Experts Discuss Optimal Timing of New Prostate Cancer Therapies

Johann De Bono, MB CHB, PhD, MSC

Layering of therapies and advances in next-generation imaging and sequencing are key reasons that outcomes are improving in advanced prostate cancer (PC). However, optimal timing of therapies will be essential to ensure that patients benefit from all available drugs that improve survival, according to experts who participated in a recent Peer Exchange™ discussion. “We’ve got to find drugs that improve survival, and you want as many of your patients to benefit from as many of those drugs as possible,” said Chris Parker, MD, FRCR, MRCP. “You don’t want them to die after having 1 or 2.”

Gains in Making Earlier Assessments

The panelists discussed the importance of next-generation imaging for identifying early metastases, and which patients with rising prostate-specific antigen (PSA) levels should receive aggressive therapy. Other topics included recent studies showing that addition of docetaxel or abiraterone acetate (Zytiga) to androgen-deprivation therapy (ADT) improved survival in metastatic, hormone-sensitive PC; sequencing or combining therapies for metastatic castrationresistant PC (mCRPC); and new therapies for metastatic disease, including androgen receptor (AR)-targeted therapies, immune checkpoint inhibitors, and prostate-specific membrane antigen (PSMA)—directed radioligand therapy.Early detection and monitoring of treatment response in mPC are among the most important advantages of the newest next-generation imaging modalities, such as whole-body, diffusion-weighted magnetic resonance imaging (WB-DWI) and PSMA-positron emission tomography (PET), according to Bertrand Tombal, MD, PhD. Parker added that WB-DWI is markedly better than older methods, such as PSA testing or computed tomography (CT), for assessing response to treatment with radium-223 in patients with bone metastases. “For the first time, we can certainly see who’s benefiting and who’s not,” he said.

However, Tombal cautioned that these highly sensitive tests may have lower specificity and may lead to unnecessary treatment of noncancerous lesions. For example, he noted that PSMA-PET performed in patients with rising PSA levels may show an oligometastatic deposit that is easily removable with surgery or treatable with radiation therapy (RT). However, he stated that based on findings, 20% of these lesions are noncancerous, so treatment of all suspicious lesions may constitute overtreatment.

Conversely, these imaging modalities may be used as a follow-up to PSA measurement to prevent unnecessarily aggressive treatment in individuals with rising PSA and negative imaging. “People often say...you’re treating a lot of patients based on [PSMA-PET], but they don’t see the other part, which is the number of patients we save from aggressive treatment because they have a negative PET PSMA [or] a negative whole-body MRI,” said Tombal.

The panelists also discussed the potential for next-generation imaging to delay the administration of ADT by detecting more patients with oligometastatic disease for which RT and surgery are still viable options. “I think there’s far too much use of early ADT,” said Parker. “My bias is to treat radically where appropriate with radiotherapy or even with surgery [for] oligometastatic disease.”

ADT Partners in the Front-line Setting

Parker added that RT of small oligometastatic lesions may provide the possibility of cure for a small proportion of patients. “If I had oligometastatic disease, I could have hormonal therapy alone and be certain of not being cured, or I could have radical radiotherapy with a chance of being cured.”Until recently, ADT alone was the standard of care (SOC) for metastatic hormone-sensitive PC. However, data from the CHAARTED1 and STAMPEDE2 trials showed that addition of docetaxel to ADT significantly improves survival, and the LATITUDE trial³ showed that addition of abiraterone, a drug that blocks endogenous androgen synthesis, to SOC improves overall survival (OS) and radiographic progression-free survival. The results from these trials provide 2 new options for treatment of metastatic hormone-sensitive PC. However, the panelists disagreed on which agent should be added to ADT in the frontline setting.

Although Parker noted that underpowered data from STAMPEDE (from the time when both the docetaxel and abiraterone arms were open) suggest no difference in OS when docetaxel or abiraterone are added to ADT, he stated that the fewer adverse effects associated with abiraterone would likely make it more favorable for patients in the frontline setting. Parker added that although some data suggest that OS is similar between the 2 agents, time to progression tends to be much longer with abiraterone.

However, Johann de Bono, MB ChB, PhD, MSc, noted that patients will likely receive both treatments over the course of their disease and may be better able to tolerate the greater toxicity of docetaxel when used earlier in disease progression. De Bono added that patients who start and remain on abiraterone for a long period may not be healthy enough to receive docetaxel when they eventually become resistant to abiraterone. “Let your patients get all the active drugs to maximize benefit. The likeliest way of doing that is to give docetaxel first because it’s much easier than giving abiraterone later on,” he said.

Potential for Combinations in MCRPC

De Bono also noted that the wide cost difference between docetaxel and abiraterone may also influence treatment decisions if patients have to pay out of pocket for medication. “Docetaxel is 18 weeks of an inexpensive generic drug, and abiraterone is probably $30,000 or more [over] 2 years,” said de Bono. Joe O’Sullivan, MD, FRCPI, FFR RCSI, FRCR, moderator of the session, added that clinicians should consider that starting with docetaxel or abiraterone may affect the biology of the cancer and thus the effectiveness of cancer treatments in later settings. He said that these potential differences in cancer biology deserve further investigation.With multiple therapeutic agents available for mCRPC, it is important to sequence and layer therapies based on the biology of the mechanisms of action and previous treatments the patient has received, the panelists said.

Although de Bono expressed concern that introducing too many drugs early in disease progression may lead to early resistance, he stated that biologically appropriate combination strategies, such as radium-223 and hormonal therapy for patients with bone metastases, may be better than single-agent therapy. However, combination strategies are not always appropriate. De Bono cited data from the PLATO trial⁴ showing that addition of abiraterone after progression on enzalutamide did not improve survival outcomes, which suggests that the clinical benefit of sequencing or layering these drugs is likely minimal. “PLATO has shown quite clearly that if you’re progressing on enzalutamide and you add abiraterone, there’s no benefit,” he explained.

Tombal noted that adding chemotherapies such as docetaxel or cabazitaxel (Jevtana) to existing treatments may be appealing from an intellectual standpoint, but this regimen could lead to excessive financial and treatment toxicity with minimal clinical benefit for many patients. Because of the lack of clinical evidence supporting a particular sequence, the panelists agreed that the goal of treatment should be to figure out how to include as many therapies as possible while adjusting for the patient’s treatment history and type of metastasis. For example, early in treatment for bone metastases, before the development of visceral metastases, Parker uses radium-223 with an AR-targeted agent.

Investigations into this strategy are continuing. In November, after the Peer Exchange™ program was held, the phase III ERA223 trial exploring radium-223 plus abiraterone in patients with asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC was unblinded early. Bayer, the manufacturer of radium-223, reported that the unblinding followed the recommendation of an independent data monitoring committee, which observed more fractures and deaths in patients receiving both radium-223 and abiraterone compared with patients receiving abiraterone alone.⁵

Although the presence of AR splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) was recently shown to predict poorer outcomes in men who received hormonal therapy for mCRPC,⁶ the panelists agreed that the use of chemotherapy or AR-targeted therapy should not be based on AR-V7 status. They suggested that the lower response to AR-targeted therapies in these patients may be because they have more CTCs overall, not necessarily because the splice variant itself doesn’t respond to the AR drugs. “There’s very strong evidence that…up to 30% of patients with AR-V7-positive disease respond very well to abiraterone and enzalutamide [Xtandi],” said de Bono.

New Concepts for Advanced Disease

He also noted that tumor biopsies are molecularly heterogeneous, with different portions containing wild-type AR, no V7, and V7. Furthermore, the poor dynamic range of the laboratory test for AR-V7 makes it too unreliable for guiding management, according to de Bono. Overall, the panelists agreed that trials are needed to determine the appropriate sequencing and layering of therapy in mCRPC. “The so-called therapeutic layering is the halfway house between sequential on the one hand and combination on the other,” said Parker. “We don’t even know whether there’s any benefit to combination rather than sequential. We need to answer the simple questions first.”The panelists discussed potential new therapies for mPC, including AR-targeted therapies, immune checkpoint inhibitors, and PSMA-directed radioligands (Lutetium-177 PSMA). According to de Bono, drugs that target the AR splice variants, either by inhibiting the spliceosome or targeting the AR terminus, are being studied in clinical trials, and will likely be more effective for targeting this common resistance mechanism of PC than agents targeting the ligand-binding domain. Although pembrolizumab (Keytruda) is approved for mismatch-repair-deficient (dMMR) cancers of any solid tumor, it has been slow to make inroads for prostate cancer. However, de Bono noted that pembrolizumab has had “spectacular responses” for men with dMMR PC in the end-stage setting. “The mismatch repair prostate cancers [along with other solid tumors] have much higher PD-L1 expression—they have more immune cell infiltration,” he said.

De Bono predicted that at least half of dMMR PCs will respond to immunotherapy, but noted that ongoing trials may not demonstrate a significant benefit because they do not limit patient selection based on mismatch repair status. The activity of pembrolizumab in PC without dMMR is unclear, but de Bono predicted that data within the next year will provide some answers.

A Pragmatic Approach Moving Forward

The panelists also discussed the potential utility of therapeutic radioisotopes attached to PSMAtargeted therapy, notably Lutetium-177-PSMA, which yielded a >50% decrease in PSA in an interim analysis of 17 of 30 patients in the phase II RECIST trial.⁷ Although retrospective and single-arm treatment trials suggest strong clinical activity as well as a dramatic and durable clinical response, the panelists agreed that randomized trials involving larger numbers of patients are needed to determine clinical response and survival benefit as well as the optimal isotope, targeting vehicle, dosage, and interval of dosing.The panelists concluded that many new opportunities for improving outcomes with improved imaging and strategic delivery of different treatment options are on the horizon, although Tombal cautioned that clinicians should carefully consider the role of these new therapies in clinical practice, and “not jump on the first hype.”

“We’re living in an exciting phase, but...it’s a phase in which we can do a lot of good, but we can also do a lot of harm,” said Tombal. “We have to think about what we do...and still try to better deliver what we know is working well.”

References

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2. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. doi: 10.1016/S0140-6736(15)01037-5.
3. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi: 10.1056/NEJMoa1704174.
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5. Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol. 2017;35(19):2149-2156. doi: 10.1200/JCO.2016.70.1961.
6. Hofman MS, Sandhu S, Eu P, et al. Lutetium-177 PSMA (LuPSMA) theranostics phase II trial: efficacy, safety and QoL in patients with castrate-resistant prostate cancer treated with LuPSMA. Presented at the 2017 European Society for Medical Oncology Congress; September 8-12, 2017; Madrid, Spain. Abstract 7850. cslide.ctimeetingtech.com/library/esmo/browse/search/2xzM#2Bb390vU. Accessed December 20, 2017.