Cover Story

Success of abiraterone trials prompts ‘mind shift’ in prostate cancer treatment

Abiraterone acetate is poised to challenge docetaxel as the standard addition to androgen deprivation therapy for treatment of newly diagnosed, metastatic castration-resistant prostate cancer.

The LATITUDE and STAMPEDE trials — results of which were presented at this year’s ASCO Annual Meeting and subsequently published in The New England Journal of Medicine — showed the addition of abiraterone acetate (Zytiga, Janssen) and prednisone to ADT reduced risk for death by nearly 40%.

There also is a safety benefit.

Docetaxel — an IV chemotherapy — can cause nausea, constipation, diarrhea, neutropenia or fatigue during its 18-week dosing schedule. Abiraterone, an oral adrenal inhibitor traditionally used in later-line therapy, is administered until disease progression and has relatively few side effects.

“These two trials have created a mind shift. Instead of waiting for hormonal therapy to fail and then give abiraterone, we should probably give it upfront to patients starting hormonal therapy for the first time,” Emmanuel S. Antonarakis, MD, associate professor of oncology at Johns Hopkins School of Medicine, told HemOnc Today. “There are now two standards of therapy, the other being chemohormonal therapy.”

Although abiraterone conferred unprecedented survival benefits and is better tolerated, not all oncologists agree it should replace docetaxel in the absence of a head-to-head comparative trial. Some point to abiraterone’s much higher price. Others wonder whether combining abiraterone and docetaxel with ADT would further prolong survival.

HemOnc Today asked urologic oncologists and researchers about the promise of abiraterone; the potential impact of its long-term use; if its cost in comparison with docetaxel is prohibitive; and whether abiraterone soon will be challenged by other therapies for the treatment of metastatic hormone-resistant prostate cancer.

‘Spectacular’ results

Docetaxel became the standard of care in this patient population following results from the CHAARTED study, published in 2015 in The New England Journal of Medicine. The results, based on median follow-up of 28.9 months, showed docetaxel improved median OS from 44 months to 57.6 months.

Abiraterone typically has been reserved as second-line therapy for men resistant to ADT. The LATITUDE and STAMPEDE trials — both supported by Janssen, the manufacturer of abiraterone — evaluated whether abiraterone would be more beneficial if used earlier.

In both studies, men received 1,000 mg abiraterone daily to reduce the production of testosterone and other androgens from the adrenal glands, the testes and the prostate tumor by targeting the protein CYP17A1. Patients also received low-dose prednisone (5 mg) to replace a decrease in glucocorticoid, a stress hormone that helps transform glucose and fat into energy.

The LATITUDE trial included 1,199 men with newly diagnosed metastatic prostate cancer who had at least two of three other factors associated with a poor outcome: a Gleason score of 8 or higher; a minimum of three metastatic bone lesions; or measurable metastases in visceral organs, such as the liver.

Maha Hussain, MD, FACP, FASCO
Maha Hussain

“I am delighted to see the results of LATITUDE and the fact that it preselected a higher-risk metastatic disease population; stratifying for risk is critical to better personalize therapy,” Maha Hussain, MD, FACP, FASCO, associate director for clinical sciences research at Robert H. Lurie Comprehensive Cancer Center of Northwestern University and a HemOnc Today Editorial Board Member, told HemOnc Today. “Based on LATITUDE and CHAARTED, the findings demonstrate that it’s the high-risk, high-volume patients who seem to benefit from treatment that maximizes systemic therapy.”

Karim Fizazi, MD, PhD, chief of the department of cancer medicine at Gustave Roussy in Villejuif, France, presented results from the LATITUDE study at ASCO. At median follow-up of 30 months, the addition of abiraterone and prednisolone to ADT doubled median time to progression compared with ADT plus placebo, from 14.8 months to 33 months. Further, a greater proportion of men assigned the combination achieved 3-year OS (83% vs. 76%).

More men treated with abiraterone than ADT alone experienced high blood pressure (20% vs. 10%), low potassium level (10.4% vs. 1.3%) or liver enzyme abnormalities (5.5% vs. 1.3%).

“Abiraterone did exactly what we wanted it to do,” Fizazi said during his presentation. “Most men did not complain about any specific side effects from the drug. We need to be cautious when using abiraterone in men who have an increased risk for heart problems, such as those with diabetes, and we have to monitor hypertension.”

The ongoing STAMPEDE trial began in 2005 in the United Kingdom. Nicholas James, MBBS, PhD, professor of clinical oncology at Queen Elizabeth Hospital Birmingham, and colleagues assigned 1,917 men to abiraterone plus ADT or ADT alone. Unlike the LATITUDE trial, only half of the men in the STAMPEDE trial had metastatic disease.

STAMPEDE uses a multiarm, multistage platform design to test different first-line therapies.

At a median follow-up of 40 months, men who received abiraterone plus ADT demonstrated a 54% reduction in symptomatic bone complications. Median OS was not reached in the combination arm and was 34.7 months in the ADT-alone arm.

“The results, I have to say, are spectacular,” James said following his presentation. “We think this is possibly one of the biggest survival advantages ever recorded in a common adult tumor. ... The take-home message, particularly when you compare it with the LATITUDE trial, which produced almost identical results, is paradigm-shifting for prostate cancer — reimbursement being the main issue.”

‘Obscenely expensive’

The retail cost of abiraterone — estimated at $8,000 to $9,000 per month before discounts or rebates — creates a quandary for oncologists, especially because men who show no signs of disease progression could be on treatment for 2 or 3 years.

By comparison, docetaxel carries a price tag of about $32,000 for a six-dose cycle.

Still, the higher toxicity profile of docetaxel factors into costs. Following his ASCO presentation, James said abiraterone’s low toxicity profile could help reduce the costs of skeletal-related events associated with chemotherapy.

“The upside of abiraterone is that it is not very toxic compared with most of the agents we use to treat cancer,” Ian Tannock, MD, PhD, DSc, a retired professor who spent 35 years practicing at Princess Margaret Cancer Centre in Toronto, told HemOnc Today. “The downside is it is obscenely expensive and the drug companies are holding patients to ransom. The cost of making abiraterone is probably about the cost of making aspirin. It costs virtually nothing to make and yet they sell it at these unbelievable prices.”

In a statement to HemOnc Today, Janssen said it responsibly prices its products and is committed to ensuring patients have broad access to its medicines.

“When pricing our medicines, we consider the value they provide to patients and society, the need to ensure they are affordable and accessible, and the need to sustain our capacity to develop new medicines,” the statement read.

The availability of a generic version of abiraterone would greatly reduce costs. That, however, appears unlikely.

The FDA approved abiraterone for the treatment of metastatic, castration-resistant prostate cancer in April 2011. The agent’s “composition of matter” patent expired on Dec. 13, 2016.

However, in 2014, the United States Patent and Trademark Office (PTO) granted Janssen a “method of treatment” patent that protects the specific administration of abiraterone combined with prednisone, allowing Janssen to prevent generic versions of abiraterone worldwide until Aug. 24, 2027.

Companies have filed abbreviated new drug applications with the FDA seeking approval to market generic versions of abiraterone in the United States before the patent expires.

“We can’t speculate when the PTO will render a decision/ruling,” Janssen said in a statement to HemOnc Today. “We believe that [the patent] is valid and will vigorously defend the patent in any IPR proceedings.”

The 30-month stay for such lawsuits filed before April 2016 expires in October 2018. However, the ultimate length would be subject to the outcome of any district court litigation decision.

If Janssen loses the patent case and files an appeal, it could delay a generic brand of abiraterone from hitting the open market until early 2020. If it wins the case, its patent is likely to be retained until 2027.

“If abiraterone becomes generic, the cost will probably be equivalent or lower than six doses of docetaxel,” Antonarakis said. “If it does not become generic, it will probably be five to 10 times more expensive.”

That is significant, Hussain said, because of the duration men may remain on abiraterone.

“Abiraterone doesn’t have the acute side effects of chemotherapy, but it does have its own side effects — impacting cardiovascular issues and hypertension — and this is not a finite duration of treatment,” Hussain said. “It is taken until disease progression, which could be 3 or 4 years. That is when you get into the financial toxicities — including patients’ out-of-pocket costs.”

Although it is recommended that abiraterone be taken on an empty stomach, Szmulewitz and colleagues presented data from a randomized phase 2 clinical trial at this year’s Genitourinary Cancers Symposium showing that taking a quarter dose of abiraterone with a low-fat breakfast appeared noninferior to taking a standard dose in a fasting state.

Treatment cost will be a concern even if a generic version of abiraterone becomes available, according to Neeraj Agarwal, MD.
Treatment cost will be a concern even if a generic version of abiraterone becomes available, according to Neeraj Agarwal, MD. “If the copay remains $200 or $300 or $500 a month, the absolute price of the drug doesn’t matter to the patient who cannot afford it,” he said.

Photo by Jonathan Martinez, visual communication specialist, Huntsman Cancer Institute.

The two doses had an identical median time to progression of 14 months, although the lower dose could save an estimated $6,500 a month.

“Even if abiraterone becomes generic, it won’t become free,” Neeraj Agarwal, MD, director of the genitourinary medical oncology program at University of Utah Huntsman Cancer Institute, told HemOnc Today. “If the copay remains $200 or $300 or $500 a month, the absolute price of the drug doesn’t matter to the patient who cannot afford it.”

Abiraterone vs. docetaxel

Cost aside, oncologists agree specific indications should be considered when deciding between abiraterone and docetaxel.

“Both docetaxel and abiraterone have been established in individual trials, but they have not been compared with each other,” Agarwal said. “That’s why it is challenging for us. Which should we pick?”

The STAMPEDE trial, which has accrued more than 9,000 men, could help answer that question. Results from study arms comparing abiraterone and docetaxel are scheduled for presentation at the European Society for Medical Oncology Congress this month.

Although STAMPEDE trial results presented at ASCO showed the survival benefit of abiraterone appeared similar for men with and without metastatic disease, the use of abiraterone for men with low-volume prostate cancer is “highly debated” worldwide, Fizazi said.

However, Sumanta K. Pal, MD, associate professor of medical oncology at City of Hope and a HemOnc Today Editorial Board Member, said further study is needed to determine if abiraterone is appropriate for men with nonmetastatic disease, who may be able to receive more definitive therapies such as radiation.

“The confidence interval for abiraterone straddles 1 and that, to me, suggests that we haven’t completely defined the benefit of abiraterone in the [nonmetastatic] population,” Pal said at the time of the presentation.

Agarwal said he uses chemotherapy more often when a patient has visceral metastases.

“If somebody has liver metastases or any metastases outside of the bone and lymph node, I tend to use docetaxel,” he said. “If I don’t see visceral metastases, then I tend to go with abiraterone and prednisone.”

Patient profiles also are a consideration, Antonarakis said. If a patient is fit for chemotherapy, he may prefer it for 18 weeks rather than taking a pill for 2 or 3 years.

“Abiraterone is a whole new paradigm because your patient is not coming in for an infusion every few weeks for six cycles,” David M. Nanus, MD, professor of medicine and urology at Weill Cornell Medicine, told HemOnc Today. “With six cycles of docetaxel, patients are often wiped out by the time they’re done, and it might take a few months to recover afterward.”

The general rule when deciding between docetaxel and abiraterone is to consider the volume of disease and the overall health of the patient, Tannock said.

“The question I have is, should we be using both?” he added.

PEACE1, a phase 3 study, is recruiting participants to compare the clinical benefit of ADT with or without docetaxel, abiraterone, prednisone and radiotherapy. The intrigue of a docetaxel-abiraterone combination is tempered by concerns about the safety and efficacy of such a potent combination of therapy and its potential long-term effects.

“I am absolutely excited about PEACE1 and [data on] docetaxel with abiraterone,” Hussain said. “However, we also have to be careful about tolerability. Sometimes more may not be better, hence the need for testing in prospective trials to demonstrate feasibility and value to patients’ terms of quality and quantity of life.”

Cost, again, is a concern.

“Although they are, hopefully, efficacious together, they also come with a higher price tag and a much bigger bag of toxicities,” Agarwal said. “The key is not to treat everybody with more and more drugs. The result may be no quality of life left for a large number of patients who may not need this aggressive therapy upfront.”

Other treatment options

In addition to the enthusiasm surrounding abiraterone and its potential to be the new standard of care in the treatment of metastatic, castration-resistant prostate cancer, several ongoing clinical trials are investigating other strategies to reduce androgen exposure.

Results of those trials also could be practice changing, and again raise questions about the standard of care.

A pair of studies scheduled for completion in 2020 — ENZAMET and ARCHES — are evaluating enzalutamide (Xtandi; Astellas, Medivation) with ADT.

The TITAN trial, also scheduled for completion in 2020, is designed to assess apalutamide (ARN-509, Aragon Pharmaceuticals) with ADT.

The ARASENS trial will evaluate darolutamide (ODM-201/BAY-1841788, Bayer) with ADT and docetaxel. Trial completion is expected in 2022.

Orteronel (TAK-700, Takeda/Millennium) also is being evaluated with ADT. Like abiraterone, orteronel is an androgen synthesis enzyme blocker, but it is less likely to inhibit the production of cortisol and did not require concomitant therapy with prednisone in a large NCI-sponsored phase 3 SWOG trial in metastatic hormone-sensitive prostate cancer, which recently completed accrual of more than 1,300 patients.

“That’s a huge advantage,” said Agarwal, study chair of the phase 3 SWOG study. “Oncologists and urologists are concerned about using prednisone for so long in patients expected to live for 3 to 5 years. Even at 5 mg daily, prednisone has the potential to cause osteoporosis, and there are data suggesting that glucocorticoid receptor stimulation may lead to prostate cancer progression.”

There also is a growing interest in the potential of PD-1 immunotherapies and PARP inhibitors for the treatment of prostate cancer.

“The new frontier will be to explore other classes of therapy altogether and, in my opinion, those are the two that have generated, by far, the most excitement in the prostate cancer space in the last 2 years,” Antonarakis said. “There’s no question that the LATITUDE and STAMPEDE trials were practice changing, but they were not really conceptually or scientifically novel concepts.

“Many of us expected they would improve survival and it’s important that this proof came, but now we need to move beyond that,” Antonarakis added. “PD-1 immunotherapy and PARP inhibitors caused a lot of buzz at the ASCO meeting this summer.”

The prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20% to 25%, according to a review by Antonarakis and Benjamin A. Teply, MD, published in Expert Review of Clinical Pharmacology.

Identification of these underlying repair defects may present unique treatment opportunities with PARP inhibitors, including olaparib (Lynparza, AstraZeneca), which received FDA breakthrough designation status for the treatment of hormone-resistant disease in men with BRCA1, BRCA2 or ATM mutations. The agent — the first FDA-approved PARP inhibitor — is indicated for patients with BRCA-mutated ovarian cancer.

Mateo and colleagues evaluated 400 mg olaparib in 50 patients with metastatic castration-resistant prostate cancer. All previously received docetaxel, and 98% had received abiraterone or enzalutamide. Results, published in The New England Journal of Medicine, showed 11 of 49 evaluable patients had a 50% or greater PSA decline with olaparib.

Researchers then tested patients for genes related to homologous recombination repair, including BRCA1, BRCA2, ATM, PALB2, CHEK2 and FANCA. Ten of the patients who demonstrated PSA response had tumors with homologous recombination deficiency as defined by a deleterious mutation in one of those genes.

Further, 88% of the 16 patients on the trial with homologous recombination deficiency responded to treatment.

“For about 80% of men with prostate cancer — those without these mutations — PARP inhibitors won’t work,” Antonarakis said. “But when they work in patients with the right mutations, the responses can be dramatic and long lasting.”

A randomized phase 3 trial is comparing olaparib with abiraterone or enzalutamide for treatment of men with metastatic castration-resistant prostate cancer who harbor germline or somatic mutations in BRCA1, BRCA2 or ATM.

Other PARP inhibitors undergoing evaluation in phase 2 or phase 3 trials in hormone-resistant prostate cancer include rucaparib (Rubraca, Clovis), approved for the treatment of ovarian cancer; niraparib (Zejula, Tesaro), approved for women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer; and talazoparib (BMN 673, Pfizer).

New targets, biomarkers

As the genetic landscape of metastatic prostate cancer is further defined, additional targeted agents may become available for the population.

According to a study presented by Sonpavde and colleagues at this year’s Genitourinary Cancers Symposium, a liquid biopsy test identified at least one change in circulating tumor DNA in 94% of men with metastatic, castration-resistant prostate cancer. Higher numbers of changes, including changes to the androgen receptor gene, appeared associated with shorter time to failure (HR = 1.42) and poorer survival (HR = 2.51).

The most common recurrent somatic mutations were in TP53 (36% of patients); androgen receptor (22%); APC (10%); NF1 (9%); EGFR, CTNNB1 and ARID1A (6% each); and BRCA1, BRCA2 and PIK3CA (5% each). The most common genes with increased copy numbers included androgen receptor (30%), MYC (20%) and BRAF (18%).

Quick identification of these genes through a liquid biopsy has potential to inform treatment decisions and allow clinicians to make adjustments faster.

“Circulating-tumor DNA offers a simple and convenient way to assess an individual’s tumor DNA and composition and, often, it can reveal new mutations that clinicians can use to personalize therapy,” Pal, who was not involved with the study, said during a press conference at the meeting. “For example, BRAF is typically associated with melanoma, and there are approved drugs that are used in melanoma that can target this mutation. Perhaps there might be some relevance for these agents in certain types of prostate cancer that bear these same mutations.”

Molecular subtyping also could be used to predict which patients are most likely to respond to ADT.

A study by Zhao and colleagues, published this year in JAMA Oncology, showed the identification of prostate cancer subtypes based on luminal and basal lineage may help guide use of ADT. Men with luminal B prostate tumors responded better to postoperative ADT than men with nonluminal B tumors.

“There are no prospectively validated biomarkers in clinical use right now, but I anticipate [there will be],” Agarwal said. “We’ll likely see five or six of these drugs approved in the next 2 to 5 years.

“Many patients may not need any of these newer drugs because their median survival is going to be in the range of 7 to 8 years with standard ADT alone, per data from SWOG 9346 trial,” Agarwal added. “On the other side, some patients are really going to need these newer drugs, and the key is to find the biomarkers to select these patients to achieve an ideal balance of cost effectiveness, toxicities and efficacy.”

Based on the findings of the LATITUDE and STAMPEDE trials and the potential of targeted therapy, oncologists with whom HemOnc Today spoke agreed researchers are on the precipice of significantly extending the lives of men with prostate cancer.

“Having more choices moving forward with a multitargeted anticancer strategy is going to be critical,” Hussain said. “At the end of the day, this is a smart cancer and it adapts. If we can prevent this disease from progression and getting to its deadliest phase, it would be a huge accomplishment.” – by Chuck Gormley

Click here to read the POINTCOUNTER, “Should oncologists recommend hormone therapy plus abiraterone for patients with nonmetastatic prostate cancer?”

References:

Fizazi K, et al. N Eng J Med. 2017;doi:10.1056/NEJMoa1704174.

James N, et al. N Eng J Med. 2017;doi:10.1056NEJMoa1702900.

James N, et al. Lancet. 2016;doi:10.1016.S0140-6736(15)01037-5.

Mateo J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1506859.

Sonpavde G, et al. Abstract 149. Presented at: Genitourinary Cancers Symposium; Feb. 16-18, 2017; Orlando, Fla.

Sweeney CJ, et al. N Eng J Med. 2015;doi:10.1056/NEJMoa1503747.

Szmulewitz RZ, et al. Abstract 176. Presented at: Genitourinary Cancers Symposium; Feb. 16-18, 2017; Orlando, Fla.

Teply BA and Antonarakis ES. Expert Rev Clin Pharmacol. 2017;doi:10.1080/17512433.2017.1338138.

Zhao SG, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2017.0751.

For more information:

Neeraj Agarwal, MD, can be reached at neeraj.agarwal@hci.utah.edu.

Emmanuel S. Antonarakis, MD, can be reached at eantona1@jhmi.edu.

Maha Hussain, MD, FACP, FASCO, can be reached at maha.hussain@northwestern.edu.

David M. Nanus, MD, can be reached at dnanus@med.cornell.edu.

Ian Tannock, MD, PhD, DSc, can be reached at ian.tannock@uhn.ca.

Disclosures: Agarwal reports he is a consultant for Clovis, Eisai, EMD Serono, Exelixis, Genentech, Merck, Novartis and Pfizer. Antonarakis reports he is a consultant for or receives research funding from Astellas, AstraZeneca, Bayer, Clovis, Dendreon, Essa, Genentech, Janssen, Johnson & Johnson, Medivation, Merck, Novartis, Sanofi and Tokai. Hussain reports she received research funding from AstraZeneca, Bayer, Genentech and Pfizer, and honorarium from OncLive. Nanus and Tannock report no relevant financial disclosures.

Abiraterone acetate is poised to challenge docetaxel as the standard addition to androgen deprivation therapy for treatment of newly diagnosed, metastatic castration-resistant prostate cancer.

The LATITUDE and STAMPEDE trials — results of which were presented at this year’s ASCO Annual Meeting and subsequently published in The New England Journal of Medicine — showed the addition of abiraterone acetate (Zytiga, Janssen) and prednisone to ADT reduced risk for death by nearly 40%.

There also is a safety benefit.

Docetaxel — an IV chemotherapy — can cause nausea, constipation, diarrhea, neutropenia or fatigue during its 18-week dosing schedule. Abiraterone, an oral adrenal inhibitor traditionally used in later-line therapy, is administered until disease progression and has relatively few side effects.

“These two trials have created a mind shift. Instead of waiting for hormonal therapy to fail and then give abiraterone, we should probably give it upfront to patients starting hormonal therapy for the first time,” Emmanuel S. Antonarakis, MD, associate professor of oncology at Johns Hopkins School of Medicine, told HemOnc Today. “There are now two standards of therapy, the other being chemohormonal therapy.”

Although abiraterone conferred unprecedented survival benefits and is better tolerated, not all oncologists agree it should replace docetaxel in the absence of a head-to-head comparative trial. Some point to abiraterone’s much higher price. Others wonder whether combining abiraterone and docetaxel with ADT would further prolong survival.

HemOnc Today asked urologic oncologists and researchers about the promise of abiraterone; the potential impact of its long-term use; if its cost in comparison with docetaxel is prohibitive; and whether abiraterone soon will be challenged by other therapies for the treatment of metastatic hormone-resistant prostate cancer.

‘Spectacular’ results

Docetaxel became the standard of care in this patient population following results from the CHAARTED study, published in 2015 in The New England Journal of Medicine. The results, based on median follow-up of 28.9 months, showed docetaxel improved median OS from 44 months to 57.6 months.

Abiraterone typically has been reserved as second-line therapy for men resistant to ADT. The LATITUDE and STAMPEDE trials — both supported by Janssen, the manufacturer of abiraterone — evaluated whether abiraterone would be more beneficial if used earlier.

In both studies, men received 1,000 mg abiraterone daily to reduce the production of testosterone and other androgens from the adrenal glands, the testes and the prostate tumor by targeting the protein CYP17A1. Patients also received low-dose prednisone (5 mg) to replace a decrease in glucocorticoid, a stress hormone that helps transform glucose and fat into energy.

PAGE BREAK

The LATITUDE trial included 1,199 men with newly diagnosed metastatic prostate cancer who had at least two of three other factors associated with a poor outcome: a Gleason score of 8 or higher; a minimum of three metastatic bone lesions; or measurable metastases in visceral organs, such as the liver.

Maha Hussain, MD, FACP, FASCO
Maha Hussain

“I am delighted to see the results of LATITUDE and the fact that it preselected a higher-risk metastatic disease population; stratifying for risk is critical to better personalize therapy,” Maha Hussain, MD, FACP, FASCO, associate director for clinical sciences research at Robert H. Lurie Comprehensive Cancer Center of Northwestern University and a HemOnc Today Editorial Board Member, told HemOnc Today. “Based on LATITUDE and CHAARTED, the findings demonstrate that it’s the high-risk, high-volume patients who seem to benefit from treatment that maximizes systemic therapy.”

Karim Fizazi, MD, PhD, chief of the department of cancer medicine at Gustave Roussy in Villejuif, France, presented results from the LATITUDE study at ASCO. At median follow-up of 30 months, the addition of abiraterone and prednisolone to ADT doubled median time to progression compared with ADT plus placebo, from 14.8 months to 33 months. Further, a greater proportion of men assigned the combination achieved 3-year OS (83% vs. 76%).

More men treated with abiraterone than ADT alone experienced high blood pressure (20% vs. 10%), low potassium level (10.4% vs. 1.3%) or liver enzyme abnormalities (5.5% vs. 1.3%).

“Abiraterone did exactly what we wanted it to do,” Fizazi said during his presentation. “Most men did not complain about any specific side effects from the drug. We need to be cautious when using abiraterone in men who have an increased risk for heart problems, such as those with diabetes, and we have to monitor hypertension.”

The ongoing STAMPEDE trial began in 2005 in the United Kingdom. Nicholas James, MBBS, PhD, professor of clinical oncology at Queen Elizabeth Hospital Birmingham, and colleagues assigned 1,917 men to abiraterone plus ADT or ADT alone. Unlike the LATITUDE trial, only half of the men in the STAMPEDE trial had metastatic disease.

STAMPEDE uses a multiarm, multistage platform design to test different first-line therapies.

At a median follow-up of 40 months, men who received abiraterone plus ADT demonstrated a 54% reduction in symptomatic bone complications. Median OS was not reached in the combination arm and was 34.7 months in the ADT-alone arm.

“The results, I have to say, are spectacular,” James said following his presentation. “We think this is possibly one of the biggest survival advantages ever recorded in a common adult tumor. ... The take-home message, particularly when you compare it with the LATITUDE trial, which produced almost identical results, is paradigm-shifting for prostate cancer — reimbursement being the main issue.”

PAGE BREAK

‘Obscenely expensive’

The retail cost of abiraterone — estimated at $8,000 to $9,000 per month before discounts or rebates — creates a quandary for oncologists, especially because men who show no signs of disease progression could be on treatment for 2 or 3 years.

By comparison, docetaxel carries a price tag of about $32,000 for a six-dose cycle.

Still, the higher toxicity profile of docetaxel factors into costs. Following his ASCO presentation, James said abiraterone’s low toxicity profile could help reduce the costs of skeletal-related events associated with chemotherapy.

“The upside of abiraterone is that it is not very toxic compared with most of the agents we use to treat cancer,” Ian Tannock, MD, PhD, DSc, a retired professor who spent 35 years practicing at Princess Margaret Cancer Centre in Toronto, told HemOnc Today. “The downside is it is obscenely expensive and the drug companies are holding patients to ransom. The cost of making abiraterone is probably about the cost of making aspirin. It costs virtually nothing to make and yet they sell it at these unbelievable prices.”

In a statement to HemOnc Today, Janssen said it responsibly prices its products and is committed to ensuring patients have broad access to its medicines.

“When pricing our medicines, we consider the value they provide to patients and society, the need to ensure they are affordable and accessible, and the need to sustain our capacity to develop new medicines,” the statement read.

The availability of a generic version of abiraterone would greatly reduce costs. That, however, appears unlikely.

The FDA approved abiraterone for the treatment of metastatic, castration-resistant prostate cancer in April 2011. The agent’s “composition of matter” patent expired on Dec. 13, 2016.

However, in 2014, the United States Patent and Trademark Office (PTO) granted Janssen a “method of treatment” patent that protects the specific administration of abiraterone combined with prednisone, allowing Janssen to prevent generic versions of abiraterone worldwide until Aug. 24, 2027.

Companies have filed abbreviated new drug applications with the FDA seeking approval to market generic versions of abiraterone in the United States before the patent expires.

“We can’t speculate when the PTO will render a decision/ruling,” Janssen said in a statement to HemOnc Today. “We believe that [the patent] is valid and will vigorously defend the patent in any IPR proceedings.”

The 30-month stay for such lawsuits filed before April 2016 expires in October 2018. However, the ultimate length would be subject to the outcome of any district court litigation decision.

PAGE BREAK

If Janssen loses the patent case and files an appeal, it could delay a generic brand of abiraterone from hitting the open market until early 2020. If it wins the case, its patent is likely to be retained until 2027.

“If abiraterone becomes generic, the cost will probably be equivalent or lower than six doses of docetaxel,” Antonarakis said. “If it does not become generic, it will probably be five to 10 times more expensive.”

That is significant, Hussain said, because of the duration men may remain on abiraterone.

“Abiraterone doesn’t have the acute side effects of chemotherapy, but it does have its own side effects — impacting cardiovascular issues and hypertension — and this is not a finite duration of treatment,” Hussain said. “It is taken until disease progression, which could be 3 or 4 years. That is when you get into the financial toxicities — including patients’ out-of-pocket costs.”

Although it is recommended that abiraterone be taken on an empty stomach, Szmulewitz and colleagues presented data from a randomized phase 2 clinical trial at this year’s Genitourinary Cancers Symposium showing that taking a quarter dose of abiraterone with a low-fat breakfast appeared noninferior to taking a standard dose in a fasting state.

Treatment cost will be a concern even if a generic version of abiraterone becomes available, according to Neeraj Agarwal, MD.
Treatment cost will be a concern even if a generic version of abiraterone becomes available, according to Neeraj Agarwal, MD. “If the copay remains $200 or $300 or $500 a month, the absolute price of the drug doesn’t matter to the patient who cannot afford it,” he said.

Photo by Jonathan Martinez, visual communication specialist, Huntsman Cancer Institute.

The two doses had an identical median time to progression of 14 months, although the lower dose could save an estimated $6,500 a month.

“Even if abiraterone becomes generic, it won’t become free,” Neeraj Agarwal, MD, director of the genitourinary medical oncology program at University of Utah Huntsman Cancer Institute, told HemOnc Today. “If the copay remains $200 or $300 or $500 a month, the absolute price of the drug doesn’t matter to the patient who cannot afford it.”

Abiraterone vs. docetaxel

Cost aside, oncologists agree specific indications should be considered when deciding between abiraterone and docetaxel.

“Both docetaxel and abiraterone have been established in individual trials, but they have not been compared with each other,” Agarwal said. “That’s why it is challenging for us. Which should we pick?”

The STAMPEDE trial, which has accrued more than 9,000 men, could help answer that question. Results from study arms comparing abiraterone and docetaxel are scheduled for presentation at the European Society for Medical Oncology Congress this month.

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Although STAMPEDE trial results presented at ASCO showed the survival benefit of abiraterone appeared similar for men with and without metastatic disease, the use of abiraterone for men with low-volume prostate cancer is “highly debated” worldwide, Fizazi said.

However, Sumanta K. Pal, MD, associate professor of medical oncology at City of Hope and a HemOnc Today Editorial Board Member, said further study is needed to determine if abiraterone is appropriate for men with nonmetastatic disease, who may be able to receive more definitive therapies such as radiation.

“The confidence interval for abiraterone straddles 1 and that, to me, suggests that we haven’t completely defined the benefit of abiraterone in the [nonmetastatic] population,” Pal said at the time of the presentation.

Agarwal said he uses chemotherapy more often when a patient has visceral metastases.

“If somebody has liver metastases or any metastases outside of the bone and lymph node, I tend to use docetaxel,” he said. “If I don’t see visceral metastases, then I tend to go with abiraterone and prednisone.”

Patient profiles also are a consideration, Antonarakis said. If a patient is fit for chemotherapy, he may prefer it for 18 weeks rather than taking a pill for 2 or 3 years.

“Abiraterone is a whole new paradigm because your patient is not coming in for an infusion every few weeks for six cycles,” David M. Nanus, MD, professor of medicine and urology at Weill Cornell Medicine, told HemOnc Today. “With six cycles of docetaxel, patients are often wiped out by the time they’re done, and it might take a few months to recover afterward.”

The general rule when deciding between docetaxel and abiraterone is to consider the volume of disease and the overall health of the patient, Tannock said.

“The question I have is, should we be using both?” he added.

PEACE1, a phase 3 study, is recruiting participants to compare the clinical benefit of ADT with or without docetaxel, abiraterone, prednisone and radiotherapy. The intrigue of a docetaxel-abiraterone combination is tempered by concerns about the safety and efficacy of such a potent combination of therapy and its potential long-term effects.

“I am absolutely excited about PEACE1 and [data on] docetaxel with abiraterone,” Hussain said. “However, we also have to be careful about tolerability. Sometimes more may not be better, hence the need for testing in prospective trials to demonstrate feasibility and value to patients’ terms of quality and quantity of life.”

Cost, again, is a concern.

“Although they are, hopefully, efficacious together, they also come with a higher price tag and a much bigger bag of toxicities,” Agarwal said. “The key is not to treat everybody with more and more drugs. The result may be no quality of life left for a large number of patients who may not need this aggressive therapy upfront.”

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Other treatment options

In addition to the enthusiasm surrounding abiraterone and its potential to be the new standard of care in the treatment of metastatic, castration-resistant prostate cancer, several ongoing clinical trials are investigating other strategies to reduce androgen exposure.

Results of those trials also could be practice changing, and again raise questions about the standard of care.

A pair of studies scheduled for completion in 2020 — ENZAMET and ARCHES — are evaluating enzalutamide (Xtandi; Astellas, Medivation) with ADT.

The TITAN trial, also scheduled for completion in 2020, is designed to assess apalutamide (ARN-509, Aragon Pharmaceuticals) with ADT.

The ARASENS trial will evaluate darolutamide (ODM-201/BAY-1841788, Bayer) with ADT and docetaxel. Trial completion is expected in 2022.

Orteronel (TAK-700, Takeda/Millennium) also is being evaluated with ADT. Like abiraterone, orteronel is an androgen synthesis enzyme blocker, but it is less likely to inhibit the production of cortisol and did not require concomitant therapy with prednisone in a large NCI-sponsored phase 3 SWOG trial in metastatic hormone-sensitive prostate cancer, which recently completed accrual of more than 1,300 patients.

“That’s a huge advantage,” said Agarwal, study chair of the phase 3 SWOG study. “Oncologists and urologists are concerned about using prednisone for so long in patients expected to live for 3 to 5 years. Even at 5 mg daily, prednisone has the potential to cause osteoporosis, and there are data suggesting that glucocorticoid receptor stimulation may lead to prostate cancer progression.”

There also is a growing interest in the potential of PD-1 immunotherapies and PARP inhibitors for the treatment of prostate cancer.

“The new frontier will be to explore other classes of therapy altogether and, in my opinion, those are the two that have generated, by far, the most excitement in the prostate cancer space in the last 2 years,” Antonarakis said. “There’s no question that the LATITUDE and STAMPEDE trials were practice changing, but they were not really conceptually or scientifically novel concepts.

“Many of us expected they would improve survival and it’s important that this proof came, but now we need to move beyond that,” Antonarakis added. “PD-1 immunotherapy and PARP inhibitors caused a lot of buzz at the ASCO meeting this summer.”

The prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20% to 25%, according to a review by Antonarakis and Benjamin A. Teply, MD, published in Expert Review of Clinical Pharmacology.

Identification of these underlying repair defects may present unique treatment opportunities with PARP inhibitors, including olaparib (Lynparza, AstraZeneca), which received FDA breakthrough designation status for the treatment of hormone-resistant disease in men with BRCA1, BRCA2 or ATM mutations. The agent — the first FDA-approved PARP inhibitor — is indicated for patients with BRCA-mutated ovarian cancer.

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Mateo and colleagues evaluated 400 mg olaparib in 50 patients with metastatic castration-resistant prostate cancer. All previously received docetaxel, and 98% had received abiraterone or enzalutamide. Results, published in The New England Journal of Medicine, showed 11 of 49 evaluable patients had a 50% or greater PSA decline with olaparib.

Researchers then tested patients for genes related to homologous recombination repair, including BRCA1, BRCA2, ATM, PALB2, CHEK2 and FANCA. Ten of the patients who demonstrated PSA response had tumors with homologous recombination deficiency as defined by a deleterious mutation in one of those genes.

Further, 88% of the 16 patients on the trial with homologous recombination deficiency responded to treatment.

“For about 80% of men with prostate cancer — those without these mutations — PARP inhibitors won’t work,” Antonarakis said. “But when they work in patients with the right mutations, the responses can be dramatic and long lasting.”

A randomized phase 3 trial is comparing olaparib with abiraterone or enzalutamide for treatment of men with metastatic castration-resistant prostate cancer who harbor germline or somatic mutations in BRCA1, BRCA2 or ATM.

Other PARP inhibitors undergoing evaluation in phase 2 or phase 3 trials in hormone-resistant prostate cancer include rucaparib (Rubraca, Clovis), approved for the treatment of ovarian cancer; niraparib (Zejula, Tesaro), approved for women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer; and talazoparib (BMN 673, Pfizer).

New targets, biomarkers

As the genetic landscape of metastatic prostate cancer is further defined, additional targeted agents may become available for the population.

According to a study presented by Sonpavde and colleagues at this year’s Genitourinary Cancers Symposium, a liquid biopsy test identified at least one change in circulating tumor DNA in 94% of men with metastatic, castration-resistant prostate cancer. Higher numbers of changes, including changes to the androgen receptor gene, appeared associated with shorter time to failure (HR = 1.42) and poorer survival (HR = 2.51).

The most common recurrent somatic mutations were in TP53 (36% of patients); androgen receptor (22%); APC (10%); NF1 (9%); EGFR, CTNNB1 and ARID1A (6% each); and BRCA1, BRCA2 and PIK3CA (5% each). The most common genes with increased copy numbers included androgen receptor (30%), MYC (20%) and BRAF (18%).

Quick identification of these genes through a liquid biopsy has potential to inform treatment decisions and allow clinicians to make adjustments faster.

“Circulating-tumor DNA offers a simple and convenient way to assess an individual’s tumor DNA and composition and, often, it can reveal new mutations that clinicians can use to personalize therapy,” Pal, who was not involved with the study, said during a press conference at the meeting. “For example, BRAF is typically associated with melanoma, and there are approved drugs that are used in melanoma that can target this mutation. Perhaps there might be some relevance for these agents in certain types of prostate cancer that bear these same mutations.”

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Molecular subtyping also could be used to predict which patients are most likely to respond to ADT.

A study by Zhao and colleagues, published this year in JAMA Oncology, showed the identification of prostate cancer subtypes based on luminal and basal lineage may help guide use of ADT. Men with luminal B prostate tumors responded better to postoperative ADT than men with nonluminal B tumors.

“There are no prospectively validated biomarkers in clinical use right now, but I anticipate [there will be],” Agarwal said. “We’ll likely see five or six of these drugs approved in the next 2 to 5 years.

“Many patients may not need any of these newer drugs because their median survival is going to be in the range of 7 to 8 years with standard ADT alone, per data from SWOG 9346 trial,” Agarwal added. “On the other side, some patients are really going to need these newer drugs, and the key is to find the biomarkers to select these patients to achieve an ideal balance of cost effectiveness, toxicities and efficacy.”

Based on the findings of the LATITUDE and STAMPEDE trials and the potential of targeted therapy, oncologists with whom HemOnc Today spoke agreed researchers are on the precipice of significantly extending the lives of men with prostate cancer.

“Having more choices moving forward with a multitargeted anticancer strategy is going to be critical,” Hussain said. “At the end of the day, this is a smart cancer and it adapts. If we can prevent this disease from progression and getting to its deadliest phase, it would be a huge accomplishment.” – by Chuck Gormley

Click here to read the POINTCOUNTER, “Should oncologists recommend hormone therapy plus abiraterone for patients with nonmetastatic prostate cancer?”

References:

Fizazi K, et al. N Eng J Med. 2017;doi:10.1056/NEJMoa1704174.

James N, et al. N Eng J Med. 2017;doi:10.1056NEJMoa1702900.

James N, et al. Lancet. 2016;doi:10.1016.S0140-6736(15)01037-5.

Mateo J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1506859.

Sonpavde G, et al. Abstract 149. Presented at: Genitourinary Cancers Symposium; Feb. 16-18, 2017; Orlando, Fla.

Sweeney CJ, et al. N Eng J Med. 2015;doi:10.1056/NEJMoa1503747.

Szmulewitz RZ, et al. Abstract 176. Presented at: Genitourinary Cancers Symposium; Feb. 16-18, 2017; Orlando, Fla.

Teply BA and Antonarakis ES. Expert Rev Clin Pharmacol. 2017;doi:10.1080/17512433.2017.1338138.

Zhao SG, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2017.0751.

For more information:

Neeraj Agarwal, MD, can be reached at neeraj.agarwal@hci.utah.edu.

Emmanuel S. Antonarakis, MD, can be reached at eantona1@jhmi.edu.

Maha Hussain, MD, FACP, FASCO, can be reached at maha.hussain@northwestern.edu.

David M. Nanus, MD, can be reached at dnanus@med.cornell.edu.

Ian Tannock, MD, PhD, DSc, can be reached at ian.tannock@uhn.ca.

Disclosures: Agarwal reports he is a consultant for Clovis, Eisai, EMD Serono, Exelixis, Genentech, Merck, Novartis and Pfizer. Antonarakis reports he is a consultant for or receives research funding from Astellas, AstraZeneca, Bayer, Clovis, Dendreon, Essa, Genentech, Janssen, Johnson & Johnson, Medivation, Merck, Novartis, Sanofi and Tokai. Hussain reports she received research funding from AstraZeneca, Bayer, Genentech and Pfizer, and honorarium from OncLive. Nanus and Tannock report no relevant financial disclosures.