiraterone or enzalutamide – both AR-targeting drugs.  Of the 78 men in the study who had detectable CTCs, 55 percent had PSMA in varying amounts.  Of these, 21 percent had at least 2 or more PSMA-positive CTCs per milliliter (mL) of blood, and 19 percent had 100 percent PSMA-positive CTC cells (homogeneous expression), while the remainder of men had various degrees of PSMA heterogeneity or loss of PSMA expression.

Now here’s a point of great interest:  “Having two or more PSMA-positive CTCs per mL was associated with shorter overall and progression-free survival [worse outcomes] with abiraterone and enzalutamide,” says Armstrong.  But there’s a big however:  “These men who would ordinarily do worse are the ones that may be able to experience improved outcomes with PSMA-targeting lutetium-177!  As we’ve shown previously using PSMA PET imaging, the more PSMA you have in your cancer, the greater the tumor is targeted by the radioligand therapy, and the better you do in terms of response and survival.  Instead of this being a poor prognosis, this is predictive of benefit.”

Armstrong is planning a new phase 3 study at Duke and other centers, to test the ability of PSMA-positive CTCs in men with mCRPC who have progressed on hormonal therapies to predict the benefits of simultaneous treatment with ADT and PSMA-Lutetium-177 (PluvictoTM).  He believes timing – before the cancer becomes more heterogeneous – may make a difference, and “giving these drugs earlier in the course of disease might make more sense and work better.”

Red and Blue Lines Tell a Story

There is a picture that goes with this story.  Let’s look at it for a moment.  Each line represents one patient in Armstrong’s study. The blue lines represent patients who have PSMA-positive CTCs.  Some of the blue lines are long; those men have more PSMA-positive CTCs per mL of blood – some more than 5.  Some of the blue lines are short. These men don’t have as many PSMA-positive CTCs.

Ordinarily, as we discussed, men with a lot of PSMA-positive CTCs are less likely to do well over the long term.  But what might seem like a minus is actually a plus:  these men with the longest blue lines – or any blue line showing 2 CTCs or more per mL – may actually be the ones most likely to do better with PSMA-targeted radioligand therapy!  This is where research can be transformative.  “Here is a form of precision medicine that is changing the survival rates for a group of men who, until now, did not have nearly so much hope,” says Armstrong.

But what about the men with very little or even zero blue – men whose prostate cancer makes hardly any PSMA, or none at all?  If you are one of these men, don’t lose heart!  Armstrong and others are actively closing in on markers for other prostate cancer cells, including neuroendocrine cancer cells.  When they find them, and they will, then two things will happen:  First, they will be able to see them with a different type of PET scan, using a radioactive tracer.  Then, they will be able to switch out the radioactive imaging tracer and attach a more powerful, cancer-killing radioactive molecule. “We are learning quite a lot about these PSMA-negative CTCs and developing new radioligand therapies or smart bombs for these previously undruggable tumors to help men with advanced prostate cancer, such as those with neuroendocrine-type tumors,” says Armstrong.  They know how to do this now: PSMA-targeting therapy has pointed the way.  So if you are not in the PSMA-positive group, know that help is coming for your specific cancer, too.

Janet Worthington
Janet Farrar Worthington is an award-winning science writer and has written and edited numerous health publications and contributed to several other medical books. In addition to writing on medicine, Janet also writes about her family, her former life on a farm in Virginia, her desire to own more chickens, and whichever dog is eyeing the dinner dish.