Although the advent of checkpoint blockade immunotherapies has inspired more excitement among oncologists than any other recent anticancer therapeutic development,

researchers and clinicians alike are wrestling with an array of questions concerning how best to translate this new modality into practice.

Despite the promising developments in this arena, many patients with cancer respond inadequately to immune checkpoint monotherapy, and others develop serious (grade 3-4) toxicities that require treatment cessation.

 Understanding the evidence and questions concerning dosing, treatment schedules, efficacy, and safety of immune checkpoint inhibitors as monotherapy and in combination regimens is essential to optimize their use in clinical practice.

Monoclonal antibodies that inhibit the CTLA-4 and PD-1/PD-L1 pathways significantly extend survival compared with conventional treatment in patients with targetable malignancies. The list of immune-responsive cancers now spans melanoma, non—small cell lung cancer (NSCLC), urothelial bladder cancer, head and neck squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, renal cell carcinoma (RCC), and tumors with high mutational loads in patients with germline mutations involving DNA mismatch repair, particularly colorectal cancer (CRC).

As of December 5, the FDA had approved 6 checkpoint inhibitors to treat 1 or more of these malignancies: ipilimumab (Yervoy), a CTLA-4 inhibitor; nivolumab (Opdivo) and pembrolizumab (Keytruda), both PD-1 inhibitors; and atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), all PD-L1 inhibitors.

Table. FDA Recommendations for Checkpoint Immunotherapies

Although these agents broadly share similar adverse event (AE) profiles, each has a unique dosing recommendation and schedule (Table

) Several experts discussed relevant questions concerning the administration of these agents in interviews with 

Historically, most monoclonal antibodies were dosed according to body weight because body size was thought to affect pharmacokinetics (PKs).

 Early studies of pembrolizumab used the same approach, but as more PK data became available, researchers revisited the need for weight-based dosing. Pembrolizumab, nivolumab, and atezolizumab are now approved at fixed doses for treating several tumor types.

Evidence supports fixed checkpoint inhibitor dosing. In one recent study, researchers combined PK data on pembrolizumab with response data for patients with advanced melanoma or NSCLC.

 Comparing individual areas under the exposure curve with exposure ranges from pembrolizumab doses in early trials, 2 mg/kg every 3 weeks (Q3W) and 10 mg/kg Q3W or every 2 weeks (Q2W) showed that a 200-mg fixed dose pharmacokinetically resembled weight-based dosing among patients with CRC, head and neck cancer, NSCLC, and urothelial cancer. Although patients weighing more than 90 kg had the lowest PK exposure, they still fell well within the range associated with near-maximum efficacy in prior studies.

Such findings make sense, according to Elizabeth Plimack, MD, MS, chief of genitourinary medical oncology and director of genitourinary clinical research at Fox Chase Cancer Center in Philadelphia. For inhibitors of the PD-1 pathway, “there’s no dose—response relationship,” she said. “We’re using much higher doses than are needed to saturate the receptors. An immune checkpoint inhibitor is training the immune system. The immune system has memory, and so we see that the durability of the antitumor effect continues after we stop treatment.”

Multiple studies’ findings have shown that dosing PD-1 agents above 1 mg/kg does not boost efficacy.

 In one systematic review and meta-analysis of data on patients with advanced melanoma or RCC, nivolumab doses of 2 or 10 mg/kg yielded similar objective response rates (ORRs) but significantly better progression-free survival (PFS) and overall survival (OS) than 0.3 mg/kg.13 Nivolumab is approved at 3 mg/kg or 240 mg, depending on the indication.

Patients who received pembrolizumab had similar outcomes at either 2 or 10 mg/kg.13 “[Past] a certain dose [of either agent], no further improvement was observed in patient outcomes,” the reviewers concluded. “Therefore, effective and minimum doses need to be determined so that patients can achieve maximum therapeutic benefit with minimum adverse effects.”

The AEs of immune checkpoint blockade result from inflammatory effects of T-cell disinhibition.

 The PD-1/PD-LI inhibitors show no dose—toxicity relationship, which means that dose reduction is not an appropriate way to manage AEs, said Plimack. If patients develop grade 3-4 immunerelated AEs, they should stop treatment and receive high doses of corticosteroids.

However, dose clearly affects both the efficacy and safety of the anti—CTLA-4 antibody ipilimumab.3,4,14 In a phase II dose-ranging study of patients with advanced melanoma, the ORR was highest among those who received 10 mg/kg ipilimumab (11.1%), intermediate at 3 mg/kg (4.2%), and lowest at 0.3 mg/kg (0%).14 The 10-mg/kg cohort experienced 21 grade 3-4 immune-related gastrointestinal AEs, while the 3-mg/kg group developed 3 such events and the 0.3-mg/kg had none.14

Phase III data also support dose—efficacy and dose–toxicity relationships for ipilimumab. In a trial of more than 700 patients with advanced melanoma, the median OS was 15.7 months in the 10-mg/kg ipilimumab cohort compared with 11.5 months in the 3 mg/kg group (HR, 0.84; 95% CI, 0.70 to 0.99).15 However, rates of serious treatment-related AEs, such as diarrhea and colitis, were 37% in the 10-mg/kg group and only 18% in the 3-mg/kg group.15 Immune-related gastrointestinal symptoms typically do not occur until nearly 6 weeks of ipilimumab therapy, when patients have received several doses.12 Only about 10% of treated patients develop grade 3-4 diarrhea at 3-mg/kg ipilimumab, but this AE been fatal fatal.12,16

Phase II data are sufficient to decide on clinical doses of checkpoint inhibitors, according to Plimack. She typically bases dosing on the FDA recommendations listed on the labels, but noted that the agency seems to be increasingly open to approving fixed doses of immune checkpoint inhibitors rather than requiring weight-based dosing.

“You waste less drug when you use fixed dosing, whereas with weight-based dosing, you have to waste a vial, so it saves not a trivial amount of money,” noted Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center and co-director of its melanoma program.

Schedule greatly affects ease of treatment, particularly in the maintenance or adjuvant setting, according to experts. “Schedule is more important than dose in terms of choice” of an immune checkpoint inhibitor, said Plimack. “It’s very inconvenient for patients to have to come every 2 weeks for treatment.”

Currently, pembrolizumab has a somewhat more convenient treatment schedule (Q3W) than nivolumab (Q2W),

 but that will change if the FDA approves a supplemental biologics license application to add a second dosing schedule for nivolumab (480 mg every 4 weeks [Q4W]).

The pendulum will keep swinging back and forth in favor of one or another anti—PD-1/anti– PD-L1 agent as manufacturers seek approvals for extended dosing schedules, said Weber. He and other experts are comfortable with dosing nivolumab Q4W in stable patients. “At induction, you want to see them more frequently, but for patients on maintenance or adjuvant nivolumab, you don’t need to see them as often,” Weber said. Although anti–PD-1 and anti–PD-L1 agents do not show dose-related toxicity, treatmentassociated AEs appear to take longer to resolve than AEs stemming from anti–CTLA-4 therapy.

Furthermore, the expanding population of patients on immune checkpoint inhibitors will include those with a higher risk of toxicities, heightening the need to educate patients about AEs and follow them closely, said Pavlos Msaouel, MD, PhD, chief fellow in hematology and oncology at The University of Texas MD Anderson Cancer Center. “If you are really concerned about toxicity, then you might want to start by seeing patients every 2 weeks to make sure the drug doesn’t stay in their system for too long without follow-up,” Msaouel said. “For most patients, follow-up every 3 to 4 weeks is fairly tolerable for this type of regimen, but there are always exceptions to that rule. For example, if patients have a history of autoimmune phenomena, I would be more suspicious of toxicities and would want more frequent follow-up.”

If a patient has very active, completely uncontrolled Crohn disease, or has psoriasis requiring a lot of immunosuppressive therapy, Msaouel tries to avoid immune checkpoint therapy entirely.

“But if a patient has a remote history of autoimmune disease that appears resolved or very well controlled, and that does not require immunosuppressive therapy, we would give an immune checkpoint inhibitor, but keep a closer eye on the patient.” That includes frequent visits regardless of approved dosing schedule, he said.

He added that patients tend to be far more accepting of frequent dosing early in treatment, but that twice-monthly treatment can become onerous over the longer term, such as during maintenance therapy. At MD Anderson, a trial of nivolumab and ipilimumab (NCT03274258) in patients with renal medullary carcinoma features a more spread-out dosing schedule for nivolumab (480 mg Q4W), he noted.

Longer dosing intervals also save money, a key consideration in the current healthcare climate. During a plenary session at the 2015 American Society of Clinical Oncology Annual Meeting, experts estimated that widespread use of immunotherapy drugs could cost the United States $174 billion annually, exceeding $1 million per patient, and that switching from a schedule of Q2W to Q3W would save payers thousands of dollars per patient per month.

Questions persist about optimal dose, schedule, and treatment strategies for checkpoint inhibition. For example, many patients with immune-sensitive cancers often do not respond to checkpoint inhibitor monotherapy. Thus, researchers are investigating whether combination regimens can increase the probability and quality of treatment response.

So far, efficacy results are relatively promising. Compared with ipilimumab monotherapy, reduceddose nivolumab (1 mg/kg) plus standard-dose ipilimumab (3 mg/kg) produced significantly higher rates of objective response, OS, and PFS in the phase II CheckMate 069 trial and the phase III CheckMate 067 trials of patients with previously untreated advanced melanoma.20,21 The FDA has approved the regimen at a dosing schedule of Q3W for 4 doses, followed by nivolumab at 240 mg once Q2W.

However, combining checkpoint inhibitors can increase the risk of serious immune-related AEs.18 In a 3-year update of CheckMate 067, ipilimumab plus reduced-dose nivolumab led to grade 3-4 AEs more than twice as frequently (59%) as monotherapy with either nivolumab (21%) or ipilimumab (28%).

Therefore, researchers are experimenting with lowering the anti—CTLA-4 dose instead of the anti–PD-1 dose. In a large multicenter phase Ib trial of patients with advanced melanoma (KEYNOTE-029), reduced-dose ipilimumab (1 mg/kg) plus standard-dose pembrolizumab (2 mg/kg) showed favorable safety compared with separate data on standard-dose ipilimumab plus reduced-dose nivolumab.24 Rates of grade 3-4 AEs were 45% at a median of 17 months of follow-up compared with 55% at 9 months of follow-up among patients who received standard-dose ipilimumab plus reduced-dose pembrolizumab in CheckMate 067.

“This result was expected, since the occurrence of side effects with ipilimumab monotherapy is known to be dose dependent,” wrote Michael A. Postow, MD, of Memorial Sloan Kettering Cancer Center, in an editorial accompanying the KEYNOTE-029 report.19

Although adding reduced-dose ipilimumab to pembrolizumab produced higher rates of AEs than are observed with pembrolizumab alone, the ORR of 61% also was nearly 3 times higher, he added. The KEYNOTE-029 regimen was associated with more toxicity than has been reported for either pembrolizumab or ipilimumab monotherapy, particularly with regard to hypothyroidism, hyperthyroidism, pneumonitis, hepatitis, and hypophysitis.24 But crucially, reducing the dose of ipilimumab appeared to reduce the risk of anti— CTLA-4-associated colitis and diarrhea, which have been fatal in rare cases.24,19

Nonetheless, the work is far from over. The fact that 2-year OS rates were generally similar between CheckMate 067 and KEYNOTE-029 “stresses the need to continue to refine and improve the combination of ipilimumab with anti— PD-1,” Postow wrote. “The first obvious step will be completion of ongoing randomized trials testing various doses and schedules of the combination of reduced-dose ipilimumab with standard-dose pembrolizumab,” he noted.

 Lessons from these trials should help inform trials of additional anti— PD-1 combinations, he said.

Reduced-dose ipilimumab plus standard-dose pembrolizumab is showing promise in other cancers besides melanoma. In September 2017, the phase III CheckMate 214 study was stopped early after nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) yielded superior OS compared with standard-of-care sunitinib (Sutent) in patients with treatment-naïve advanced or metastatic RCC.25 The findings also reinforced concerns about toxicity, however, since rates of treatment cessation for AEs were 24% with nivolumab-ipilimumab and 12% with sunitinib.26 Researchers also are experimenting with combining 2 lowered doses of checkpoint inhibitors. In an ongoing phase I/II trial (NCT02941744), they are testing low fixed doses of ipilimumab (50 mg) plus nivolumab (10 mg) as adjuvant therapy after resection of melanoma macrometastases. Safety findings are scheduled to be reported in 2018. Another study (NCT03233152) is evaluating a low fixed dose of nivolumab (40 mg/4 mL) in combination with intratumoral ipilimumab (50 mg/10 mL) after resection of recurrent glioblastoma.

Additional trials are examining various doses and schedules of other checkpoint inhibitor combinations, as well as combinations of checkpoint inhibitors plus other anticancer strategies such as vaccines, radiation, chemotherapy, IDO pathway inhibitors, cytokine-directed therapies, oncogenic pathway inhibitors, and T-cell therapies, among others.

Another question is how best to select doses and schedules for trials of new immune checkpoint inhibitors or new combinations. Early-phase studies usually evaluate objective antitumor activity, which can complicate the selection of doses and schedules for phase III trials that investigate a stricter OS endpoint.28 However, because agents such as nivolumab work by stimulating the immune system, the same dose might be appropriate across multiple tumor types.28

By incorporating clinical safety and efficacy data with analyses of relationships between dose and exposure response,28 one research team tested the hypothesis that nivolumab monotherapy is optimized at 3 mg/kg regardless of tumor type. Safety findings were similar at doses ranging from 0.1 to 10 mg/kg, regardless of tumor type. ORRs also were similar across doses in melanoma and RCC, but doses of 3 and 10 mg/kg yielded higher ORRs in NSCLC than doses of 1 mg/kg, even though peripheral receptors were saturated at dosesof 0.3 mg/kg and higher. The researchers emphasized the value of integrating dose-response and exposure-response data with efficacy and safety data in the immune-oncology setting.

In addition to dosing questions, the ideal scheduling of anti—PD-1 and anti–CTLA-4 antibodies remains unclear, experts have noted.

 For example, therapies that target PD-1/PD-L1 usually are administered continuously, despite a lack of robust evidence that ongoing treatment is necessary. In terms of duration of immunotherapy, Weber said: “I’d be hard pressed to believe that maintenance therapy lasting more than a year is really going to make a difference.” Hopefully, future studies will help clarify these questions.

Harris SJ, Brown J, Lopez J, Yap TA. Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol Med. 2016;13(2):171-193. doi: 10.20892/j.issn.2095-3941.2016.0015.

Tsirigotis P, Savani BN, Nagler A. Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies. Ann Med. 2016;48(6):428-439. doi: 10.1080/07853890.2016.1186827.

Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. Immunity. 2016;44(5):1069-1078. doi:10.1016/j.immuni.2016.04.023.

Fay AP, Moreira RB, Filho PRS, Albuquerque C, Barrios CH. The management of immune-related adverse events associated with immune checkpoint blockade. Expert Rev Qual Life Cancer Care. 2016;1(1):89-97. doi:10.1080/23809000.2016.1142827.

Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2017.

Keytruda [package insert]. Whitehouse Station, NJ: Merck Sharp Corp; 2017.

Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2017.

Tecentriq [package insert]. South San Francisco, CA: Genentech, Inc; 2017.

Bavencio [package insert]. Rockland, MA: EMD Serono, Inc; 2017.

Imfinzi [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

Freshwater T, Zondic A, Ahamadi M, et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer. 2017;5:43. doi: 10.1186/s40425-017-0242-5.

Postow MA, Callahan MK, Wolchok, JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974-1982. doi:10.1200/JCO.2014.59.4358.

Chen R, Peng PC, Wen B, et al. Anti-programmed cell death (PD)-1 immunotherapy for malignant tumor: a systematic review and meta-analysis. Transl Oncol. 2016;9(1):32-40. doi:10.1016/j.tranon.2015.11.010.

Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomized, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):1470-2045. doi:10.1016/S1470-2045(09)70334-1.

Ascierto PA, Vecchio MD, Robert C, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomized, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18(5):611-622. doi: 10.1016/S1470-2045(17)30231-0.

Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. doi:10.1056/NEJMoa1003466.

Andrews A. Treating with checkpoint inhibitors—figure $1 million per patients. Am Health Drug Benefits. 2015;8(spec issue):9.

Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD. Combination immunotherapy: a road map. J Immunother Cancer. 2017;5:16. doi: 10.1186/s40425-017-0218-5.

Postow M. Reduced-dose ipilimumab with standard-dose pembrolizumab: is less more? Lancet Oncol. 2017;18(9):1144-1145. doi:10.1016/S1470-2045(17)30518-1.

Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017. doi:10.1056/NEJMoa1414428.

Lartin J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival (OS) results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients with advanced melanoma (CheckMate 067). In: Proceedings from the 2017 Annual Meeting of the American Association Cancer Research; April 1-5, 2017; Washington, DC. Abstract CT075. cancerres.aacrjournals.org/content/77/13_Supplement/CT075.

Callahan MK, Kluger H, Postow MA, et al. Nivolumab plus ipilimumab in patients with advanced melanoma: updated survival, response, and safety data in phase I dose-escalation study. J Clin Oncol. 2017;JCO2017722850. doi: 10.1200/JCO.2017.72.2850.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356. doi: 10.1056/NEJMoa1709684.

Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 2017;18(9):1202-1210. doi:10.1016/S1470-2045(17)30428-X.

CheckMate-214 study evaluating Opdivo in combination with Yervoy stopped early for demonstrating overall survival benefits in patients with previously untreated advanced or metastatic renal cell carcinoma [news release]. Princeton, NJ: Bristol-Myers Squibb; September 7, 2017. news.bms.com/press-release/corporatefinancial-news/checkmate-214-study-evaluating-opdivo-combination-yervoy-stopp. Accessed November 11, 2017.

Escudier B. Tannir N, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab + ipilimumab v sunitinib (N+I) v sunitinib for treatment-naive advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5. doi: 10.1093/annonc/mdx440.029.

Chowdhury PS, Chamoto K, Honjo T. Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy [published ahead October 26, 2017]. J Intern Med. doi: 10.1111/joim.12708.

Agrawal S, Feng Y, Roy A, Kollia G, Lestini B. Nivolumab dose selection: challenges, opportunities and lessons learned for cancer immunotherapy. J Immunother Cancer. 2015;3(2):141. doi:10.1186/2051-1426-3-S2-P141.

Articles

Practical Questions on Checkpoint Agents Arise

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,

 with more than 26,700 deaths likely to occur in the United States this year.

 Additionally, the incidence of metastatic prostate cancer (mPC), which accounts for 3% of newly diagnosed cases, is rising.

These statistics reflect more than 7 decades of stagnancy in the treatment of newly diagnosed, hormone-naïve, metastatic disease, researchers say.

 Only a few years ago, these patients routinely received androgen-deprivation therapy (ADT) without chemotherapy, which oncologists reserved for ADT failure.

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.

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.

Prior to CHAARTED, researchers seeking to improve outcomes in mPC considered a 2- or 3-month survival benefit noteworthy.

 CHAARTED more than quadrupled that benchmark and spurred strong interest in using chemotherapy earlier, before mPC becomes castration resistant.

 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,

 a result that researchers have called “remarkable.”

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; 

 <.001), cut the chances of treatment failure by about 70% (HR, 0.30; 

 <.001), and approximately halved the likelihood of serious bone complications compared with ADT monotherapy in men newly diagnosed, locally advanced or mPC.

 In LATITUDE, adding abiraterone and prednisone to ADT lowered the risk of death by 38% (HR, 0.62; 

 <.001) and significantly improved progression-free survival (HR, 0.5; 

 <.001) compared with ADT only in men with metastatic castration-sensitive disease.

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.

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 

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.

 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.

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.

 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.

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.

 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.

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.

 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.”

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&mdash;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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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.

Amy Karon, MPH

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