Matthew R. Smith, MD, PhD

We now have an abundance of treatment options for prostate cancer, but important unmet needs remain. We have 4 approved androgen receptor pathway inhibitors. This is valuable to managing an individual patient because the differences in the safety and tolerability profile of those drugs may help optimize the therapy choices for an individual patient, but it's important to know that patients derive most or all of the benefit from an androgen pathway inhibitor with the first drug.

There's a tremendous cross-resistance between available androgen receptor pathway inhibitors, and the switch from 1 androgen receptor pathway inhibitor to the other, for progression is associated with very low response rates in a short duration of response. That there's this high cross-resistance between androgen receptor pathway inhibitors is notable and represents an area of major unmet need. A number of studies are attempting to address this by either adding an additional targeted therapy to extend the benefit of an androgen receptor pathway inhibitor or using novel approaches to target the androgen receptor pathway and achieve responses after progression despite a conventional or currently available androgen receptor pathway inhibitor.

We continue to make steady progress in the management of metastatic prostate cancer. One of the important recent developments is the positive results of PSMA lutetium [lutetium-177–PSMA-617]in a phase 3 clinical trial in patients with treatment-refractory mCRPC. That study shows improvement in progression-free and overall survival with PSMA lutetium compared with best standard of care in patients with mCRPC and cancer progression, despite prior therapy with an androgen receptor pathway inhibitor as well as docetaxel. We anticipate that the positive results will lead to regulatory approval, and when available, it will be an important option for patients with very advanced disease. There are other PSMA targeted approaches in development that are also interesting. We expect that future development plans will include introduction of PSMA-targeted therapy in earlier lines of metastatic prostate cancer.

This is an exciting time in prostate cancer. We have more options than ever to manage patients with advanced disease. My key advice to my colleagues who care for patients with prostate cancer is to follow the evidence. We have strong evidence that androgen receptor pathway inhibitors, when introduced early, improve clinical outcomes, including progression-free, metastasis-free, and overall survival. Despite that evidence, data from the community suggests that there were low rates of uptake in certain clinical settings. We need to have shared decision-making with patients and consider interventions that have proven benefit, including a wide range of disease states from mCSPC, non-metastatic CRPC, as well as CRPC.

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Matthew R. Smith, MD, PhD, discusses areas of unmet needs and clinical pearls for the management of patients with mCRPC.

Unmet Needs and Key Takeaways in mCRPC

For most patients in our practice, the second drug after androgen deprivation therapy is an androgen receptor pathway inhibitor, and that would be true in either metastatic castration-sensitive prostate cancer, non-metastatic CRPC, or in mCRPC. With progression on an androgen receptor pathway inhibitor, we have choices. The disease state we're now talking about would be patients with mCRPC and disease progression despite prior androgen receptor pathway inhibitors. Among available approved options, our standard approach would be to use docetaxel. That's not a decision we would take lightly. An important point to make here is that we wouldn't switch systemic treatments in this setting based on PSA progression alone. We would continue the androgen receptor pathway inhibitor until radiographic and/or clinical progression.

There are now newer options for at least molecular subsets of patients in this disease state, including olaparib, based on the results of the pivotal PROfound (NCT02987543) study. The study included patients with mCRPC and disease progression on an androgen receptor pathway inhibitor and patients could also have received prior docetaxel, and about half of the patients did receive that. PROfound also included patients with a germline or somatic mutation in a DNA repair gene, and it showed an improvement in progression-free and overall survival in favor of olaparib, at least in the 

 primary cohorts. This is important information and a strong rationale to do tumor genetic testing and germline genetic testing in patients. We typically offer germline genetic testing for all of our patients at diagnosis with metastatic prostate cancer and then do tumor genetic testing typically after they develop mCRPC and progression after first-line treatment.

Prostate cancer expert Dr Smith elaborates on treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on systemic therapy.

Treatment Options upon Progression on ADT

My personal experience with darolutamide is well aligned with the published results from the ARAMIS study. The drug has a favorable safety profile. We participated in the ARAMIS trial and, candidly, it was quite difficult to distinguish between placebo and darolutamide treatment patients during the blinded portion of the trial. My post-approval experience has been similar to that. Patients report a good quality of life during treatment. It would be rare to require a treatment interruption or dose reduction with darolutamide, so the tolerability has been consistent with what's been reported from the ARAMIS trial. Our efficacy experience is similar with most patients experiencing durable PSA response and relatively long time to progression before requiring a change in systemic treatment.

Matthew R. Smith, MD, PhD, shares his personal experience using darolutamide for patients with prostate cancer.

Experience with Darolutamide in Clinical Practice

In my practice, androgen receptor pathway inhibitors are a mainstay of treatment for patients with non-metastatic and metastatic castration-resistant prostate cancer. This class of drugs has brought approval across a wide spectrum of clinical disease states from metastatic castration-sensitive prostate cancer (mCSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC).

There are currently 4 approved androgen receptor pathway inhibitors in the United States: 3 anti-androgens—apalutamide, enzalutamide, and darolutamide—and an androgen receptor pathway inhibitor, abiraterone acetate. The efficacy of these agents, while rarely studied head-to-head, appears remarkably similar based on cross-trial comparisons. The choice of agents tends to focus on the expected tolerability in an individual patient. In non-metastatic castration-resistant prostate cancer, for example, there are 3 approved drugs: apalutamide, enzalutamide, and darolutamide. They were approved based on pivotal studies of remarkably similar design and, candidly, efficacy results that are highly overlapping with marked improvements in metastasis-free survival in each of the 3 trials and in overall survival benefit in the final survival analysis for each of those studies.

In contrast to the 2 other drugs, darolutamide does not cross the blood-brain barrier well and may lack some of the CNS side effects associated with the other drugs. Consistent with that nonclinical information, cross-trial comparison between the SPARTAN, PROSPER, and ARAMIS trials suggest that darolutamide lacks some of the CNS [central nervous system] toxicity with what appears to be less fatigue and no risk for falls or fractures. This case illustrates the importance of having choices so a patient who was intolerant of enzalutamide was able to still benefit from an androgen receptor pathway inhibitor by subsequent treatment with darolutamide. He tolerated that treatment well and continued to respond.

Dr Matthew Smith discusses next generation androgen receptor inhibitors and data from clinical trials with these agents.

Next Generation Androgen Receptor Inhibitors

The patient had reported no family history of prostate cancer, but that's a relatively insensitive predictor of having an inherited alteration in a cancer susceptibility gene. The lack of a family history would not discourage me from recommending both germline and tumor genetic testing in this patient. We offer germline genetic testing to all patients with recurrent or de novo metastatic disease and specific younger individuals with high-risk localized disease for the purpose of looking for either DNA repair defects or mismatch repair. Identification of either of those alterations could inform subsequent treatment decisions. For patients who do not have germline alterations or did not have prior germline testing, we'd also recommend tumor genetic testing. We typically recommend that at progression, despite first-line treatment for mCRPC because that's the first point at which that information would currently be actionable. For patients who have an identified pathogenic mutation in a DNA repair gene, whether germline or somatic, they may be candidates for a PARP inhibitor either after an androgen receptor pathway inhibitor or after an androgen receptor inhibitor and docetaxel. The prevalence of those mutations is approximately 10% of mismatch repair alterations. MSI [microsatellite instability]high is less common at about 1% to 3%. In the rare patient who has those alterations, we would consider treatment with pembrolizumab.

Prostate cancer expert, Matthew R. Smith, MD, PhD, shares his thoughts about importance of testing in treatment of metastatic castration-resistant prostate cancer (mCRPC).

The Role of Molecular Testing in mCRPC

 For patients who've received primary androgen deprivation therapy, the standard options as first-line treatment for mCRPC include an androgen receptor pathway inhibitor—drugs like abiraterone acetate or enzalutamide, or docetaxel chemotherapy. There are other approved options including sipuleucel-t. Other agents like radium-223 would typically be used in later lines of therapy. There are approved PARP inhibitors, but those 2 are approved only in specific molecular subsets and in later lines of therapy.

In this case, we have a patient with castration-resistant prostate cancer. He had previously documented metastases by conventional imaging, but interestingly enough, at the time of his progression to CRPC, conventional imaging showed no detectable cancer, and it was really only what remained visible or was visible by PSMA PET, a more sensitive imaging modality. In this case[…]it sort of falls in this gray area of whether he's metastatic or non-metastatic by conventional nomenclature. We certainly know he has distant spread, but it's whether or not it's detectable by conventional imaging. The choice of initial salvage therapy with enzalutamide is very reasonable. He did have a PSA decline, as most patients would, but in this older gentleman with some other medical comorbidities, he did not tolerate therapy well and chose to discontinue treatment because of what he described as profound fatigue and difficulty with ambulation. I certainly would not be enthusiastic about persisting or pursuing continued treatment given those side effects.

He was monitored closely while off treatment for several months, and only when we saw a resolution of those symptoms were we comfortable in retreating him. We made the decision to treat him with darolutamide based on his disease state and prior intolerance of enzalutamide. Darolutamide lacks blood-brain barrier penetration. While there are no head-to-head phase 3 trials between darolutamide and enzalutamide, comparison between the phase 3 studies in non-metastatic CRPC suggests a better tolerability of darolutamide. Further support for that point was made in a French trial (ODENZA) that did a head-to-head comparison looking at patient preference between darolutamide and enzalutamide. In that trial, darolutamide had the edge with more patients preferring darolutamide over enzalutamide.

Thankfully, the patient did tolerate darolutamide well and remains on treatment and his PSA continues to decline on therapy, but we do recognize that mCRPC is not yet an approved indication for darolutamide. This patient kind of falls in this gray area because his PSMA PET was the only basis for visible metastatic disease when we treated him. The other reason that it was reasonable to treat him in this fashion was that he had an intolerance of prior enzalutamide treatment.

Dr Matthew R. Smith reviews initial treatment options for a patient with metastatic castration-resistant prostate cancer (mCRPC).

Matthew R. Smith, MD, PhD | Authors

Articles

Unmet Needs and Key Takeaways in mCRPC

Treatment Options upon Progression on ADT

Experience with Darolutamide in Clinical Practice

Next Generation Androgen Receptor Inhibitors

The Role of Molecular Testing in mCRPC

Initial Treatment Options for mCRPC