PARP Inhibitors, PSMA-Directed Therapy Augment the Prostate Cancer Armamentarium

Partner | Cancer Centers | <b>Memorial Sloan Kettering Cancer Center </b>

Antiandrogen agents, PARP inhibitors, and prostate-specific membrane antigen-directed therapy have broadened the armamentarium in prostate cancer.

Antiandrogen agents, PARP inhibitors, and expectantly, prostate-specific membrane antigen (PSMA)-directed therapy, each of which have shown robust improvements in overall survival, have broadened the armamentarium in prostate cancer, explained Susan F. Slovin, MD, PhD. However, when it comes to patient selection, the primary considerations will be the agents’ adverse effect (AE) profile, the tumors’ mutational profile, and the necessity of using next-generation imaging to determine treatment eligibility, respectively.

“It’s very nice to have this kind of review and update to remind us that patients are not wedded to one treatment, that throughout their oncologic continuum and their oncologic lifetime, they really can get a diversity of drugs that will help improve their quality of life, have an antitumor effect, and improve their survival,” said Slovin, a 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 nonmetastatic castration-resistant prostate cancer (CRPC), metastatic castration-naïve and hormone-sensitive prostate cancer, and the role of PARP inhibitors and PSMA-directed therapy and imaging in metastatic CRPC (mCRPC).

In the interview, Slovin, who chaired the event, discussed the use of antiandrogen agents, PARP inhibitors, and PSMA-directed therapy across the prostate cancer care continuum.

OncLive®: Starting with the presentation that Daniel C. Danila, MD, gave on the treatment of nonmetastatic CRPC, what is important to take away regarding the use of the 3 approved antiandrogen agents?

Slovin: In the setting of treating patients with nonmetastatic CRPC, we have a large variety of treatments. The most important thing is looking at the toxicity and the patient profile in terms of the sensitivity of the patient. Are there drugs that cross react? However, any 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 be aware that all of these agents have survival benefits, and therefore it would be very reasonable to go forward with any of these treatment options. A careful description of the drug, its possible interactions with the medications that the patient may already be on, along with the recognition that there might be any sort of allergic reactions, should be taken into consideration. We’re very fortunate to have as many drugs as we do, and there is really no right answer. It really depends on the expertise of the physician and their guidance toward the drug that will fit the patient’s needs.

Moving on to the presentation Deaglan McHugh, MD, gave on the treatment of metastatic castration-naïve and hormone-sensitive prostate cancer, what were his main takeaways for the community setting?

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

Once again, it’s a discussion regarding toxicities, interactions with other drugs, and the potential benefit that will be derived. Someone who is more symptomatic may benefit from a combination with chemotherapy, but the point is that all these agents have been FDA approved in the setting of a survival benefit and therefore are appropriate drugs. I wish I could tell anybody, ‘Use one drug over another.’

However, it really depends on the patient, the drugs the patient is on, and how you think the patient will benefit. If somebody is older and very subject to falls, one might think twice before giving enzalutamide because of its potential for crossing the blood-brain barrier. We have a plethora of drugs, and one is not necessarily exclusionary over the other.

The other aspect is the patients who have no evidence of disease, the patients who are castration-resistant without metastatic disease, or M0. Here again we have drugs that have been FDA approved, including enzalutamide, apalutamide, and darolutamide. All of these agents are very similar, yet different in terms of their chemical profiles.

The one thing that we always want to be concerned about in an older patient is whether we should be a little bit more careful in terms of prescribing a drug based on the AEs. All these agents have very impressive survival benefits, as well as radiographic progression-free survival benefits. So, it’s a doctor’s paradise in terms of giving these drugs, and a lot of the concern is whether darolutamide could even be moved up earlier than previously expected.

Wassim Abida, MD, PhD, gave a lecture on the use of PARP inhibitors in mCRPC. How should this class of agents be utilized in clinical practice?

There are a lot of data out there about PARP inhibitors. In some ways, it’s very misleading because every patient coming in [is asking about them]. Although it is appropriate to do genomic testing for every patient, whether there’s a family history, metastatic disease, or known history of [a] BRCA [mutation]—all of which [which render patients] potential candidates [for treatment with a PARP inhibitor]—not every patient will respond.

The takeaway point is the broadness of olaparib [Lynparza] in terms of being used in a wider variety of mutations and the fact that you have to at least have had 1 of the androgen receptor [AR]–signaling inhibitors first vs rucaparib [Rubraca], which is much more narrow in its spectrum of BRCA1/2 and less encompassing of some of the other “actionable” mutations and also the fact that it is recommended after an AR signaling inhibitor and docetaxel. There is a little bit of finessing here, in terms of which agents people will use.

The issue for olaparib is people may be a little bit too “trigger happy,” because of its broadness and [people will] use it empirically, as opposed to really reading about its limitations. Some of the mutations that have been cited, particularly ATM really had minimal or no activity in terms of being susceptible to the drug, which is important because it’s an oral medication, and we at least now have a way of looking at a potential biomarker for monitoring people who are susceptible to these drugs. Therefore, that is very important.

The final presentation, given by Michael J. Morris, MD, centered around the use of PSMA-directed imaging and treatment. How will that modality affect current practice?

mCRPC remains a challenge, and every few years we come up with another drug that seems to be a winner. The [VISION trial (NCT03511664)]produced a winner [in 177Lu-PSMA-617]. [The investigators of VISION studied] a beta emitter, a radiopharmaceutical, coupled to a small molecule of PSMA. This little intact molecule seeks out PSMA on the cancer cell, at which point the binding leads to internalization of the complex, at which point the radionuclide is then released internally and [acts as] sort of a bone seeking radiopharmaceutical. It’s extremely interesting. The [agent shows a] similar benefit to all our other drugs in oncology, including chemotherapy. The one caveat is that it’s likely going to be [used] in patients who have had AR signaling inhibitors first, along with docetaxel, thereafter, before they will be able to be [eligible for treatment]. What needs to be determined at this time is whether a companion PSMA scan, a PET scan, will be a necessary, if not a sufficient indicator of targeting that will be part of eligibility for getting 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 include actinium and radium. The whole periodic table is lighting up for us. It really is a segue into a completely different and effective treatment modality.

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

We, for the past several years, have had a very diverse portfolio in how to treat patients with prostate cancer. It’s no longer just chemotherapy or hormone therapy. We have all these other treatments, including CAR T cells, bispecific antibodies, and novel biologic agents that may affect the tumor microenvironment that we didn’t have before. These meetings are very refreshing in the sense that whenever we forget that one treatment doesn’t work, there’s still within the compendium, a lot of treatment left and a lot more hope for patients, which is the most important thing to remember.