Metastatic prostate cancer is associated with marked decreases in overall survival and treatment-related quality of life. For most patients, disease progresses after androgen-deprivation therapy (ADT). From that point on, a variety of treatment approaches are employed for metastatic castration-resistant prostate cancer (mCRPC), but no single guiding principle dictates the optimal drug or sequence of agents. Treatment paradigms, as recommended by specialty societies, are often nuanced according to geographic region.
“Our goal is for all patients to receive all the viable treatment options,” said Sandy Srinivas, MD, Professor of Medicine at Stanford University Medical Center.
Subsequent to ADT, six therapies are approved for first-line mCRPC by the U.S. Food and Drug Administration, all having shown an overall survival benefit: the androgen receptor (AR) axis– targeting agents abiraterone and enzalutamide, the chemotherapeutic agents docetaxel and cabazitaxel, the alpha-emitting radionuclide radium-223 (Ra-223), and the immunotherapeutic sipuleucel-T. All have category 1 recommendations from the National Comprehensive Cancer Network® (NCCN).1
In patients who have disease progression on enzalutamide or abiraterone, the NCCN’s preferred second-line choice is docetaxel and sipuleucel-T, with Ra-223 also receiving a category 1 recommendation for use in certain circumstances. The use of a subsequent AR-targeting agent in this setting is listed as “other.” Upon further disease progression, the same options are acceptable, with cabazitaxel noted as an additional preferred agent. For patients with the appropriate molecular profiles, the paradigm also now includes inhibitors of poly(ADP-ribose) polymerase (PARP) and the anti–PD-1 antibody pembrolizumab.1, 2
“We are now using AR-targeting agents much earlier than we used to, so when men [have disease progression] to mCRPC, they commonly have already had a potent AR inhibitor either in the hormone-sensitive setting or the nonmetastatic CRPC setting. That landscape has changed fairly dramatically just in 2 or 3 years,” said Andrew J. Armstrong, MD, Professor of Medicine, Surgery, Pharmacology, and Cancer Biology, Duke University School of Medicine, and Director of Research, Duke Cancer Institute Center for Prostate and Urologic Cancers.
We are now using AR-targeting agents much earlier than we used to, so when men [have disease progression] to mCRPC, they commonly have already had a potent AR inhibitor either in the hormone-sensitive setting or the nonmetastatic CRPC setting. That landscape has changed fairly dramatically just in 2 or 3 years.Andrew J. Armstrong, MD
Whatever the setting, Dr. Armstrong said he chooses between these AR-targeting agents “not based on efficacy,” as their outcomes are similar. “The choice between agents is based on potential side effects, quality of life, drug–drug interactions, patient comorbidities and anticipated toxicities, and the likely out-of-pocket costs to patients and differential costs to health-care systems. That’s how these treatment decisions are being made,” he said.
“The good news for patients is that men with advanced prostate cancer are living longer, but when their disease progresses on an AR inhibitor, they will have more limited subsequent options. It has become well accepted that not only does cross-resistance occur, but it’s expected,” he said. “This is an area of active research and hope.”
Since abiraterone and enzalutamide both target androgen signaling pathways—albeit differently—there are common mechanisms of resistance. Those implicated in driving resistance are generally either dependent on or independent of ligand-binding domain-driven reactivation of AR signaling.3 This has led many to question the wisdom of a sequential AR-directed approach in mCRPC.
“There are few patients for whom back-to-back AR-targeted therapy is the right thing to do,” said Alicia K. Morgans, MD, MPH, Associate Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago.
“We know that response to a second AR-targeted agent, after an initial one, is very low. In those instances, we would typically want to draw on or use a therapy that has a unique mechanism of action or that has demonstrated efficacy in a later line of therapy,” she said.
While not yet well understood, it is believed that declining benefit from AR-targeting agents is a result of acquired (and cross) resistance. Men whose circulating tumor cells harbor the androgen receptor splice variant 7 (AR-V7)—a group poised to increase in size with earlier use of these drugs—can be expected to have poor outcomes with approved AR-targeting therapies, although there are also other means of acquired resistance.4
The presence of the AR-V7 variant in circulating tumor cells (CTC) can help guide treatment decisions. “If CTC AR-V7 detection is positive using one of two clinically validated assays (Epic Sciences nuclear AR-V7 protein assay or the Johns Hopkins mRNA assay), that absolutely predicts cross-resistance between enzalutamide and abiraterone, but a negative test does not guarantee there’s not another mechanism of cross-resistance,” Dr. Armstrong explained.
Both clinical trial data and real-world evidence show declining efficacy for a second agent with the same mechanism of action and support switching to a different class.
In a post hoc analysis of 88 docetaxel-naive patients enrolled in COU-AA-302, Smith et al concluded there is “limited benefit” for subsequent treatment with abiraterone or enzalutamide, even though two-thirds received intervening chemotherapy: “This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone.”5
Similarly, the large PLATO trial reported “limited benefit with abiraterone after enzalutamide … concordant with several retrospective studies.”6 Furthermore, a chart review of various regimens tested at Duke University showed “clear cross-resistance for abiraterone and enzalutamide” based on median progression-free survival < 4 months and small declines in prostate-specific antigen (PSA) with their sequential use.7
The CARD trial also concluded that sequential AR-targeting agents used sequentially were inferior to cabazitaxel in patients with disease progression after both docetaxel and either abiraterone or enzalutamide. Median imaging-based progression-free survival was 8.0 months with cabazitaxel, vs 3.7 months with either sequence of the AR-targeting drug (hazard ratio [HR] = 0.54; P < .001).8 De Wit et al proposed the “poor outcomes” with a second AR-targeting agent were likely due to a shared mechanism of resistance.
The CARD population included patients who had disease progression within 12 months of their initial AR-directed therapy, leading some to question whether patients already had hormonally resistant disease, Dr. Morgans said. “This was refuted, I think, by the control arm of the recent phase III PROfound trial of olaparib vs a second AR-targeted agent in patients with DNA repair defects.9 Regardless of the duration of response to their initial AR-targeted therapy, patients receiving a second one had inferior progression-free survival—3.55 months—which is very consistent with CARD,” she pointed out.
A modest benefit for sequencing, however, was suggested by Kahlaf et al in newly diagnosed mCRPC.10 Patients receiving abiraterone followed by enzalutamide had a PSA response rate of 36% and a 4-month longer time to PSA progression, vs enzalutamide followed by abiraterone (P = .036).
Another exception came from a retrospective analysis of real-world patients in the Flatiron Health database who were treated with abiraterone, enzalutamide, or docetaxel after initial treatment with an AR-targeting agent.11 Second-line abiraterone or enzalutamide yielded better survival than docetaxel, although the authors acknowledged the shortcomings of retrospective data and potential for “residual confounding and missingness.”
As is true for other solid tumors, the data suggest that the redundant use of products in the same category may have limited clinical benefit and may not be appropriate for the general population of patients with mCRPC .
As Dr. Morgans observed, “From multiple trials, we’ve seen a pretty consistent message that a second AR-targeted agent should not be our standard of care unless there’s a truly compelling reason for a particular patient. Those reasons are relatively few and far between.”
“First-line mCRCP treatment depends on what I used in combination with standard ADT in the metastatic castration-sensitive setting,” Dr. Morgans said. “A general principle of my practice is that sequencing AR-targeted agents—even if separated by docetaxel or Ra-223 or sipuleucel-T—will be poorly effective for most patients, most of the time.”
“If I’ve used chemotherapy, most commonly I would choose an AR-targeting agent, though other options include sipuleucel-T or Ra-223. If I used an AR-targeting agent earlier, options include chemotherapy, sipuleucel-T, and Ra-223 if the patient has bone-only metastases. In either case, if a clinical trial is available, I would offer that,” she said.
Dr. Morgans’ approach reflects recommended practice, according to Schulte et al, who in the 2020 ASCO Educational Book noted that superiority has not been shown for any single treatment or sequence.12 The authors advised clinicians to consider what treatment was used in metastatic castration-sensitive prostate cancer and choose therapy based on a different mechanism of action.
For treatment after the use of an AR-targeting agent, according to Dr. Armstrong, “Docetaxel and Ra-223 have a similar survival benefit and are not mutually exclusive, so it’s more a question of which to use first.” He tends to select docetaxel for “more rapid disease progression, especially outside the bone” but appreciates that Ra-223 allows patients to “defer the side effects of chemotherapy.”
There are not always specific medical indications to guide our treatment. Patient preferences are critical, and if we don't ask the patient, we won't know what these are.Alicia K. Morgans, MD, MPH
“There are a lot of patients who, for one reason or another—because of personal experience, a loved one who had chemotherapy, or they don’t want to lose their hair—say they would prefer to not be treated with chemotherapy. This is something we consider, as is possible financial toxicity, which is particularly an issue with copays for oral agents,” Dr. Morgans said.
“Symptomatic metastases, such as bone pain, can be important as well,” she continued. “Depending on prior lines of treatment, Ra-223 would absolutely be a preference for some patients.”
While Ra-223 is approved for symptomatic patients, “interesting” data from an international early access program of 708 patients with mCRPC showed better outcomes for patients with bone-only asymptomatic disease than for those with symptomatic disease, 13 according to Dr. Morgans. This included overall survival (HR = 0.486), time to progression (HR = 0.722), and time to first symptomatic skeletal event (HR = 0.328). Significantly more patients also completed treatment. “We may want to move medications like Ra-223 into a setting where patients can get more cycles of therapy,” she commented.
“For the patient with bone-dominated disease, Ra-223 should always be considered,” Dr. Srinivas agreed. Reiterating her goal of delivering all effective treatments, she advised using Ra-223 before docetaxel. “Ra-223 is better tolerated than chemotherapy and gives a good outcome. If you use chemotherapy first and the patient’s disease progresses, you cannot guarantee it will progress with bone only. You could have lost that opportunity,” she pointed out.
The potential for either treatment to reduce bone marrow reserves makes it harder to give subsequent therapy, according to Dr. Armstrong. “You can’t assume you’ll be able to go to the next one and complete a full treatment course on time, at full dose. The hope is you could use treatment holidays in between to allow recovery…. But you have to be vigilant about treatment holds and reductions and follow blood counts carefully.”
In the COVID-19 era, treatment-related immunosuppression and exposure has grown in concern, especially for this often-elderly population, the experts agreed.
“We are fortunate to have options that allow a patient to choose the therapy that is right for him,” Dr. Morgans commented, emphasizing the importance of shared decision-making. “There are not always specific medical indications to guide our treatment. Patient preferences are critical, and if we don’t ask the patient, we won’t know what these are.”
Liquid biopsies are now often used to identify a range of molecular alterations in DNA, RNA, or protein that could predict treatment outcomes with novel therapies. Currently, DNA repair enzyme mutations in genes such as BRCA2 are linked to better outcomes with PARP inhibitors, and tumors that have high levels of microsatellite instability can respond dramatically to immune checkpoint blockade.
It is critical to identify these two subsets, Dr. Srinivas emphasized, commenting that she prefers to use olaparib or rucaparib before docetaxel, but the goal is “to give one irrespective of whether it’s pre- or postchemotherapy.”
Tumor or liquid biopsy molecular profiling can also reveal other genetic alterations, such as TP53 mutation, PTEN and RB1 loss, and CDK12 amplification, that can be informative as to acquired resistance and potential experimental treatments, Dr. Armstrong added.
“Unfortunately, most men with mCRPC do not have actionable mutations, either hereditary or tumor-specific. These men have a major unmet need for better treatment options, which are being explored in clinical trials. These range from PSMA-targeted therapies to immunotherapy combinations,” he said.
Many other specialty societies around the world have echoed this recommendation with the following statements14-23:
The rising incidence of mCRPC and the approval of new therapies in the past few years have translated into increased costs for individuals and societies. The relationship between outcomes and the cost of treatment, therefore, is an important area of research.
Ramaswamy et al, in 2020, performed a retrospective analysis on 3,174 chemotherapy-naive men in the Veterans Health Administration database and found resource utilization and monthly health-care costs per patient were approximately $1,000 lower with enzalutamide than abiraterone.24 This was true for all-cause total costs (medical and pharmacy) (P = .0002) and prostate cancer– related costs (P < .0001).
Two studies estimated the budget impact of Ra-223 in patients with mCRPC, finding no negative net impact on infusion centers and health plans. Hansen et al estimated the budget implications to infusion centers of adding Ra-223 as an option, finding an annual impact of only $600 to $6,000 (depending on adoption rate).25 From a U.S. payer perspective, Valderrama et al determined that adding Ra-223 to a health plan’s formulary minimally increased the plan’s per-member cost by only $0.02 per month.26
Recognizing that symptomatic skeletal events result in a higher cost of care, Dutch investigators evaluated the incidence of these events and the efficacy and safety of Ra-223 as compared to enzalutamide, abiraterone, and cabazitaxel, all used after docetaxel.27 Ra-223 resulted in costs that were €7,390 lower than enzalutamide and €6,092 lower than abiraterone (driven by lower drug costs and prevention of symptomatic skeletal events), as well as €4,465 lower than cabazitaxel (driven by lower medication and administrative costs and fewer adverse events). Quality-adjusted life-years with Ra-223 were slightly higher than with abiraterone and cabazitaxel but slightly lower than with enzalutamide. They calculated an approximately 60% chance that Ra-223 was the most cost-effective regimen.
These informative studies aside, a 2018 systematic review and cost analysis based on 38 eligible studies of mCRPC produced “a very heterogeneous picture regarding the value for money for different recommended chemotherapies, AR-targeting therapies, immunotherapeutic agents, and radionuclides.”28 Grochtdreis et al explained that unclear methodologies and risk of bias rendered uncertainty to the interpretation of these results. Randomized controlled trials are needed, they said, to fully determine cost-effectiveness and to prevent “unjustified health-care system costs.”
Certainly, for patients, financial toxicity remains a concern. “The out-of-pocket expenses are largely derived from the oral agents. For these, every month, the patient has a copay. This can be substantial and have a major impact on a patient’s resources,” Dr. Armstrong noted.
To this end, a number of specialty organizations have developed “value frameworks” for estimating and communicating relative treatment benefits. The current version of the NCCN Evidence Block™ for mCRPC shows that, for second-line therapy, Ra-223 has gained a “block” (meaning increased in value) while abiraterone has lost one.29 On the ESMO Magnitude of Clinical Benefit Scale, Ra-223 is rated highest in benefit and quality of life, with a score of 5 as compared to 4 for the AR-targeting agents and docetaxel.30
These rankings are important in showing that payers recognize the different levels of benefit in different lines of treatment—information they often cite in support of their policies. Clinical guidelines and payers are both beginning to challenge the sequenced use of novel antihormonal agents, the data suggest.
With the introduction of novel agents in advanced prostate cancer, the range of treatment options with notable benefits has widened. The armamentarium not only includes novel AR-targeting agents, chemotherapeutics, an immunotherapeutic, and a radionuclide, but also new agents targeting other oncogenic and genomic pathways—particularly inhibitors of PARP and PD-1.
At the same time, the optimal patient selection, development of resistant patterns, and therefore the effective sequential use of these agents remains uncertain. As stated in the NCCN Guidelines, “Evidence-based guidance on the sequencing of agents in either [the] pre- or post-docetaxel [setting] remains unavailable.”31
Meanwhile, quality of life during treatment is increasingly recognized as a pivotal component in cancer care, and this varies by regimen and according to patient experience. The patient’s underlying health, the patient’s preferences, treatment tolerability, treatment availability, and cost are part of the equation. Individualization of treatment remains key to optimizing outcomes for patients with mCRPC.
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