New Standard in Metastatic Prostate Cancer Hits Prime Time

Nicholas J. Vogelzang, MD

Although there have improvements in the treatment of men with prostate cancer during the past 15 years, patients with advanced disease continue to pose a clinical challenge. Prostate cancer remains the third leading cause of cancer death among men,¹ with more than 26,700 deaths likely to occur in the United States this year.² Additionally, the incidence of metastatic prostate cancer (mPC), which accounts for 3% of newly diagnosed cases, is rising.³

These statistics reflect more than 7 decades of stagnancy in the treatment of newly diagnosed, hormone-naïve, metastatic disease, researchers say.^4,5 Only a few years ago, these patients routinely received androgen-deprivation therapy (ADT) without chemotherapy, which oncologists reserved for ADT failure.⁶

That picture started to change when the results of the CHAARTED (E3805) trial, first reported at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that adding docetaxel to ADT extended overall survival (OS) by a median of 13.6 months compared with ADT alone.⁷

That type of OS benefit had “never been seen in metastatic prostate cancer trials and is rarely seen in clinical trials for metastatic solid malignancies,” Voskoboynik and colleagues observed.⁸ Prior to CHAARTED, researchers seeking to improve outcomes in mPC considered a 2- or 3-month survival benefit noteworthy.⁹ CHAARTED more than quadrupled that benchmark and spurred strong interest in using chemotherapy earlier, before mPC becomes castration resistant.⁸ The multiarm STAMPEDE trial confirmed that dual therapy with docetaxel and ADT extended OS by 15 months compared with ADT alone in men with metastatic hormone-naïve (hormone-sensitive) prostate cancer,¹⁰ a result that researchers have called “remarkable.”¹¹

Now another set of clinical trial findings, reported at the 2017 ASCO Annual Meeting, is shaking up the treatment paradigm with the prospect of dramatic gains without chemotherapy in advanced disease settings (Table).

Table. Practice-Changing Research in Prostate Cancer Trials

Additional survival analyses from STAMPEDE and the results of the LATITUDE trial showed that ADT plus abiraterone acetate (Zytiga), a next-generation adrenal inhibitor, appeared to match or exceed the benefit of ADT plus docetaxel in the metastatic setting. In STAMPEDE, adding abiraterone and prednisolone to ADT lowered the risk of death by about 37% (HR, 0.63; P <.001), cut the chances of treatment failure by about 70% (HR, 0.30; P <.001), and approximately halved the likelihood of serious bone complications compared with ADT monotherapy in men newly diagnosed, locally advanced or mPC.¹² In LATITUDE, adding abiraterone and prednisone to ADT lowered the risk of death by 38% (HR, 0.62; P <.001) and significantly improved progression-free survival (HR, 0.5; P <.001) compared with ADT only in men with metastatic castration-sensitive disease.^4,13

But even definitive results from large welldesigned clinical trials do not necessarily transform practices quickly, easily, or uniformly. Physicians and patients might be slow to adopt new regimens and treatments for a variety of reasons, including discomfort with change, questions about trial design and generalizability, or concerns about costs, adherence, safety, or tolerability.¹⁴

A New, Earlier Standard of Care

Have the findings from CHAARTED, STAMPEDE, and LATITUDE changed practice? How might they do so in the future, and which questions and controversies remain? Several prostate cancer experts discussed these questions in interviews with OncologyLive^®.For newly diagnosed, hormone-naïve prostate cancer, the results of these 3 clinical trials truly are practice changing, experts said. Physicians who conventionally treated advanced prostate cancer with leuprolide or bicalutamide “are really beginning to see the light,” said Nicholas Vogelzang, MD, a medical oncologist at Comprehensive Cancer Centers of Nevada in Las Vegas. “They’re well on the path now to saying that these patients need input from medical oncology.”

Others agreed. “Earlier therapy with either docetaxel or abiraterone does represent the standard of care on the basis of the STAMPEDE and LATITUDE trials,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope in Duarte, California. That includes patients who are hormone experienced or who have undergone surgical castration, he said. “Virtually all patients with advanced prostate cancer with demonstrated metastatic disease will be candidates for either chemotherapy or abiraterone.”

Some debate persists about how much adding docetaxel or abiraterone to ADT will benefit patients with previously diagnosed prostate cancer that later metastasizes, said Robert Dreicer, MD, section chief of medical oncology and deputy director of the University of Virginia Cancer Center. “At this juncture, although I acknowledge the controversy, I currently manage all patients with newly appreciated metastatic disease in the same manner, by adding either docetaxel or abiraterone,” he said. The data from STAMPEDE, CHAARTED, and LATITUDE “are practice changing,” he concluded. “The addition of docetaxel or abiraterone to ADT is the standard of care in the management of newly appreciated patients with metastatic prostate cancer.”

The CHAARTED and STAMPEDE results on docetaxel have changed practice already in the United Kingdom. In a large-scale analysis of practice patterns, oncology referrals for newly diagnosed prostate cancer rose by 26% during the 5 months after STAMPEDE results were reported compared with the previous 5 months.¹⁵ Notably, referrals of docetaxel-eligible patients increased by nearly 60% and prescriptions of docetaxel jumped by 253%. In another survey of 111 urologic oncologists in the United Kingdom, 87% said STAMPEDE would affect how they treated hormone-sensitive metastatic and locally advanced high-risk prostate cancer.16 Nearly all (96%) of the oncologists said they would offer patients with high-volume metastatic disease docetaxel plus ADT, although fewer would do so for low-volume metastatic locally advanced or relapsed disease. Survey respondents cited many reasons for their responses, underscoring the complexity of these treatment decisions.¹⁶

Docetaxel: Still Relevant?

A lack of similar studies in the United States makes it difficult to assess the uptake of ADT plus docetaxel here, the experts said. “However, based on my clinical experience with patients referred in, I believe docetaxel has been widely adopted in practice settings and is being seen as the standard of care for patients deemed docetaxel candidates,” said Dreicer. “I believe that the recent LATITUDE and STAMPEDE trials will have a similar impact and will lead to broad adoption."Some experts said abiraterone might replace docetaxel in many cases. “It is likely that LATITUDE and STAMPEDE will change practice patterns right away,” said Pal. “It is unlikely that oncologists will remain tethered to docetaxel in the setting of patients with metastatic castrationsensitive disease.” He still discusses the option of docetaxel with his patients, but many of them “shy away” because of stigmas surrounding chemotherapy, he said. “Thus, I highly anticipate that abiraterone plus prenisolone will be the preferred choice of therapy.”

Patients also are justifiably concerned about fatigue, myelosuppression, infection, and neuropathy with docetaxel, according to Pal. In the larger study in the United Kingdom, 36% of docetaxel recipients with newly diagnosed mPC developed grade 3/4 neutropenias and 18% developed febrile neutropenia. Obtaining a complete blood count on day 7 of the first docetaxel cycle did not prevent febrile neutropenia, nearly 40% of patients required dose reductions, one-third delayed treatment, and 12% stopped docetaxel entirely.

But not all medical oncologists see a clear-cut choice between docetaxel and abiraterone. Some balk at abiraterone’s potential to cause hypertension and hepatitis, Vogelzang said. In STAMPEDE, during a median of 40 months of follow-up, abiraterone was associated with a 6% rate of grade 3 or higher alanine aminotransferase (ALT) increases, and with a 5% rate of grade 3 or higher hypertension compared with rates of 1% or less among patients who received ADT only.¹⁷ In LATITUDE, abiraterone was tied to a 2-fold rise in the risk of grade 3 hypertension (20% over 30.4 months of follow-up versus 10% for placebo) and to an increased rate of grade 3 or higher increases in aspartate aminotransferase and ALT.¹³

Abiraterone requires much longer-term treatment than docetaxel, which increases its cumulative risk of adverse events, Pal noted. “It is important to keep in mind that 6 cycles [of docetaxel] are administered and then the patient is effectively done with chemotherapy until they develop castration-resistant disease,” he said. “On the other hand, with abiraterone, the therapy is maintained indefinitely or until progression is observed. With this in mind, the patient exposes himself to a milder but a longer duration of toxicity.

“The earlier use of abiraterone clearly has shown a survival benefit with a similar magnitude that we see with docetaxel in this setting,” said Daniel P. Petrylak, MD, whose research helped establish a role for docetaxel in the treatment of patients with advanced prostate cancer. “The real issue is, which do you select and should the patient receive 2 years of abiraterone or 6 cycles of docetaxel? There are pros and cons to both; this gives physicians another option to use in these patients.”

“There are situations where it may be preferable to give docetaxel over abiraterone or vice versa,” said Petrylak, who is a professor of medicine and co-director of the Signal Transduction Research Program at Yale Cancer Center. “So if somebody wants to get their treatment over with in 6 cycles, 18 weeks, rather than taking 2 years of abiraterone, they would get docetaxel in that situation. Conversely, if someone has neuropathy or just can’t tolerate chemotherapy, abiraterone is a reasonable alternative. Remember, too, that you can see liver function abnormality and fluid retention with abiraterone, so it may not be appropriate to give that drug to that type of patient.”

In some cases, cost may tip the scales against abiraterone, which has been estimated at $115,000 a year.¹⁸ A generic version has been delayed by a patent dispute, and for now, “it is an expensive endeavor,” Pal noted. One patient recently paid $2800 a month for abiraterone after his insurance company denied coverage, Vogelzang recalled.

“For my guys on a fixed income, that’s not feasible,” he said. “For patients with hormone-sensitive metastatic prostate cancer, insurance companies may say it’s a lot cheaper from their perspective to give docetaxel instead of abiraterone.”

Medicare Part B also typically approves coverage for intravenous docetaxel but not for oral abiraterone, he noted. “It creates a dilemma, and it’s nuanced, depending on the indications for the patient.”

Only head-to-head trials can definitively compare the superiority and risks of adding docetaxel versus abiraterone to ADT for newly diagnosed, hormone-sensitive mPC, said the experts.

“I believe there will be continued use of docetaxel in some patients, with others and perhaps most patients receiving abiraterone,” said Dreicer.

Abiraterone for Nonmetastatic Disease

Would triple therapy with docetaxel, abiraterone, and ADT improve survival more than dual therapy with either regimen? The PEACE1 trial in Europe (NCT01957436) is attempting to answer this question. Surpassing the marked benefits of the dual therapy regimens will not be easy, Pal said. When patients with newly diagnosed hormone-sensitive mPC have multiple predictors of poor outcomes, Vogelzang will consider docetaxel and abiraterone in addition to a luteinizing hormone-releasing hormone agonist—either leuprolide or goserelin, he said. “I’ve seen a small increase in liver enzymes, but nothing worth worrying about.”Some oncologists also consider abiraterone in combination with radiation therapy for men with earlier-stage nonmetastatic disease.¹⁹ In STAMPEDE, about 26% of patients had newly diagnosed, node-negative prostate cancer; another 20% had newly diagnosed, node-positive, nonmetastatic disease; and about half of patients had newly diagnosed mPC.

Confidence intervals for estimates of OS crossed 1.0 among patients with nonmetastatic disease (HR, 0.75; 95% CI, 0.48-1.18), but not among patients with node-negative disease (HR, 0.69; 95% CI, 0.49-0.96). That makes it difficult to know whether or when to use abiraterone outside the setting of mPC, the experts said. “This is something I struggle with every day in my practice,” said Vogelzang. “When someone has a PSA of 3000 with painful bone metastases, that’s simple. I give them everything— Lupron [leuprolide], abiraterone, and docetaxel. But it’s not as obvious with lower-risk patients.”

For patients with probable nodal involvement, Vogelzang is comfortable prescribing either abiraterone or docetaxel based on the characteristics of STAMPEDE and CHAARTED participants, he said. “I firmly believe in the STAMPEDE paradigm,” he added. “If it’s good enough for widespread metastatic disease, it should be good enough for oligometastatic or limited metastatic disease. If I was going to prescribe Lupron and bicalutamide, I would do Lupron and abiraterone.”

Dreicer also said he would consider abiraterone in nonmetastatic settings, but only “in highly selected, high-risk patients; that is, node-positive patients with a detectable PSA post prostatectomy.” In contrast, Pal would not consider abiraterone in the setting of nonmetastatic disease. “Although there was some emphasis on this in the presentation of the STAMPEDE trial, it is important to bear in mind that the confidence interval around the benefit from abiraterone in this setting crossed 1.0, implying that at this point in time, abiraterone does not quite meet the mark for nonmetastatic patients,” he said. “It is possible that this may change with further follow-up.”

Future Research

Petrylak said survival data are not yet mature to recommend earlier use of abiraterone for patients with nonmetastatic disease, although he noted that the STAMPEDE researchers feel the evidence supports it. “Without the survival benefit, I think what you really need is an informed discussion with your patient as to whether you’re going to give them these drugs or not,” he said. “If this is someone who is young, has aggressive disease right off the bat—an example would be a patient with lymph node-positive prostate cancer, maybe 47 years old, and their PSA is going up a month after they’ve had their prostate out—that’s someone I would use the earlier treatment with. I think what we really need to do is to wait for the survival data to come back and see if it’s reasonable to do this.”The CHAARTED, STAMPEDE, and LATITUDE trials not only are changing practice, but also have spurred more randomized controlled trials of investigational treatments or new combination regimens for mPC, both in the hormone-naïve and castration-resistant settings. “A host of phase III studies are either underway or completed but not yet reported that build upon some of the data we have now,” said Dreicer.

For example, an ongoing phase II trial is evaluating the novel androgen receptor (AR) inhibitor enzalutamide (Xtandi) in men with high-risk prostate cancer who have undergone radical prostatectomy (NCT01927627). In another phase II study, researchers are exploring whether lowering the dose of enzalutamide improves fatigue and adverse cognitive effects while maintaining active drug levels (NCT03124615). Apalutamide (ARN509), an investigational nonsteroidal antiandrogen agent, is also in early-phase trials in subgroups such as men with metastatic castration-resistant prostate cancer and those who have undergone radical prostatectomy. Patients who cannot tolerate abiraterone might fare better with these newer agents, Vogelzang said.

Pal said that he is eagerly awaiting the results of the phase III Southwest Oncology Group trial 1216, which is comparing ADT plus bicalutamide with ADT plus orteronel (TAK-700), a nonsteroidal CYP17A1 inhibitor, in men with mPC (NCT01809691). “It is possible that this trial may also be practice-changing,” he said. Other researchers are investigating whether adding the next-generation oral AR-targeting agent darolutamide (ODM-201) to ADT and docetaxel improves outcomes in patients with M1 prostate cancer in the ARASENS trial (NCT02799602).

“Trials such as this are critical,” said Pal. “It is important to acknowledge that although outcomes have improved for metastatic castration sensitive prostate cancer, it still remains an incurable disease.”

Similarly, Petrylak noted, “you’re not preventing castration-resistant disease with these drugs, you’re not curing anyone. I think that what you’re doing is improving survival, delaying progression, delaying pain with these earlier agents. It’s a multitude of different factors that are being positive with these trials. We don’t have a cure yet. We have the control.”

For exactly this reason, “we need to go harder for bigger gains,” said Vogelzang. “I don’t believe in incrementalism. I think a trial of leuprolide and abiraterone with or without docetaxel is incrementalism. It would take a lot of patients to show a little bit of benefit.” Instead, a trial might target bone metastases by adding radium-23 (Xofigo) to a backbone regimen of leuprolide, abiraterone, and docetaxel, he said. “For selected patients, I already do that. I wait until the patient is done with docetaxel and then I consolidate with radium. But this needs prospective study.”

BRCA mutations also need more therapeutic research in the metastatic setting, the experts commented. Only a few such trials are planned or underway. But “if 20% of all metastatic prostate cancer patients have DNA repair enzyme deficiencies, shouldn’t we be identifying them and [considering] double-stranded DNA-damaging agents like PARP inhibitors?” Vogelzang asked. “These are some of the burning questions I think would advance the field, but the trials will be big, expensive, and will take a long time. Bottom line, we should assume we’ve got benefit from leuprolide, docetaxel, and abiraterone and add on that. Our goal should be to eradicate the disease.”

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