The following questions and responses have been lightly edited for grammatical purposes. 

1) What’s the significance of a CDK12 mutation, and what are some of the treatment options?

Dr. Phull: CDK12 involves this idea of homologous recombination repair. There’s a DNA repair pathway in the body where cells that are deficient in homologous recombination repair are very sensitive to PARP inhibitors [a type of targeted therapy that is often used to treat metastatic prostate cancer] and also to platinum-based chemotherapy. These include cells with BRCA mutations, for example.

CDK12 is also implicated in that pathway. It’s a tumor suppressor gene, and patients who have CDK12 alterations usually have higher neoantigen loads on their prostate cancer cells. These cancer cells are often infiltrated by lymphocytes, which suggests the immune system is trying to attack them. So this is a very important and relatively new marker.

What’s interesting is that patients with CDK12-altered prostate cancer often do worse than those without the mutation. Unlike BRCA1 or BRCA2 mutations, these patients may not respond as well to PARP inhibitors.

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That’s where immunotherapy is being explored. There’s emerging data suggesting we might be able to use the immune system to fight these cancer cells, just like it does every day in our bodies. Checkpoint inhibitors, or what we call immunotherapy, are already used in many different cancers to help re-engage the immune system. Cancer cells are very good at masking themselves to escape immune surveillance, but our immune system is also very good at identifying invaders, whether they’re cancerous or infectious.

The idea is, in CDK12-altered prostate cancer, could we use checkpoint inhibitors like PD-1-targeted treatments? The data is still preliminary, and we definitely need more research, but it’s an exciting time. These newer markers have both prognostic and diagnostic implications, which could open the door to more personalized care.

2) What are the potential benefits and risks of PARP inhibitors?

Dr. Phull: I tell patients, if you have homologous recombination repair gene mutations, especially BRCA1, BRCA2, CHEK2, or ATM, PARP inhibitors can be very effective.

Nowadays, for male patients who haven’t received prior androgen receptor blockade, PARP inhibitors are sometimes used as an initial first-line treatment for metastatic castration-resistant prostate cancer. For example, we might use abiraterone along with olaparib, which is a PARP inhibitor. There’s also data for using enzalutamide (Xtandi) with talazoparib. All these drugs with the “-parib” suffix, those are PARP inhibitors.

They’re definitely becoming more involved in frontline treatment, but they can also be used in relapsed or refractory cases.

Before I go deeper into the risks and benefits, I’ll say something that might surprise you. I mentioned earlier that every patient deserves genetic testing up front. We should know the gene profile of their cancer, ideally what they were born with, within the first month or two of diagnosis.

Maybe that happens in my practice or in academic centers, but across the country, it’s still relatively rare. Even in lung cancer, where genetic information is essential for guiding treatment, up to 50% or more of patients don’t get genomic sequencing. That’s something we need to fix. If the technology is available and we have the awareness, why isn’t it happening more often?

Now, back to your question: what are the risks and benefits?

A lot of patients say, “I’d prefer a pill.” When people hear “chemotherapy,” they think about hair loss, nausea, vomiting, and being in bed. The idea of taking a pill sounds a lot easier, no needles, and no sitting in a chair for hours. That part is true. PARP inhibitors are pills, and by the time many prostate cancer patients get to this treatment, they’re already on oral medications. It’s a wonderful thing to be able to offer that as an option, sometimes even before chemotherapy.

That said, there are risks. Like with any medication, the side effects listed on the package insert include everything that could possibly go wrong, but that doesn’t mean those things are common. If you read the side effects for Tylenol or ibuprofen, you’d think you’d never take those drugs. So we always have to put the risks in context.

For PARP inhibitors, the most common side effects are rashes, leg swelling, occasionally diarrhea or constipation, some nausea (although that’s rare), drop in blood count (white cells, red cells, and platelets), and liver inflammation, which is why we check liver function regularly.

We usually monitor your blood counts and metabolic panel monthly. Some patients think, “Well, I’m on a pill—do I still need labs?” Yes, absolutely. These are powerful drugs, and monitoring helps us catch any changes early.

One of the biggest themes in cancer care now is early recognition of side effects. Not because we failed, but because catching them early allows us to act. That might mean adjusting the dose, adding supportive meds, or stopping the drug and trying something else.

When we don’t talk about these “real-world” side effects or if patients feel afraid to report them, we’re missing opportunities to make the treatment journey better. Many people, even with metastatic disease, can live for years on effective targeted therapies. And during that time, we can often find the right dose and combination that works for them and keeps the side effects manageable.

So again, it’s about reclaiming your life. You’re not tethered to a chemotherapy pole. You’re taking a pill that may allow you to travel, work, and live your life much as you would if you weren’t in treatment. It’s a really powerful vision for what cancer care can look like today.

Watch the full webinar discussion here.