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Expert FAQ on mCRPC
Experts Answer Questions on Managing mCRPC in a Rapidly Evolving Disease Paradigm

Released: March 14, 2022

Expiration: March 13, 2023

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In this commentary based on a live webinar, experts Rana R. McKay, MD; Michael Schweizer, MD; and Matthew R. Smith, MD, PhD, discuss the latest developments and answer questions from healthcare professionals on managing metastatic castration-resistant prostate cancer (mCRPC).

Trials in patients with castration-resistant prostate cancer (CRPC) continue androgen deprivation therapy (ADT) as the presumed standard of care. Is continuing ADT necessary?

Michael Schweizer, MD:
My patients regularly ask me whether they should continue ADT. The short answer is that there are minimal data to support stopping standard ADT in the castration‑resistant setting. In prostate cancer, the androgen receptor (AR) is a key driver even in the castration‑resistant setting—meaning that tumors could progress if ADT is stopped. Furthermore, many patients will have been on ADT so long that it is unlikely they would recover testosterone quickly, if at all.

That being said, I do have some skepticism about continuing ADT in patients with late‑stage disease that may have transformed into a small‑cell or neuroendocrine variant. I would also be interested in seeing development of AR inhibitor–sparing options for patients earlier in their disease course, perhaps in the biochemical recurrence setting.

Matthew R. Smith, MD, PhD:
I agree. I would add that there is an extraordinary body of work indicating that intensification of AR inhibition across the entire spectrum of prostate cancer improves overall survival (OS). It is difficult to imagine that allowing testosterone to recover would be helpful for disease control in the setting of mCRPC. At ASCO GU 2022, the PRESIDE trial reported on the question of continued AR targeting with enzalutamide in conjunction with docetaxel in patients with chemotherapy-naive mCRPC who had progressed on enzalutamide. The study reported that continuing enzalutamide improved progression-free survival (PFS) vs placebo in patients receiving docetaxel after progression on enzalutamide.

Will more aggressive management of metastatic hormone-sensitive prostate cancer (mHSPC) translate to a longer time to castration resistance?

Rana R. McKay, MD:
Yes, treatment intensification in the hormone‑sensitive setting delays time to CRPC. At the end of 2021, we saw data from the PEACE-1 trial showing that intensification with abiraterone and docetaxel seems to improve OS in the de novo setting. I anticipate that practice will shift toward using that strategy.

We have to consider differences between real‑world practice vs clinical trials. Even now, many patients with mHSPC are receiving ADT alone, representing an unmet need. Intensification in the hormone‑sensitive setting will change time to CRPC and how we treat CRPC.

Matthew R. Smith, MD, PhD:
I agree. I would add that CRPC means something different in a patient who had intensified therapy. For example, in the context of PEACE‑1, if a patient progressed to CRPC, it would mean they are refractory to both ADT and abiraterone.

In the VISION trial of 177Lu-PSMA-617 vs standard of care in patients with mCRPC previously treated with an AR therapy and a taxane, what were the strategies used by investigators to mitigate dropout?

Michael Schweizer, MD:
I believe the investigators mostly focused on physician and patient education and ensuring that when patients enrolled, both physicians and patients understood the possibility of being randomized to the control arm. We all want our patients to receive these promising new drugs, but it is only by having some patients receive treatment on the control arm that we can draw conclusions regarding the efficacy of newer drugs. Although the dropout rate was still higher in the standard-of-care arm following the introduction of these mitigation efforts, the dropout rate improved from 56% to 16%. This approach enabled the VISION trial to clearly prove that the use of 177Lu-PSMA-647 in prostate-specific membrane antigen (PSMA)-positive mCRPC was effective.

Matthew R. Smith, MD, PhD:
Dropout is a common challenge in clinical trials. In studies performed in patients with nonmetastatic CRPC (nmCRPC), we have asked patients to either not have their prostate-specific antigen (PSA) checked or to ignore their PSA results to keep them on study.

What do you foresee in terms of healthcare professionals adopting PSMA PET imaging?

Michael Schweizer, MD:
In my clinic, we use PSMA PET imaging most often to evaluate for micrometastatic disease that may be driving a rise in PSA in patients who have exhausted site‑directed therapy options (eg, prostatectomy and salvage radiation). In cases where we are finding oligometastatic disease, we consider site-directed radiation. However, we lack prospective data on how to treat the oligometastatic and/or micrometastatic disease that we can now identify. This new imaging modality is causing a shift toward redefining metastasis much earlier than before.

I anticipate that we are going to start obtaining PSMA PET scans when we want to assess eligibility to receive lutetium PSMA, which I think likely will be approved by the FDA very soon. PSMA PET imaging will be able to then help us direct PSMA-targeting therapies.

Matthew R. Smith, MD, PhD:
I agree. I believe this will change management of prostate cancer in the United States, where we have not had routine use of PSMA PET imaging. Other parts of the world already have adopted PSMA PET imaging for use in diagnosis and/or selection of PSMA‑targeted therapy. At our institution, I think this will become the imaging modality and staging test of choice in various settings.

With the availability of PSMA PET imaging technology, it seems we are seeing a decline in the disease state of nmCRPC. How will that affect management as the recurrent setting becomes common in CRPC?

Matthew R. Smith, MD, PhD:
Diagnoses of nmCRPC are decreasing because we now have advanced PSMA PET imaging that can visibly detect metastases at lower PSA levels, meaning patients are being reclassified as metastatic. If I could go back in time to when we designed the SPARTAN study, a key study in nmCRPC, I wish we could have required PSMA PET/CT and used it as a stratification factor in this population with no detectable metastases by conventional imaging. We now know that a subset of patients eligible for SPARTAN and similar nmCRPC trials (ie, PROSPER and ARAMIS) would have had PSMA PET–positive disease. That is not speculation—there was a study that looked at that question retrospectively in data largely from Germany. Indeed, the data from the SPARTAN, PROSPER, and ARAMIS trials remain very relevant and provide the most compelling evidence for intervening with an AR pathway inhibitor in patients who have progressed to CRPC, are negative on conventional imaging, and are positive for metastatic disease by PSMA PET/CT.

How do we even define CRPC and mCRPC?

Rana R. McKay, MD:
I think we are moving away from the current terminology of “nmCRPC,” “mHSPC,” and “mCRPC” and toward “first‑line therapy,” “second‑line therapy,” etc—essentially describing these disease states in the context of testosterone levels and better imaging technologies. These states may not be relevant in the future, when patients with hormone-sensitive disease receive intensification and with the introduction of metastasis‑directed therapy. However, it will be a challenge to align our evolving understanding with established regulatory standards.

Michael Schweizer, MD:
I agree. When the term CRPC was first conceived, it was when we lacked effective modern therapies. At this point, what does it mean to be castration resistant? For example, progressing on just leuprolide is quite different from progressing on leuprolide plus taxane chemotherapy plus darolutamide. I think it makes perfect sense to use “lines of therapy” terminology similar to what is used in other solid tumors.

Matthew R. Smith, MD, PhD:
Accurately summarizing a patient’s disease status requires more than the label of “CRPC.” For example, a complete description might include: “68‑year‑old man with mCRPC with sites of disease X, Y, and Z, now with disease progression after the following systemic therapies.” The other terminology is largely irrelevant. Biologically, there is probably no difference if the patient received docetaxel for mHSPC or mCRPC—even more so with AR pathway inhibitors used continuously to progression.

Michael Schweizer, MD:
As Dr McKay mentioned, it will be interesting seeing how the FDA responds to this evolution in terminology, because many approvals are based on these old terms. We still use “CRPC” in our clinic notes. It is difficult to abandon well-established terminology, but I think we need to, because these terms can confuse the situation.

What could potentially explain the different results on first-line PARP inhibition reported for the PROpel and MAGNITUDE trials?

Rana R. McKay, MD:
To summarize, data from the phase III PROpel trial reported a radiologic PFS benefit with first-line olaparib plus abiraterone in patients with mCRPC who were unselected for homologous recombination repair (HRR) mutation, with both the biomarker-negative and -positive subgroups demonstrating a PFS benefit. By contrast, data from the phase III MAGNITUDE trial reported a radiologic PFS benefit with niraparib plus abiraterone only in patients with an HRR mutation in this setting; the benefit was not observed in the biomarker-negative patients.

The divergent results are likely due to differences in trial design and the patients who enrolled on the study. MAGNITUDE prescreened patients for HRR mutation status and had a separate cohort for patients without HRR mutations, whereas PROpel assessed HRR status retrospectively. The results may also reflect differences in selectivity and/or PARP trapping between PARP inhibitors.

Could you comment on the safety of PARP inhibitors as a class?

Rana R. McKay, MD: 
An important adverse event of the PARP inhibitor class is myelosuppression, of note anemia and thrombocytopenia. This is particularly common in refractory disease, where patients often have received prior therapies with myelosuppressive effects (eg, chemotherapy, radiation therapy, stereotactic body radiation therapy, radiopharmaceuticals). Gastrointestinal toxicities can also happen, but it is vital for healthcare professionals to monitor complete blood counts and know dose modification strategies for the different PARP inhibitors. Even when hemoglobin drops into the 8‑9 g/dL range, various approaches can be taken to mitigate toxicity and maximize time on therapy.

As PARP inhibitors move into earlier settings, we need to be cognizant of the long‑term risk of myelodysplastic syndromes (MDS). MDS is uncommon, but its risk increases in patients who are treated with earlier disease and presumably have a longer lifespan and who may be treated for an indefinite period of time.

How will you select patients in the clinic for treatment intensification, especially given the older age of many of our patients?

Rana R. McKay, MD:
Before considering treatment intensification in the clinic, we must first demonstrate that these novel treatments are efficacious and safe. I need to know whether a new approach just delays progression or actually improves survival before I will consider using it in the clinic.

Second, we need the trial data to reflect current practice. MAGNITUDE and PROpel do not necessarily reflect our current use of treatment intensification in hormone‑sensitive disease.

Third, it is vital to know who exactly was enrolled on both MAGNITUDE and PROpel. Patients transitioning from hormone‑sensitive disease to CRPC are a very heterogeneous population with important differences in disease burden. MAGNITUDE was specifically designed for patients who were not on opioids and who filled out a pain inventory to demonstrate that they had asymptomatic to minimally symptomatic disease, whereas PROpel permitted patients to have symptomatic pain and/or opiate use at baseline.

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