Future Directions for the Treatment of mCRPC
Tomasz M. Beer, MD, FACP, shares unmet needs and clinical pearls for the management of patients with mCRPC.
Tomasz M. Beer, MD, FACP: The question is what are the unmet needs in metastatic CRPC [Castration-resistant prostate cancer]? I would say that there are a lot of them. When I think about unmet needs, my mind first goes to those heavily pretreated patients who are running out of treatment options altogether. That’s obviously the most pressing unmet need. But when we think about it, we should be aiming higher than sequential single-agent therapies that produce disease control for a period of time, and then the disease emerges with resistance. There is a need for much more effective therapies earlier on, that control the disease long term, and ultimately that produce durable disease-free status for our patients. While there’s an unmet need for late-stage therapeutics, I’d like the field to think hard about innovative combination therapies and aim high and aspire to produce, reliably produce complete remissions that are durable.
Are there other ongoing trials that are likely to change the treatment landscape? There are so many interesting studies out there, it’s almost hard to offer a list without worrying that I’ll forget something that is important to mention. But let me talk a little bit about several classes of agents and think about which ones might be most interesting. One area that I would think about is other targeted agents. We saw the initial results with ipatasertib and I’m very interested in seeing longer-term follow-up and more data on drugs like that that target specific genomic alterations in tumors. I’d like to see a situation where when we do a molecular analysis of a tumor, it’s not just for whether they qualify for PARP [poly ADP-ribose polymerase] inhibitors, but to access a pharmacopeia of targeted drugs that are individualized. I’m looking for those.
We’re seeing an awful lot of activity with PARP inhibitors in a variety of combinations. Time will tell where those go, but certainly something to pay attention to.
We’re seeing a lot of activity in a variety of immunotherapeutic areas, and here I would highlight some innovative technologies like bispecific antibodies that target prostate cancer cells through a cell surface antigen and T-cells and bring those physically together to activate an immune response. The first generation of those is going to target PSMA, [Prostate-specific antigen] but there are other antigens on the surface of cells that are also likely to be exploited with that technology.
A different approach that’s interesting in this area is antibody-drug conjugates. These are, at this point, early-stage phase 1/phase 2 studies, but we’re seeing more and more such agents to a variety of cell surface antigens, some prostate-cancer specific and some that are relevant to multiple cancers, where an antibody is used to deliver a pharmaceutical payload that is internalized by the cancer cell and delivered locally. That class of drugs is certainly of great interest.
Finally, one of the big trends in the field has been the movement of next-generation hormonal agents into earlier stages of disease. That is probably the most important development in terms of making a difference for patients. We’ve seen drugs like abiraterone, enzalutamide, apalutamide move from advanced metastatic castration-resistant prostate cancer to newly-diagnosed disease, and in the case of enzalutamide and apalutamide, into non-metastatic CRPC. We’ve seen darolutamide start directly in non-metastatic CRPC, and now being evaluated for newly-diagnosed metastatic disease. There are some additional studies in that space that are looking at multi-drug combinations for newly-diagnosed high-risk localized disease and for initial biochemical recurrence, PSA [Prostate-specific antigen] rises in a hormone-naïve setting. I would anticipate that we’re going to continue to see the trend towards earlier use of multi-drug hormonal combinations. That’s had a big impact on progression-free survival and overall survival on the disease, and although it is more of a learning how to use a set of drugs than developing completely new drugs, in terms of impact it’s a very important area to keep an eye on.
Key takeaways for metastatic CRPC is that field is evolving fast. The key nowadays is an individualized approach to patients based on their prior treatment experience, based on their comorbidities, and based on their tumor genotype. That’s the triad of things that we consider strongly in selecting therapies for individuals with metastatic CRPC. Then I guess the last pearl would be keep an eye out for new drug approvals because there’s a lot going on in the field, and I genuinely expect that every year or so the standard of care will evolve as we get new tools and learn new things. It’s a very dynamic field.
Transcript Edited for Clarity
A 62-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer
Jan. 2017
Initial presentation
- A 62-year-old man is found to have a firm prostate nodule of 1.5 mm on his routine physical exam
Clinical workup
- PSA 15.5 ng/mL
- Family history of prostate cancer
- Hypertension
- Digital rectal exam and transrectal ultrasound (TRUS) of the prostate confirm advanced adenocarcinoma of the prostate and Gleason score of 7 (3 + 4)
- MRI shows lack of metastasis and node involvement (cT2bN0M0)
- His ECOG PS is 1
Treatment
- In Feb. 2017, patient was treated with radical prostatectomy (RP) with nerve sparing surgery and there were no complications.
- PSA levels go down to 0.3 ng/ml post-operatively but rise to 1.5 ng/ml within 3 months.
- Patient receives local salvage radiation therapy and PSA goes down to 0.1 ng/ml.
- PSA levels are checked every 3 months.
Nov. 2017
- PSA doubling time increased between 2 last check-ups and now PSA is 3.5 ng/ml.
- Patient undergoes CT and bone scans and is found to 1 metastatic bone lesion.
- Patient is treated with androgen deprivation therapy (ADT), leuprolide, as continuous treatment and PSA levels go down to 0.2 ng/ml.
May 2018
- PSA levels rise to 5 ng/ml, but patient is asymptomatic and has adequate organ and bone marrow function.
- Patient meets the inclusion criteria for the ODENZA trial and is enrolled in it.
- Patient is treated with darolutamide(1200 mg/day) for 12 weeks, followed by enzalutamide (160 mg/day) for 12 weeks, in addition to continuing on ADT
- Patient is currently in the extension phase of the study and is being treated with darolutamide.
