Prostate Cancer: The VISION Trial - Episode 8

Future Treatment Landscape of mCRPC

An expert in prostate cancer comments on emerging agents and combinations in the pipeline for the treatment of mCRPC.

Scott T. Tagawa, MD, FACP: Fortunately, we’ve already had a number of different agents approved over the last 10 years and going back further, and those are in prime time, already in use. Those same drugs have been or are being studied in earlier lines of therapy where we’ve seen—particularly moving from castration-resistant prostate cancer to noncastrate, or hormone-sensitive castration-sensitive disease—where their hazard ratio for overall survival is even bigger. We’re moving earlier.

Then we have combinations. We had rationale for instance to combine a PARP inhibitor and AR [androgen receptor] pathway inhibitor. We had a randomized phase 2 trial that was positive, and we just had a press release showing that combination is positive, importantly, for PARP inhibitors in an unselected patient population in terms of genomics. We don’t know the data, so I’m not ready to use that today, but that’s an example of something that has some scientific rationale, and then is being tested with initial safety studies followed by randomized phase 2, followed by randomized phase 3. That may become a standard of care. That’s one set of trials that we have excitement over in terms of maximizing our use of the current drugs.

There are a number of other drugs out there. We know that the AR pathway is the dominant pathway throughout the lifecycle of most patients and tumors, and we know that there are resistance pathways. Subverting resistance with bypass pathways, such as AKT, we know that actually works, thanks to a positive trial. However, that trial with an AKT inhibitor has some issues with tolerability, but in principle, we’re finding ways to get around some bypass pathways or to prevent lineage plasticity. For instance, with an EZH2 inhibitor, or some other epigenetic modifier to prevent lineage plasticity and transformation to neuroendrocrine small cell prostate cancer. There are other—I don’t necessarily want to say better or more potent, just because that may be true in cells—different types of AR pathway inhibitors, such as those targeting internal domain or AR degraders. Those have made their way from preclinical studies into the clinical realm.

We all want to get immunotherapy to work better. We have, at least in the United States, sipuleucel-T, which at least in older studies led to a significant overall survival advantage. There’s a subset for on-label use of immune checkpoint inhibitors. That subset is small, about 1 in 20 to 25. Importantly, it’s 0 out of 25 if you never check, so it’s important to check. But how can we come up with different immunotherapeutics or make the existing ones work better? I mentioned radiation, for instance, more specifically PSMA [prostate-specific membrane antigen]-targeted radiation in combination. But there are a number of phase 3 trials that we expect to read out in the next few years that may lead to combinations that improve or expand the population who may benefit from an immune checkpoint inhibitor, at least as defined by anti–PD-1 or PD-L1.

PSMA is probably the leading, but not the only, cell surface target for immunotherapy right now, including for CAR [chimeric antigen receptor] T cells, which are very important and may lead to some major improvements, but it’s slow. We’re proceeding cautiously in terms of safety with those.

What’s happening more quickly are the bispecific antibodies—most common would be a cell surface target such as PSMA with CD3, but there are other things that might be on the other end of the molecule. We know that paradigm works against CD19, for instance. In preliminary presentations, it can be safe, at least in the right hands, and there can be responses. These are moving fairly rapidly from phase 1 to phase 3, at least with one agent. That’s interesting. Staying on the theme of cell surface targeting, there are antibody-drug conjugates. So using some of the same types of cell surface targets such as, and I don’t mean to sound like a broken record, PSMA. There are other important cell surface targets such as CYP1. DLL3 is a very interesting cell surface target. They’re maybe in general adenocarcinoma castration-resistant disease at a low level, but more commonly to a higher level in small cell neuroendrocrine. There may be other targets such as B7H3 and others that are with drugs in development.

Transcript Edited for Clarity