Rapid Sequencing May Alleviate Sequencing Challenges in mCRPC

William Oh, MD

The optimal sequencing of therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) has proven to be a significant clinical challenge following the approvals of additional agents, said William K. Oh, MD.

In an effort to combat this, investigators involved in the phase II PRINT trial (NCT02903160) rapidly cycled non—cross reactive pairs of approved agents in patients with newly diagnosed mCPRC, in an attempt to effectively treat intrinsic heterogeneity in the disease, as well as delay and prevent drug resistance and minimize toxicity.

In the study, patients received abiraterone acetate (Zytiga) plus prednisone for 12 weeks, followed by a second module of cabazitaxel (Jevtana) and carboplatin for 12 weeks, and then a third module of enzalutamide (Xtandi) and radium-223 dichloride (Xofigo), the latter of which was only for patients with bone metastases. As a fourth regimen, patients were treated with androgen deprivation therapy (ADT) until disease progression.

At a median follow-up of 54+ weeks, 21.1% of patients (n = 8) continued on ADT and did not require additional treatment. Moreover, the median time to prostate-specific antigen progression in the posttreatment surveillance period was 14.7+ weeks.

"Sometimes we wait for the biology to be perfect and use 2 drugs that have synergistic qualities," said Oh. "However, it can take a long time to understand how drugs work together. Instead, the right thing may be to take 2 drugs that otherwise can be safely administered together to test different methods of sequencing. The PRINT trial model has allowed us to do this quickly."

In an interview with OncLive, Oh, chief of the Division of Hematology and Medical Oncology and professor of medicine at Mount Sinai Hospital, and deputy director of Tisch Cancer Institute, discussed sequencing challenges in prostate cancer, biomarker development, and the impact of the PRINT trial.

OncLive: What are some of the challenges regarding sequencing in prostate cancer?

Oh: In prostate cancer, we find ourselves in an interesting situation because we have had a lot of phase III studies that have matured. These trials have led us to use new drugs, such as androgen receptor (AR)—targeted therapies and chemotherapy in earlier-disease settings like nonmetastatic CRPC and metastatic hormone-sensitive prostate cancer (mHSPC). However, that leaves us without an answer to what do to when patients relapse after these non-curative treatments.

Additionally, we have so many choices in the mHSPC, for example, we are unsure of whether to use chemotherapy per the CHAARTED trial, abiraterone per the LATITUDE trial, enzalutamide, or apalutamide (Erleada). How do we sequence these treatments?

Optimizing treatments in such a way to get the best outcome for each of our patients is a remaining challenge throughout the oncology space.

What emerging agents look particularly promising in prostate cancer?

We are closely watching Lutetium-177-PSMA because [radiopharmaceuticals] are a novel way of treating patients with advanced prostate cancer. We know that PSMA is quite prevalent as patients progress to mCRPC, so it represents an important target. We should be seeing results from ongoing trials reported out over the next few years.

Of course, another big story is targeted therapy in terms of BRCA mutations and other DNA damage repair (DDR) mutations. With the advent of precision medicine, targeting BRCA and other DDR mutations is creating a space for PARP inhibitors. Patients with those mutations represent about 20% of all patients with advanced metastatic prostate cancer. We will need to identify those patients by sending off germline and somatic testing, and subsequently making sure that patients are shuttled to the right treatment.

What is the status of biomarker development in prostate cancer? Are there new targets that may be worth exploring in the future?

We are still uncertain on [how to identify] novel targets for prostate cancer. We know that for example, p53 mutations, p10 loss, and TMPRSS2-ERG fusions are very common in prostate cancer, but we haven't yet figured out a way of specifically target those aberrations. That has been our biggest challenge.

We know that DDR mutations essentially lead to an actionable mutation, but only a small percentage of biomarkers are helping guide treatment selection for our patients.

Could you discuss the design of the PRINT trial? What were the findings?

In the investigator-initiated PRINT study, we gave different approved treatments in a rapid sequence rather than giving 1 drug at a time until the patient becomes resistant. Our hypothesis was that we could give short bursts of [doublet therapies] to eradicate the resistant clone.

In module 1, we gave abiraterone plus radium-223 for 3 months. That combination was eventually considered to be potentially risky, so we dropped radium-223 from that module. After 3 months, we stopped module 1 whether the patient was responding or not and switched to chemotherapy with cabazitaxel and carboplatin. After another 3 months, we stopped and switched to enzalutamide and radium-223. In this case, module 3, we continued both treatments. After 9 months of treatment, we stopped everything and continued patients on ADT alone.

At a median follow-up of up to 1 year, about 20% of patients have not needed to go back on any additional therapy. This may be an interesting way of taking existing therapies and sequencing them in a way that can optimize cell death to decrease the chance of resistance.

For the patients who did not need to go back on therapy, did they have any specific disease characteristics that may have contributed to their prolonged disease-free survival?

We are still analyzing the data. This was not a fully accrued study; there were 22 evaluable patients. We don't know why some patients with mCRPC have prolonged disease-free intervals without needing to go back on next-generation treatments. However, it does give us insight into the disease biology. We are going to be studying some biomarkers to try to assess whether there are some patients who will be best suited for this kind of sequencing.

Interestingly, this regimen was generally well tolerated. Patients with prostate cancer are usually older. Historically, when we tried to combine 4 or 5 agents, [patients could not tolerate the treatment]. In the PRINT study, we had doublets and changed those doublets every 3 months. It seemed to be very well tolerated.

Also, the trial shed light on what patients could tolerate. We were able to expose patients to treatments and know whether or not they were responding. Then if a patient did relapse, we were more poised to know what drug to use at what point.

In your opinion, is it worth doing a similar study with the drug pairs in different orders or adding in other available agents?

This model could be adapted to new drugs or new approaches. Perhaps we need to move this concept earlier to mHSPC rather than mCRPC, or even moving it into the neoadjuvant setting. Could we combine drugs and do rapid sequencing in those settings?

Patients appears to tolerate the treatment quite well. That was not surprising because we put the drugs together in a rational way.

We know that people were particularly concerned about radium-223 [and the increased risk of bone fractures]. Although we did not see that in our study, we've realized that adding bone-protecting agents like denosumab (Xgeva) and zoledronic acid should be routine when giving radium-223 or an AR-targeted agent. Certainly, if you use both together, the evidence is pretty clear that you need a bone protecting agent on board.

Liaw BC, Tsao C, Galsky MD, et al. Print: Prostate cancer intensive, non-cross reactive therapy for CRP-early observations of efficacy. J Clin Oncol. 2020;38(suppl 6; abstr 89). doi: 10.1200/JCO.2020.38.6_suppl.89