AR Degraders, Other Novel Agents Could Expand Armamentarium in mCRPC

Sandy Srinivas, MD

Despite the crowded list of treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), cross-resistance between androgen receptor–pathway inhibitors (ARPIs) and the movement of these agents to earlier lines of therapy have restricted treatment opportunities for this patient population, according to Sandy Srinivas, MD, who added that ongoing research aims to improve outcomes with novel agents, such as AR degraders.

“Although we feel that there is an enormous number of options, for many patients with mCRPC, the number of options we have today are really limited, and that represents a huge unmet need,” Srinivas explained during an interview with OncLive® during Prostate Cancer Awareness Month in September.

In the interview, Srinivas discussed the therapeutic landscape for patients with mCRPC and the challenges associated with current treatment options. She also expanded the role of radioligand therapy in prostate cancer, highlighted novel classes of agents under evaluation, and underscored the importance of clinical trials for advancing care for this patient population.

Srinivas is a medical oncologist, urologic and genitourinary specialist, and a professor of medicine (oncology; urology) at Stanford Medicine, as well as the unit-based medical director of Stanford Hospital, in Palo Alto, California. She also serves as a member of the Prostate Panel at the National Comprehensive Cancer Network (NCCN).

OncLive: In mCRPC, what are some of the current challenges in this therapeutic landscape?

Srinivas: There is an unmet need in mCRPC where we need better drugs to help prolong a patient’s life. If you look at something like the NCCN [Guidelines], it looks like we have an enormous number of options [to treat mCRPC]. However, over the years, many of these drugs have moved into earlier lines of therapy. Therefore, all our AR-targeting drugs, which have been a mainstay for us in mCRPC, have been moved to the frontline and even the localized or hormone-sensitive disease [settings].

We know that there is high cross resistance [with ARPIs], making it a challenge if a patient has had one prior novel hormone therapy when their disease becomes castration resistant. This [makes novel hormone therapy] options limited and nearly non-existent [in the mCRPC setting].

What are the drugs that we do have [for mCRPC]? Essentially, you have chemotherapy agents, such as docetaxel and cabazitaxel, and we have our radioligand targeting drugs, such as lutetium Lu 177 vipivotide tetraxetan [Pluvicto; formerly 177Lu-PSMA-617].

If a patient were to have a homologous recombination repair mutation such as BRCA, they would be able to access PARP inhibitors. However, that is a small fraction [of patients with mCRPC]. Lastly, if somebody has bone-limited disease, radium-223 [Xofigo] is an option.

What are some patient and disease factors to consider when selecting a treatment regimen for a patient with mCRPC?

There are many factors we take into consideration. [mCRPC] is a disease of [older patients], so frailty, performance status, what home support they have, and how far they live from an institution will help determine if we want to use an intravenous or oral drug. If we want to use chemotherapy, what is the hematologic toxicity profile [of the agent?] What is a patient's underlying bone marrow reserve? All of these are taken into consideration.

When was their last ARPI? Was it given in the hormone-sensitive space or for localized disease? Did the patient [stop treatment with an ARPI] for disease progression or toxicity? Did they complete a full course, where their testosterone levels allow them to see another drug? There are many things to take into consideration, especially as you think about chemotherapy or radioligand therapy.

Although radioligand therapy is exciting for older patients, it does pose some challenges because patients need to be a certain distance from their caregiver, for instance. This is unique for radioligand therapy. All these factors are in our mind when we are thinking about the best treatment for a patient sitting in front of us.

Are there situations where you may consider rechallenge with an ARPI? Are there any data to support that approach?

Almost everybody in the community will rechallenge [with an ARPI] because that's what is available. It's an oral drug, and it's easy. We give it for a month or two to see if the patient responds. Many of us in the field have said that's not the right thing to do because of the significant cross resistance [between different ARPIs]. If you see the real data, for example, if a patient received one of the ARPIs and then get a second one, their likelihood of response is approximately in the 10% to 15% range. Even If they have a response, it's short lived.

Having said that, just because of the lack of other available options, this is the most common [treatment selected]. Many of our clinical trials that we done in the [mCRPC] space look at alternate novel hormonal therapy as a comparator arm, and we have a lot of contemporary data from such trials reinforcing that [the rate of] patients responding in the second-line is very low, and even if they respond, the duration of response is extremely low.

What should community oncologists know about picking lutetium Lu 177 vipivotide tetraxetan as a potential treatment option for patients?

The FDA approval of lutetium Lu 177 vipivotide tetraxetan has been a great advance in the field of mCRPC. It's a drug that's well tolerated compared with chemotherapy, and it's convenient because you can give just one treatment every 6 weeks. It can be given to patients who have diagnostic imaging that shows they are a candidate for this treatment. Patients may have some mild fatigue, mouth dryness, and there may be some impact on bone marrow. However, compared with chemotherapy, it's a better-tolerated treatment.

For many of our patients with prostate cancer who are in their 80s and early 90s, this treatment is something that can be given with very little toxicity. For now, there are centers that are administering this therapy; it is an easy patient referral if imaging comes back [prostate-specific membrane antigen (PSMA)] positive. Fortunately, based on the [phase 3] VISION study [NCT03511664], we know that the screening fail rate is very low. Less than 15% of patients who get the imaging screening [are PSMA negative], so the majority can get the drug.

We are getting better at evaluating who's benefiting from the drug, who should get all 6 cycles [of treatment], who should stop short of 6 cycles, and [how to] recognize early progression. It is important not to put patients through the full 6 cycles if they are not deriving benefit from it.

What ongoing research could help bring novel agents into the mCRPC treatment space?

This is such an area of active interest, and even at the 2024 ESMO Congress, there was exciting data coming out. I think about [ongoing research] in 3 categories.

One, we know that the AR is active; therefore, how can we continue to explore the AR pathway? These drugs are oral and convenient. Knowing the biology, these drugs will remain active for patients with prostate cancer. I'm excited about some of the data that we have seen about AR degraders. These are also oral drugs, and we are seeing patients have a drop in prostate-specific antigen and some meaningful, durable responses with relatively low toxicity. Therefore, I'm interested in seeing how the AR degraders move forward.

Continuing along the AR pathway, there are drugs similar to abiraterone acetate [Zytiga], but they are targeting UPS11, so it's one step higher in the pathway. These drugs are also coming forward. These are oral drugs and seem to have a high level of activity in patients who have had a prior exposure to an ARPI. We are excited to see how that area of research continues.

Second, with the approval of a radioligand therapy, there's been an explosion of drugs that are in development, even within the approved space. Lutetium Lu 177 vipivotide tetraxetan is being studied in the pre-chemotherapy space. At the 2024 ESMO Congress and earlier, we saw data from similar compounds such as 177 Lu-PNT2002 in the phase 3 SPLASH study [NCT04647526], showing that patients do benefit [from radioligand therapy] in the pre-chemotherapy space. That's exciting for our patients who are not candidates for chemotherapy, potentially giving them another option.

Within the radioligand therapy space, there are different agents. Lutetium Lu 177 vipivotide tetraxetan is a beta-emitting agent; there are drugs that are alpha emitters that are being looked at; and there are different sources other than lutetium, such as lead and copper. The whole area is exciting. There are combinations that are being investigated, where these radioligand therapies are being combined with immunotherapy, PARP inhibitors, radium, and ARPIs. There is an explosion of agents and trials in this space.

Having PSMA as a target has been exciting; in addition to radioligand targeting, we now have bispecific antibodies and antibody-drug conjugates [ADCs] directed against PSMA. Within this field, we have seen multiple smaller studies showing some effect, and the same strategies are now being applied to other targets. Similar to PSMA, there is STEEP1 and B7-H3. Each of these targets, in turn, have ADCs and immunotherapy. It is an exciting time for us to be able to have all these clinical trials to allow our patients to participate in them.

How have diagnostics helped reshape the prostate cancer treatment paradigm?

The other area that is exciting is our diagnostics. PSMA imaging has changed the way we stage patients, and with that, we have identified new clinical states, such as oligometastatic sites. How we can delay time to androgen deprivation therapy for many of our patients in order to delay the adverse effects of treatment. I'm excited to see where we go in that space.

Diagnostically, the whole genomic discovery has allowed us to look at personalized medicine to see if we can either escalate care for certain patients or deescalate care for some patients who may be at in different risk category compared with what we have with our clinical factors [alone] up until now. Overall, I am excited to see where that field heads, as well.

With September being Prostate Cancer Awareness Month, what would be your main message for colleagues about the current state of the prostate cancer care?

Genomic testing is important. We still find that there are a lot of patients who don't get genomically tested, whether it be germline or somatic testing. This is important because we do have drugs that they may benefit from. Additionally, clinical trials remain prevalent across care, and we have known that many of these trials have resulted in a prolongation of lives for our patients; that work needs to continue. Thinking about a clinical trial as a first option for our patient is a top priority to move the field forward.