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Prostate Cancer Personalized Therapy

CE / CME

Expert Think Tank on Applying the Latest Data to Individualize Treatment in Prostate Cancer

Pharmacists: 1.00 contact hour (0.1 CEUs)

Nurses: 1.00 Nursing contact hour

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: August 16, 2023

Expiration: August 15, 2024

Tanya B. Dorff
Tanya B. Dorff, MD
Rana R. McKay
Rana R. McKay, MD
Alicia Morgans
Alicia Morgans, MD, MPH
Michael Schweizer
Michael Schweizer, MD
David VanderWeele
David VanderWeele, MD, PhD
CME/CE Information

Activity

Progress
1
Course Completed

CDK4/6 Inhibitors

Alicia K. Morgans, MD:
Can you each take a moment and talk about what ongoing clinical trials you are most excited about?

Rana R. McKay, MD:
It is exciting to see all the different agents that are currently being developed for advanced prostate cancer. It is a broad spectrum from antibody-drug conjugates (ADCs), bispecific antibodies, and CAR T–cell therapies, among others. First, I would like to focus on the CDK4/6 inhibitors that are being tested in prostate cancer. Three CDK4/6 inhibitors are currently approved for other diseases—ribociclib, palbociclib, and abemaciclib—and they are being examined in prostate cancer. There is a lot of crosstalk between the AR pathway and the CDK4/6 pathways. 

A phase I/IIb trial of ribociclib plus docetaxel and prednisone found an improved 6-month rPFS rate vs historical control in patients with mCRPC who had progressed on ≥1 ARSI.45 In a randomized phase II study, palbociclib plus ADT failed to improve PSA response rate compared with ADT alone in patients with RB-intact mHSPC.46

Abemaciclib is being heavily investigated across the prostate cancer spectrum, from mCRPC to mHSPC. The phase II/III CYCLONE 2 study (NCT03706365) is looking at the combination of abiraterone and prednisone plus abemaciclib for frontline mCRPC patients. The phase III CYCLONE 3 study (NCT05288166) is testing the addition of abemaciclib to abiraterone and prednisone for patients with high-risk mHSPC. So these are studies to watch for in the future.
 

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AR Degraders

Rana R. McKay, MD:
Another group of agents that I think are exciting are the AR degraders and AR pathway–targeting agents. Bavdegalutamide is an AR degrader that targets the AR for proteasomal degradation. In the phase I/II ARDENT trial, bavdegalutamide showed clinical activity in heavily pretreated mCRPC, particularly for patients with AR mutations T878 and/or H875.47 A similar agent, ARV-766, is also being tested in a phase I/II trial (NCT05067140) in patients with mCRPC who had progressed on ≥2 approved systemic therapies. ODM-208 is a CYP11A1 inhibitor that actually blocks all steroid hormone synthesis at the first step of biosynthesis in the adrenal gland.48 In a phase I trial the PSA >50 was 32%; however, ODM-208 causes adrenal insufficiency that is appropriately resolved with mineralocorticoid and glucocorticoid replacement. I think these agents are very promising areas of interest for future study.

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CAR T–Cell Therapy

Tanya B. Dorff, MD:
Immunotherapy remains challenging. The feasibility of CAR T–cell therapies targeting prostate stem cell antigen (PSCA) or PSMA has been demonstrated, but a lot of work remains to augment efficacy while balancing toxicity.49,50 These agents are still at very early stages of development, but I do think they are exciting because the exceptional responders on these trials can have long lasting control. Once we optimize dosing strategies and work out which patients are most likely to achieve durable remissions, there could be a big payoff despite the great expense and toxicity at present.

Michael T. Schweizer, MD:
I am still holding out that we will be able to make immunotherapy work for prostate cancer. I think the CAR T–cell therapies are promising but, as Dr. Dorff noted, toxicity is a concern. There are other combination approaches using checkpoint inhibitors plus another agent that look interesting.

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Bispecific Antibodies

Tanya B. Dorff, MD:
Bispecific antibodies have a higher rate of response but have struggled with toxicity and durability of remissions that are induced. Cytokine release syndrome is the most common adverse event with PSMA-targeted agents such as acapatamab (AMG 160).51 It remains to be seen whether selection of other targets, such as STEAP1 that is targeted by xaluritamig (AMG 509) or other strategies can help to balance the efficacy vs toxicity profile. These are certainly areas that will continue to be active in development. 

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LuPARP: Dose-Finding Study of Olaparib Plus 177-Lu-PSMA-617 in mCRPC

Tanya B. Dorff, MD:
I also wanted to highlight some combination therapies. We are in the early stages of combining immunotherapy with radiopharmaceuticals. There is also great interest in whether PARP inhibitors could be radiosensitizing. Data from the LuPARP phase I trial were recently presented, showing promising activity for the combination of Lu-177-PSMA-617 plus olaparib in patients with high-PSMA mCRPC.52 It is too early to say whether radiosensitization occurred and whether the combination will be effective, but I certainly think potential combinations of these active agents are a very fruitful area for investigation.

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CONTACT-02 Trial of Atezolizumab Plus Cabozantinib vs ARSI in Previously Treated mCRPC

Rana R. McKay, MD:
The randomized phase III CONTACT 02 trial (NCT04446117) just completed accrual. This study is comparing atezolizumab plus cabozantinib vs ARSI in patients with mCRPC previously treated with another ARSI, having evidence of measurable disease on imaging. Cabozantinib has a long history in prostate cancer, so it will be interesting to see those data once they are presented. 

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With which of the following patients would you discuss the possibility of enrolling on the phase III CYCLONE 3 trial of abemaciclib plus abiraterone/prednisone?

Other Potential Targets in Prostate Cancer

Rana R. McKay, MD:
Another interesting line of research is the study of cell surface proteins that are found on prostate cancer cells, and the field is looking at ways to target them through different modalities such as ADCs and bispecific antibodies. There are many cell surface molecules of interest including B7-H3, DLL3 (more commonly seen in neuroendocrine tumors), CD46, and of course, PSMA. Some strategies target 2 cell surface proteins at the same time, so it will be interesting to watch as these different novel therapies are being developed.

Tanya B. Dorff, MD:
In later disease stages, prostate cancer becomes more heterogeneous, so we may need to be looking at simultaneously targeting 2 different kinds of antigens. One antigen may be associated with neuroendocrine or aggressive variants with less AR driven antigen pathways, and the other could be PSMA or one of the other targets like PSCA or STEAP1. I think it is important to explore these combinations, but anything that is killing cancer cells provides an opportunity for immunotherapy to perhaps enter and see the cancer. Perhaps it makes sense to pair an ADC or radioligand with an immunotherapy approach.

Conclusions

Alicia K. Morgans, MD, MPH:
This conversation has brought out a lot of nuance that we do not always have the opportunity to discuss, and it is enlightening to hear the intricacies of different healthcare professionals’ practices that can give us new ways to think about the challenges we face in prostate cancer. It is encouraging to see that we are all following the SoC guidelines at a baseline level and doing what is best for our patients. Ensuring that information is communicated between patients and clinicians really helps to address some of the inequitable distribution of best practices that lead to differences in outcomes for our patients.

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