PARP inhibitors, PSMA-led therapy increase prostate cancer arsenal

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“It’s very nice to have this kind of review and update to remind us that patients are not tied to a single treatment, that throughout their oncology continuum and their oncology life, they can really get a variety of drugs that will help improve their quality of life. , have an anti-tumor effect and improve their survival, ”said Slovin, medical oncologist at Memorial Sloan Kettering Cancer Center, in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on prostate cancer.

The virtual meeting covered the treatment of castration-resistant non-metastatic prostate cancer (CRPC), castration-naive and hormone-sensitive metastatic prostate cancer, and the role of PARP inhibitors and therapy and l PSMA-led imaging in metastatic CRPC (mCRPC).

In the interview, Slovin, who chaired the event, discussed the use of antiandrogenic agents, PARP inhibitors and treatment directed against PSMA across the cancer care continuum of the prostate.

OncLive®: From Daniel C. Danila, MD’s presentation on the treatment of non-metastatic CRPC, what is important to remember about the use of the 3 approved antiandrogenic agents?

Slovenian: As part of the treatment of patients with non-metastatic CRPC, we have a wide variety of treatments. The most important thing is to look at the toxicity and the patient profile in terms of patient sensitivity. Are there any drugs that cross react? However, some or all of these drugs are very reasonable options. There are appropriate guidelines in terms of who might benefit perhaps more than another patient [from an agent], but the most important thing is for the doctor to know that all of these agents have beneficial effects on survival and therefore it would be very reasonable to go ahead with any of these treatment options. A careful description of the drug, its possible interactions with drugs the patient may already be taking, as well as the recognition that there could be all kinds of allergic reactions, should be taken into consideration. We are very lucky to have as many drugs as we do, and there really is no right answer. It really depends on the expertise of the doctor and their referral to the medication that will meet the needs of the patient.

Turning to Deaglan McHugh, MD’s presentation on the treatment of castration-naive and hormone-sensitive metastatic prostate cancer, what were his main lessons for the community setting?

We have a plethora of drugs that we are fortunate enough to have in our treatment algorithm. In the context of a person with metastatic prostate cancer sensitive to castration, the standard of care remains the consideration of androgen deprivation therapy in combination with docetaxel, enzalutamide [Xtandi], apalutamide [Erleada], or abiraterone acetate [Zytiga]. Of course, there is a possibility of darolutamide [Nubeqa] being added to that.

Again, this is a discussion regarding toxicities, interactions with other drugs, and the potential benefits that will come from them. Someone who is more symptomatic may benefit from a combination with chemotherapy, but the point is that all of these agents have been approved by the FDA for a survival benefit and therefore are appropriate drugs. I wish I could tell anyone, “Use one drug over another.”

However, it really depends on the patient, what medications they are taking and how you think the patient will benefit from them. If a person is older and very prone to falls, you may think twice before giving enzalutamide because of its potential to cross the blood-brain barrier. We have a plethora of drugs, and one is not necessarily exclusive to the other.

The other aspect concerns patients who show no signs of disease, castration resistant patients without metastatic disease, or MO. Here again we have FDA approved drugs including enzalutamide, apalutamide, and darolutamide. All of these agents are very similar, but different in terms of chemical profiles.

The only thing we always want to be concerned about in an older patient is whether we should be a little more careful in terms of prescribing a drug based on AEs. All of these agents have very impressive survival benefits, as well as radiographic progression-free survival benefits. So it’s a physician’s paradise in terms of administering these drugs, and much of the concern is whether darolutamide might even be increased sooner than expected.

Wassim Abida, MD, PhD, lectured on the use of PARP inhibitors in mCRPC. How should this class of agents be used in clinical practice?

There are a lot of data on PARP inhibitors. In some ways, this is very misleading because every patient who presents [is asking about them]. While it is appropriate to do genomic testing for every patient, whether it is a family history, metastatic disease, or a known history of [a] BRCA [mutation]- of which everything [which render patients] potential candidates [for treatment with a PARP inhibitor]- not all patients will respond.

The point to remember is the width of the olaparib [Lynparza] in terms of use in a wider variety of mutations and the fact that you must have had at least 1 of the androgen receptors [AR]- signaling inhibitors first vs rucaparib [Rubraca], which is much narrower in its spectrum of BRCA1/2 and less encompassing some of the other “actionable” mutations and also the fact that it is recommended after an inhibitor of AR signaling and docetaxel. There is a bit of finesse here, in terms of the agents that people will be using.

The problem with olaparib is that people can be a little too ‘trigger happy’, because of its breadth and [people will] use it empirically, as opposed to a real reading of its limits. Some of the mutations that have been cited, in particular AT M really had minimal or no activity in terms of sensitivity to the drug, which is important because this is an oral drug, and we at least now have a way to look at a potential biomarker to monitor people susceptible to these medications. It is therefore very important.

The final presentation, given by Michael J. Morris, MD, focused on the use of PSMA-led imaging and treatment. How will this modality affect current practice?

mCRPC remains a challenge, and every few years we come up with another drug that appears to be a winner. the [VISION trial (NCT03511664)]produces a winner [in 177Lu-PSMA-617]. [The investigators of VISION studied] a beta emitter, a radiopharmaceutical, coupled to a small molecule of PSMA. This small, intact molecule searches for PSMA on the cancer cell, at which point the binding leads to the internalization of the complex, at which time the radionuclide is then released inside and [acts as] kind of bone looking for a radiopharmaceutical. It is extremely interesting. the [agent shows a] benefit similar to all of our other oncology drugs, including chemotherapy. The only caveat is that it is probably going to be [used] in patients who first received inhibitors of AR signaling, followed by docetaxel, before they could be [eligible for treatment]. What needs to be determined at this point is whether an accompanying PSMA scan, a PET scan, will be a necessary, if not sufficient, indicator of targeting that will be part of eligibility for this treatment.

This is something the FDA will have to reckon with. But it’s very exciting, and [lutetium-177 is] one of many different radiopharmaceuticals [out there], among which actinium and radium. The whole periodic table lights up for us. It really is a transition to a completely different and effective treatment modality.

What is your overall take-home message from the IPC webinar?

For several years, we have had a very diverse portfolio on how to treat patients with prostate cancer. It’s not just chemotherapy or hormone therapy anymore. We have all of these other treatments, including CAR T cells, bispecific antibodies, and newer biologics that can affect the tumor microenvironment that we didn’t have before. These meetings are very refreshing in the sense that every time we forget that a treatment is not working, there is still a lot of treatment left in the compendium, and a lot more hope for the patients, which is the most important thing. to remember.


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