A Question of Timing

“Rethinking treatment sequencing in metastatic prostate cancer”

Subject Matter Experts: Thomas E. Keane, M.D.; Michael B. Lilly, M.D.; and Theodore S. Gourdin, M.D.

By Kimberly Mcghee And Rachel Weber
Illustration By Emma Vought

On completion of the article, the reader should be able to:

• Summarize recent findings of the LATITUDE and STAMPEDE arm G trials and discuss their implications for the sequencing of treatment
• Recognize that genomic profiling will likely have a growing role to play in the selection and sequencing of treatment in prostate cancer
• Explain why closer collaboration between urologists and medical oncologists is needed to ensure that care can nimbly adapt to evolving therapies

The American Cancer Society estimates that one in seven men will be diagnosed with prostate cancer, the most common noncutaneous cancer in men. For men with metastatic disease, the five-year survival rate is just 29 percent. The treatment for metastatic prostate cancer remained unchanged for almost six decades, but over the past 15 years new therapies have been approved that, when used together, can extend the life of men with the disease, though they do not provide a cure.

Overview of current treatments

Since 1941, androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic prostate cancer. Androgens such as testosterone stimulate prostate cancer cells to grow and metastasize. Reducing testosterone levels to 20 ng/dL has been associated with improved outcomes.^1-4

Most clinicians rely on gonadotropin-releasing hormone (GnRH) agonists to achieve castrate levels of testosterone, the goal of ADT, but these have the serious drawback of initially causing a surge in testosterone levels and typically take four weeks to achieve castration. GnRH antagonists achieve castrate levels of testosterone in 72 hours without such a surge and were shown to be noninferior to agonists in the CS21 trial, with superior results in patients with higher prostate-specific antigens (PSAs) and more metastatic disease.⁵ Some evidence suggests they may also be associated with less cardiovascular morbidity than agonists.⁶ A head-to-head clinical trial of these agents is needed to determine which provides superior androgen deprivation in which patients.

Unfortunately, most patients with metastatic prostate cancer who initially respond to ADT will develop resistance on average 18 to 24 months after beginning treatment and then are considered to have metastatic castration-resistant prostate cancer (mCRPC). Treatment options for these patients were very limited until 2004, when the chemotherapy agent docetaxel was shown to provide an increase in quality of life and overall survival.^7,8 In 2010, the first immunotherapeutic agent, sipuleucel-T (Provenge, Dendreon, Seattle, WA), an individualized treatment that leads white blood cells to attack prostate cancer cells, was approved by the FDA. Approval for abiraterone, a steroid that inhibits androgen synthesis, and enzalutamide, a nonsteroidal antiandrogen, followed in 2011 and 2012, respectively. Both abiraterone and enzalutamide are considered second-line ADT, targeting the production of testosterone not only by the testes (the goal of first-line ADT) but also by the adrenal gland and the tumor itself. Thus, they still have a role to play after the development of resistance to first-line ADT. Lastly, radium-223, approved in 2013, emits low levels of radiation in areas of bone metastasis and can be used for palliation.

The standard practice has been for urologists to treat early-stage disease with ADT and to refer patients once they develop mCRPC to medical oncologists for chemotherapy.

Efficacy of docetaxel and abiraterone in castration-sensitive disease

Therapies currently used to prolong survival in patients with mCRPC were recently shown to do so as well in patients with metastatic castration-sensitive prostate cancer (mCSPC). In 2014, two of three large randomized phase 3 trials (CHAARTED, STAMPEDE, GETUG-AFU15) showed marked improvement in four-year survival in men with mCSPC who received both docetaxel and ADT.^9-11 In 2017, the LATITUDE¹² and STAMPEDE Arm G¹³ trials established a survival benefit for abiraterone plus ADT vs. ADT alone in the same patient population.

The docetaxel findings have already changed care, and the abiraterone findings are poised to do so. Because docetaxel is now standard of care in patients with high-volume mCSPC (four or more bone metastases or metastases in the lung or liver), urologists and medical oncologists are collaborating more closely to ensure comprehensive care for these patients. Large urology practices have begun to incorporate medical oncologists, and urologists have begun participating in multidisciplinary clinics. The recent abiraterone findings have raised further questions about optimal sequencing and the benefits, as well as possible drawbacks, of using second-line androgen therapy in castration-sensitive disease.

Optimizing treatment sequence

Although docetaxel and abiraterone provide a clear survival benefit in both mCSPC and mCRPC patients, it is not known how best to sequence these treatments. Patient preference, finances, and fitness will certainly affect choice of therapy. Docetaxel is given intravenously for six doses, whereas abiraterone is taken orally and has fewer side effects but must be taken long-term. There may also be cost differences. A recent article estimated the cost for each life year gained was $26,330 for generic docetaxel and $194,087 for abiraterone.¹⁴

“Medical oncologists and urologists are faced with a question — Are you going to give therapy in addition to medical castration to newly diagnosed patients with high-volume disease and, if so, in what order?” explains MUSC Health medical oncologist Theodore S. Gourdin, M.D.

To help answer those questions, Gourdin is conducting a phase 2 trial in men with newly diagnosed untreated metastatic prostate cancer (NCT03069937) to examine whether giving docetaxel before medical castration might enhance outcomes. Preclinical data in breast cancer, another hormonally driven cancer, show improved outcomes when chemotherapy is separated from manipulation of the hormonal axis. Patients enrolled in the trial will be given six cycles of docetaxel, the first four as monotherapy and the final two in combination with degarelix, an ADT agent, which will then be continued. The study examines whether an undetectable PSA (less than .02 ng/dl), which has been correlated with better overall survival, can be obtained within ten months of treatment initiation. Seven patients have already been enrolled at MUSC Hollings Cancer Center, the lead site for the study that will eventually enroll 50 patients. Other sites include the Ralph H. Johnson VA Medical Center and the University of Maryland.

If the findings of the trial suggest that providing docetaxel before ADT improves outcomes, Gourdin would like to organize a phase 3 trial that would likely also be designed to answer questions about sequencing with abiraterone. “We would like to ask whether, in the right patient, we would be able to improve outcomes by giving chemotherapy before medical castration. What about abiraterone and chemotherapy? Do we give them all early on?” asks Gourdin. “We don’t know yet and the trial would help to shed light on these questions.”

Is there a downside to changing the sequence of treatments?

Providing treatment once reserved for mCRPC to patients with mCSPC also raises questions about whether these treatments will still work — or work as well — when the patient eventually develops castration-resistant disease.

If second-line ADT with abiraterone or enzalutamide, once reserved for mCRPC, is used earlier in mCSPC, what options remain for patients when they become resistant, wonders Thomas E. Keane, M.D., chair of the Department of Urology at MUSC and co–investigator on this trial.

”Docetaxel, which can provide a 17-month survival advantage in non–castration-resistant prostate cancer patients, offers only a three-month benefit in those with mCSPC whose cancer progresses despite second-line ADT,” explains Keane. “Could it be that multiple-agent treatment should be reserved for patients with high-volume disease?”

Answering such questions will be critical in determining the proper sequencing of newly available treatments for metastatic prostate cancer. Ongoing trials, including STAMPEDE Arm J, PEACE-1, ARCHES and ENZA-MET, are currently assessing the efficacy of ADT, docetaxel, and a second-line ADT agent vs. either ADT and docetaxel or a second-line ADT agent alone.

Using genomics to inform treatment selection

Genomic profiling will likely play a role in deciding which patients will benefit from approved and investigational therapies. Circulating tumor DNA (liquid biopsy) is an investigational technology that promises to facilitate genomic profiling in prostate cancer.¹⁵ Since the genetic landscape in prostate cancer patients varies greatly from patient to patient, and across time, data gleaned from an old tumor biopsy may have only limited relevance to metastatic disease. “Prostatectomy or the original biopsy tissue could have been obtained 20 years ago, and the genomic landscape may have changed markedly in the following years,” says Michael B. Lilly, M.D., associate director of translational research at MUSC Hollings Cancer Center. “It’s a very dynamic system. What you would find from the original sample may no longer be relevant.” Furthermore, there can be a great deal of genetic heterogeneity in a single tumor or among several tumors. For these reasons, liquid biopsies based on circulating tumor DNA in the bloodstream could provide relevant, real-time data about the genetic makeup of metastatic prostate cancer and do so in a cheaper, less invasive manner.

One example of the importance of genomic profiling to treatment selection is the recent finding that some patients with mCRPC have mutations associated with faulty DNA repair (e.g., BRCA1, BRCA2, ATM).¹⁶ Studies show that patients with such mutations could respond better to platinum chemotherapy¹⁷ or PARP inhibitors such as olaparib.¹⁸ Other patients, who have a hypermutator phenotype, may respond to checkpoint antibodies.¹⁹

“Circulating tumor DNA analysis might tell us ‘Give this’ or ‘Don’t give that’ or ‘Is the patient responding?’” says Lilly. “This technology could be a great help in clinical decision making.”

Rethinking prostate cancer vaccines

On September 15, 2017, the Data Monitoring Committee for the multinational phase 3 PROSPECT trial of the PROSTVAC V/F vaccine announced that the trial was being closed because the vaccine had failed to show efficacy in men with mCRPC. PROSTVAC, the brand name for rilimogene, is a PSA-targeted immunotherapy designed to stimulate the body’s immune response. James L. Gulley, M.D., Ph.D., chief of the genitourinary malignancies branch of the National Cancer Institute, who has been involved in the clinical development of the vaccine, expressed his disappointment at this failure but also his determination to try combination strategies, such as the PROSTVAC vaccine plus checkpoint inhibitors. A number of phase 2 trials using that strategy are underway.

Timing of therapy could again play a role. Men in the PROSPECT trial had advanced, metastatic disease and had received years of ADT that could have impaired their immune systems. Could better results be obtained if the vaccine were given in earlier-stage disease? Lilly is the principal investigator of a phase 2 trial of PROSTVAC (NCT02772562) in men at high risk for recurrence after radical prostatectomy. The trial has already enrolled 11 of the targeted 40 patients.

“It makes sense to use a vaccine as early as possible,” says Lilly. “The patients in the PROSPECT trial had very advanced cancer. This will be a more optimal trial in people who have minimal disease right after surgery and are not weakened by years of hormone suppression.”

Treatment for metastatic prostate cancer, which had been stagnant for 60 years, has quickly evolved in the past decade and a half. New agents have been introduced, some of which have shown efficacy in both castration-sensitive and castration-resistant metastatic disease. As clinicians learn how best to sequence these treatments and as more genetic biomarkers are discovered to aid in treatment selection, patients with metastatic prostate cancer may begin to see ever more meaningful survival benefit.

References

1 Klotz L, et al. J Clin Urol. 2015;33(10):1151-1156.
2 Morote J, et al. J Urol. 2007;178:1290-1295.
3 Perachino M, et al. BJU Int. 2010;105:648-645.
4 Bertaglia V, et al. Clin Genitourin Cancer. 2013;11:325-330.
5 Crawford ED, et al. J Urol. 2011 Sep;186(3):889-897.
6 Greiman AK, Keane TE. Curr Urol Rep. 2017 Jun;18(6):41.
7 Tannock IF, et al. N Engl J Med. 2004 Oct 7;351(15):1502-1512.
8 Petrylak DP, et al. N Engl J Med. 2004 Oct 7;351(15):1513-1520.
9 Sweeney CJ, et al. N Engl J Med. 2015;373:737-746.
10 James ND, et al. Lancet 2016;387:1163-1177.
11 Gravis G, et al. Lancet Oncol 2013;14:149-158.
12 Fizazi K, et al. N Engl J Med 2017;377:352-360.
13 James ND, et al. N Engl J Med 2017;377:338–351.
14 Guirgis HM. J Community Support Oncol. 2015 Oct;13(10):362-366.
15 Maas M, et al. Asian J Androl. 2017 Aug 22. doi: 10.4103/aja.aja_29_17. [Epub]
16 Pritchard CC, et al. N Engl J Med. 2016 Nov 3;375(18):1804-1805.
17 Cheng HH, et al. Eur Urol. 2016 Jun;69(6):992-995.
18 Mateo J, et al. N Engl J Med. 2015 Oct 29;373(18):1697-1708.
19 Teply BA, et al. Expert Rev Clin Pharmacol. 2017 Aug;10(8):889-898.