In rapid succession, the SPARTAN study results were presented at the 2018 Genitourinary Cancers Symposium, the data were published in The New England Journal of Medicine,¹ and the drug apalutamide -(Erleada) was approved by the U.S. Food and Drug Administration (FDA) for men with previously treated local prostate cancer with rising prostate-specific antigen (PSA) levels despite castrate androgen levels. The drug was quite effective at lowering PSA—it is a potent antiandrogen. It also delayed the time to metastatic disease on imaging and the time to symptomatic metastatic disease. 

Some in the U.S. urology community seem convinced that life with a detectable PSA is not worth living—that something must be done about the PSA elevation. This position seems foolish. It makes more sense to evaluate prostate cancer treatments by the usual criteria—either they relieve symptoms, make life longer, or make life better. 

Men with PSA elevations and no detectable masses or metastases are by definition asymptomatic from prostate cancer, though they may suffer substantially from previously applied or current treatments aimed at the prostate cancer. Until they have symptoms directly produced by the cancer, treatments can only make them feel worse in the short term, not better. Indeed, apalutamide therapy is associated with more falls and fractures; causes hypothyroidism, rash, hypertension, and peripheral edema; and can markedly alter the metabolism of many drugs. 

Prostate cancer is heterogeneous in ways we are just beginning to discover. We should be cautious in applying treatments broadly to asymptomatic men.

— Steven E. Vogl, MD

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Apalutamide is clearly an effective antiandrogen in the treatment of prostate cancer. In the only published phase II trial I could find,² it reduced PSA levels by at least 50% in 89% of 51 men with nonmetastatic prostate cancer, 80% of whom had prior therapy with less potent antiandrogens like flutamide and bicalutamide. Phase II trials of apalutamide as a single agent or in combination regimens in other prostate cancer settings (eg, with androgen suppression for metastatic disease that has not been treated, such disease refractory to androgen suppression alone, or such disease refractory to androgen suppression plus or followed by abiraterone [Zytiga], enzalutamide [Xtandi], docetaxel, or all three agents) have not been published, though trials looking at the drug in some of these settings are planned or in progress. 

In the SPARTAN trial recently published,¹ in a population with a PSA doubling time ≤ 10 months (an indicator of more aggressive disease), apalutamide prolonged the median time to radiographically detectable metastasis from 16 to 41 months, the median time to PSA progression from 3.7 to about 40 months, and reduced symptomatic disease progression at 32 months from 38% to 19%. In the study population, 77% of patients had undergone prior prostatectomy or prostate irradiation, 97% had received prior gonadotropin-releasing hormone antagonist therapy, and 73% had been given a less potent antiandrogen. 

The FDA-approved package insert extends well beyond the study population of SPARTAN and approves apalutamide for a rising PSA, even if the doubling time is long. It remains unclear whether the FDA staff involved were aware they were granting marketing approval of apalutamide for a large population specifically excluded from entry into the SPARTAN trial (and with a much better prognosis than those allowed to enter the study). 

One can assume the manufacturer, wanting to expand its market, is pleased with this development. One hopes that eager urologists with frightened patients will not jump at the opportunity to treat better-risk men with slowly rising PSA levels with a very expensive and moderately toxic drug without evidence that it does any good in this population. 

Why Not Rush to Treat With Apalutamide?

Despite the improved progression-free survival, SPARTAN did not prove that apalutamide allowed men to live longer or better. Indeed, about 5% more had fractures and 18% more had rashes, so the apalutamide-treated men lived worse, not better, early on after randomization. There may prove to be an overall survival advantage of a few percent at 2 years, but about 80% of the placebo group is alive at 2 years, so the survival analysis is premature. Hopefully, the FDA will require the manufacturer to follow the subjects of SPARTAN for another 8 years to establish and report the existence and extent of a hoped-for survival advantage. 

Androgen Suppression Is of Questionable Value for Rising PSA Without Symptoms or Metastases 

While it is popular among urologists to suppress a rising PSA after prostatectomy, when isolated local recurrence is unlikely, or after definitive radiation, a randomized study showing a survival advantage is lacking. Androgen suppression is associated with weight gain, lack of energy, loss of libido and sexual potency, and osteoporosis. Again, these men do not immediately live better after androgen levels are suppressed. 

Small benefits in overall survival have been shown in multiple studies among patients with higher-risk prostate cancer, when androgen suppression has been added before, during, and after definitive radiation therapy to the prostate. Clearly, the androgen suppression here is treating occult metastatic disease and producing some benefit. To recommend early androgen suppression for asymptomatic patients with no detectable cancer on physical or radiographic exam requires the benefit would be sufficiently large to outweigh the immediate and prolonged toxicities. 

Isn’t the Delay in Metastases Enough?

The delay in distant metastasis is an impressive endpoint, especially since bone and computed tomography scans were done at entry and every 16 weeks. By 32 months, about 78% of placebo recipients had developed detectable metastases, though only about 34% had symptoms from metastatic disease by this point. I chose the 32-month point for comparison because of the limited numbers of subjects beyond it. Since many patients developed detectable metastases without having symptoms until much later, one could make a reasonable case for deferring more therapy. 

Isn’t the Delay in Symptomatic Progression Enough?

Early apalutamide therapy reduced symptomatic progression at 32 months from about 38% to 19%. This is clearly good, but it is not enough. Even castrate-resistant prostate cancer is sensitive to modern treatment. If we fail to demonstrate an impressive survival advantage for a toxic intervention when patients are asymptomatic, we really need to demonstrate that the early intervention gives them more good days than deferring it until symptoms develop. Generating such information is difficult but has been done many times in oncology settings. 

Symptomatic disease progression in SPARTAN is a complicated endpoint because men with asymptomatic radiographic progression almost certainly had their therapy changed immediately. This probably happened two or more times in some study subjects before any symptoms developed. Time to symptomatic disease progression, then, could be the sum of the time of benefit from apalutamide or placebo and whatever effective therapies were applied after first and successive radiographic and biochemical disease progressions. These therapies were not specified in the protocol and could have varied in the two arms based on local availability of drugs and money to pay for them. 

Order of Therapies Matters

Most oncologists in 2018 would feel uncomfortable if a man with metastatic prostate cancer died without prior androgen suppression, abiraterone or enzalutamide (and probably both), docetaxel and cabazitaxel (Jevtana), and perhaps radium-223 (Xofigo) for “bone-only” disease. However, the timing and order of these interventions have not been firmly established. 

Data are not available to determine whether apalutamide is a “stand-in” for enzalutamide, better, worse, or—more complicated—different! It is unlikely any hormonal manipulation will prove curative for metastatic prostate cancer, but it is likely that early application of apalutamide will make later application of apalutamide and enzalutamide less effective. Probably abiraterone, working by depriving the androgen receptor of its ligand, will also work less well. 

In giving early androgen suppression with or without apalutamide, we now need to be concerned that we are spoiling the chance for some patients to achieve a major benefit from giving docetaxel with initial androgen suppression. The issue of order of therapy and combined therapies is very complicated—that is why we need overall survival data to cut through the complications. 

Initial Androgen Suppression and Docetaxel Improved Survival 

The most impressive improvement in prostate cancer outcomes of the past 5 years is the vastly superior survival achieved by combining docetaxel with initial androgen suppression for metastatic prostate cancer. The CHAARTED investigators recently published the 54-month update of the first of these studies.³ The patient population in this study included a minority who had received prior local therapy for nonmetastatic disease. 

The overall survival benefit in CHAARTED was limited to those with high-volume metastatic disease, defined as either visceral metastases or more than three bone metastases with at least one outside the spine and pelvis. For these patients, median survival increased from 34 to 51 months by adding docetaxel to initial androgen suppression. Just under 20% of these men had earlier presented with local prostate cancer. For these 91 men, early docetaxel improved median survival from 52 months for androgen deprivation alone to 67 months for the combination. The benefit seems comparable to that seen for men whose initial presentation was with metastases (about 80% of CHAARTED subjects). Probably because of the small numbers, early docetaxel added to androgen suppression did not statistically improve overall survival among men with prior local treatment for prostate cancer. 

Leaving aside a discussion of the intriguing implications of the CHAARTED results, we need to be concerned that the early application of androgen suppression, with or without apalutamide, will later cause some patients to lose an enhanced benefit from docetaxel given early (15-month improvement in median survival for high-volume disease with prior local therapy) vs late (3-month improvement in median survival).⁴ The issue here is not the apalutamide, but the initial androgen suppression without docetaxel. 

It seems likely that high-volume metastatic prostate cancer is biologically different from non–high-volume disease. In CHAARTED, men with metastatic prostate cancer that was not high-volume did not have prolonged survival from early docetaxel.³ It seems likely that the presence of visceral or limb metastases is a surrogate for some characteristic of the cancer itself that makes early docetaxel advantageous. If one could identify men whose cancer harbors this key sensitizing trait (assuming it is just one and not some combination of traits), then one would be tempted to apply androgen suppression with docetaxel early only for these men. 

In other words, prostate cancer is heterogeneous in ways we are just beginning to discover. We should be cautious in applying treatments broadly to asymptomatic men, some of whom we may harm in the long run by giving treatments like docetaxel too late in their disease course. This caution should be overcome if the early application of a drug like apalutamide produces a large and durable improvement in overall survival. This has not yet been demonstrated.

Androgen Suppression Is Inexpensive, Apalutamide Is Not

Until a substantial overall survival benefit is demonstrated for androgen suppression plus apalutamide for men with high and rapidly rising PSA levels but no radiographically detectable metastases, a rational society would consider the cost. The estimated cost for apalutamide is $10,920 per month, or just over $131,000 per year.⁵ Median time to PSA progression on apalutamide is about 3 years in the SPARTAN trial. The median cost to society could be as high as $393,000 per patient if the therapy stops with a 50% rise in PSA level, or higher if it proceeds until radiographic progression. 

Although physicians should do the best they can for their patients, I believe society should refuse to pay such high prices unless major benefits have been demonstrated in the quality or duration of life. These benefits have not yet been shown for apalutamide in the care of men with rapidly rising PSA levels in the setting of androgen suppression. ■

DISCLOSURE: Dr. Vogl reported no conflicts of interest.

REFERENCES 

1. Smith MR, et al: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 378:1408-1418, 2018.

2. Smith MR, et al: Phase 2 study of the safety and antitumor activity of apalutamide (ARN-509), a potent androgen receptor antagonist, in the high-risk nonmetastatic castration-resistant prostate cancer cohort. Eur Urol 70:963-970, 2016.

3. Kyriakopoulos CE, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. J Clin Oncol 36:1080-1087, 2018.

4. Tannock I, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.

5. Reuters Health News: FDA approves J&J prostate cancer treatment. February 14, 2018.