Published Date: December 2019
The choice of initial treatment for newly diagnosed metastatic castration-resistant prostate cancer (mCRPC) is far more complex than it was even a decade ago. Today, many patients with mCRPC have already received intensive upfront therapies during the hormone-sensitive stage— a “leftward” shift in treatment (based on the clinical states model we so frequently employ) which can spur a “rightward” shift in disease biology due to the earlier emergence of treatment-resistant clones.
However, our treatment armamentarium also has expanded and now includes many new options that we can potentially add to traditional androgen deprivation therapy (ADT “plus”). These include not only chemotherapy agents (docetaxel, cabazitaxel), but also direct androgen receptor (AR) inhibitors (enzalutamide, abiraterone acetate, and apalutamide, with darolutamide in the pipeline), a cell-based immunotherapy (sipuleucel-T), and radioisotope therapies (both radium-223 and, in some areas, prostate-specific membrane antigen [PSMA]-targeted agents, such as lutetium-177[177Lu]-PSMA-617). Clinicians also enjoy a deeper understanding of the biology of the underlying disease than they did a decade ago, thanks to the broad application of next-generation sequencing tools. This rapid-pace evolution in the biology, treatment, and assessment of mCRPC raises questions about how best to select and individualize first-line therapy – often in areas where level 1 clinical trial data are lacking. These topics were a major area of focus at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC 2019).
A key takeaway from this conference was that the sequential utilization of AR-targeted agents should not be considered best practice. We now have multiple studies confirming that if prostate cancer is resistant to one such agent, then it is likely to be resistant to the others in this class.1-3 I firmly believe that we need to end this conversation and instead talk about how best to sequence other types of treatment.
Another point was that once a patient develops mCRPC, it may be beneficial to prioritize chemotherapy if the patient is treatment-eligible (fit) and has high-risk characteristics: a high tumor burden, visceral metastases, a short (1 to 3-month) prostate-specific antigen (PSA) doubling time, high-risk genomics, or a history of progression during or shortly after earlier intensified treatment.4 These patients are at particular risk for rapid metastatic progression on non-chemotherapy agents, which is why it can be important to consider first-line chemotherapy. The use of chemotherapy earlier rather than later can be justified from two perspectives. The first is that clinical trial results generally support the notion that chemotherapy may be better earlier than later when the disease is more biologically resistant (consider the magnitude of benefit from the CHAARTED study versus TAX-327, or even the outcomes of patients with lesser-volume disease within many docetaxel studies).5-7 The second is the general concern is that deferring a treatment, particularly when mCRPC is rapidly progressing, may close a ‘window of opportunity’ for the patient as complications such as pain and a declining performance status accumulate.
Discussions at APCCC 2019 also reflected our growing appreciation of the need for genomic sequencing to elucidate risk for progression and potential responses to treatment. Recent and emerging evidence points to a prognostic and predictive role of variants in genes involving the mismatch repair (MMR) pathway (MSH2, MSH6, MLH1) and the homologous recombination (HR) pathway (BRCA2, BRCA1, PALB2, ATM, and CHEK2).8-10
In keeping with these advances, the current version of the National Comprehensive Cancer Network (NCCN) prostate cancer guidelines recommend tumor genetic profiling for all patients with regional or metastatic disease,11 while guidelines from the 2019 International Society of Urologic Pathologists (ISUP) recommend at least testing for variants in dMMR (by either IHC and/or MSI/gene sequencing and BRCA1/2.10
Because the genomics, primary, and metastatic tumor tissue can differ, it is preferred to test metastatic tumor tissue when feasible.10 If not, primary tumor testing is regarded as acceptable. When testing for microsatellite instability (MSI) or deficient mismatch repair (dMMR), it is preferred to use a next-generation sequencing assay that has been specifically validated for prostate cancer.11 Even when tumor genomic testing reveals no known clinically actionable mutations, it often helps shed light on prostate cancer biology and prognosis. Over time, tumor genomic testing has helped me develop a sense of the types of therapy that might benefit certain patients.
Regarding genomic germline testing, the ISUP guidelines recommend testing for variants in DNA repair genes in patients with either high-risk localized or metastatic prostate cancer.10 It is especially important to consider germline testing if patients have a family history of cancer. Patients with positive germline panel test results should be referred for genetic counseling.
Another relevant topic in today’s treatment landscape relates to steroid therapy for patients receiving abiraterone. For the treatment of mCRPC, abiraterone is labeled for use with 5 mg prednisone twice daily, which was the protocol in the COU-AA-301 and COU-AA-302 trials.12, 13 In my experience, many patients on abiraterone worry about the side effects of steroids, and many can tolerate 5 mg prednisone once daily quite effectively. Indeed, this was the protocol for the abiraterone arm of the LATITUDE trial.14 However, others will need their dose of steroid increased to control hypertension and hypokalemia resulting from mineralocorticoid excess syndrome due to the CYP17A1 inhibitory effect of abiraterone. Thus, it is crucial to closely monitor patients who are on abiraterone with a reduced-dose steroid regimen.
Experts debate not only the dose but also the choice of steroid to co-administer with abiraterone. Dexamethasone has a longer half-life than prednisone, a higher ratio of a glucocorticoid to mineralocorticoid activity, and greater single-agent activity.15 Randomized data suggest that approximately one in four patients who progress on abiraterone with prednisone achieve a PSA decline when switched to dexamethasone (in most cases, this is not accompanied by radiologic response per RECIST criteria).16, 17 Dexamethasone also may also better control mineralocorticoid excess syndrome. In a recent open-label multicenter trial, 164 patients with mCRPC who were receiving abiraterone were randomly assigned (1:1:1:1) to receive dexamethasone 0.5 mg once daily, prednisone 5 mg twice daily, prednisone 2.5 mg twice daily, or prednisone 5 mg once daily.18 Only dexamethasone (0.5 mg daily) and the highest dose of prednisone (5 mg twice daily) met a prespecified primary endpoint of decreased risk of mineralocorticoid excess. However, both these regimens (dexamethasone 0.5 mg once daily and 5 mg prednisone twice daily) led to a statistically significant increase in patients’ total body fat, and dexamethasone also was associated with statistically significant increases in serum insulin and risk for insulin resistance and with a statistically significant decrease in bone mineral density. These findings highlight the need to carefully evaluate the risks and benefits of steroid type and dose on a case-by-case basis for patients receiving abiraterone.
When it comes to abiraterone without steroids, this has been found to be feasible for selected patients.19 I will cautiously consider abiraterone without steroids for patients who are attentive and adherent, and who have a convincing medical reason to avoid steroid therapy, such as a comorbid diagnosis of diabetes or osteoporosis. I recommend that clinicians only consider abiraterone without steroids if they already have considerable experience with abiraterone and the ability to closely follow these patients throughout treatment. In many cases, steroids ultimately will be needed and will improve, not lessen, patient tolerance of therapy over time.
Experts at APCCC 2019 also discussed whether it is acceptable to administer a lower dose of abiraterone with food. We now have data supporting this strategy20 and many experts now view it as acceptable in select circumstances and with close monitoring for efficacy. In the United States, this option is usually most relevant in the setting of high insurance co-payments. The range of pharmacokinetic values in the fed low-dose setting is not substantially different from the range observed in the fasting higher-dose setting, but a low dose with food may result in suboptimal responses in some patients, presumably because they fall at the bottom of that pharmacokinetic range. For these patients, subsequent dose escalation of abiraterone may be required.
Talks at APCCC 2019 also covered the advantages and pitfalls of next-generation PSMA-based imaging modalities (PSMA PET-CT/MRI) and PSMA-targeted therapies (177Lu-PSMA-617). While these technologies are exciting, experts emphasized the need for well-designed prospective studies to assess their impact on clinical decision-making, health economics, quality of life, and overall survival relative to other available therapies in mCRPC.
In addition, a relatively new question in the field is whether and how to treat non-metastatic CRPC (nmCRPC). Although this is not a new clinical problem, recent placebo-controlled studies have highlighted the benefits of early intervention with apalutamide, darolutamide or enzalutamide. Several questions asked during the voting at APCCC 2019 sought to clarify questions around this clinical state. Experts also noted that oligometastatic prostate cancer needs further definition and study in prospective trials, which may yield a unique opportunity to provide long-term clinical benefit through the judicious use of selected therapies. Several such studies are underway and will help evaluate the use of novel systemic agents as well as local radiotherapy to oligometastatic lesions.
In my view, the lack of biomarkers to predict treatment response and the dearth of prospective head-to-head clinical trials in mCRPC speak to the importance of consensus conferences such as APCCC. The treatment of advanced prostate cancer has evolved tremendously in the past decade. As clinicians who treat mCRPC, our role is to offer reasonable therapeutic options based on the most robust available data and our clinical experience. In addition, we must work to individualize treatment recommendations based on a patient’s prior therapies, tumor genomics, comorbidities, performance status, and preferences.
Written by: Charles J. Ryan, MD is the B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology, and Transplantation.
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11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology. Prostate Cancer; version 4.2019—September 5, 2019.
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18. Attard G., Merseburger A.S., Arlt W., Sternberg C.N., Feyerabend S., Berruti A., et al. Assessment of the safety of glucocorticoid regimens in combination with abiraterone acetate: A randomized, open-label phase 2 study. JAMA Oncol. 2019;5:1159-1167.
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