Charles J. Ryan, MD
The treatment paradigm for patients with prostate cancer is evolving, with the growth of approved and newly developed agents and an increased understanding of the role of genomic drivers. According to an international panel of genitourinary oncology experts, these advancements are enabling strategies tailored for individual patients, and at the same time, prompting a need for practitioners to expand their knowledge base.
During a recent OncLive Peer Exchange®
, leading investigators in the field discussed the concepts of clarification, classification, and personalization in prostate cancer, focusing on the role of recently approved second-generation antiandrogens in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and the use of chemotherapy and novel agents in those with metastatic disease.
They also discussed emerging findings about prognostic markers and genomic features, which provide additional insights on whom, when, and how to treat. “It’s not just about metastasis, yes or no; hormone resistance, yes or no. It’s high volume, low volume, BRCA2
, etc. It’s getting more complex, and it makes it more interesting. What’s great is that we now can speak with a little more clarity to our patients about the therapy options that they have,” panelist Charles J. Ryan, MD
Daniel J. George, MD
, who served as moderator for the program, stressed the opportunity to personalize treatment by taking into consideration the differences in available therapies and the patient’s preferences, underlying physical fitness, and genomic profile. “It’s important to encompass all that into a treatment plan,” he said.
In some areas, translating advancements into clinical practice will require oncologists and urologists to become more familiar with genomic markers and biological signals, noted Bertrand Tombal, MD, PhD
. “We are facing a huge education challenge, and we should actually give as much energy to this even before we plan the next generation of trials,” he said.
Nonmetastatic Castration-Resistant Prostate Cancer
The American Cancer Society reports that an estimated 1 in 9 men is expected to receive a prostate cancer diagnosis, with 1 out of every 41 men dying because of it, indicating a high unmet need.1
In the United States, 50,000 to 60,000 men are expected to receive an nmCRPC diagnosis annually, with 34% progressing to metastatic castration-resistant prostate cancer (mCRPC) and an overall mortality of 16%.2,3
The Prostate Cancer Clinical Trials Working Group 3 defines nmCRPC as a 25% rise in prostate-specific antigen (PSA) above the nadir level of ≥1 ng/mL (minimum rise of 2 ng/ mL), serum testosterone level of <50 ng/mL (castrate level), and no evidence of local recurrence or distant metastases on conventional imaging, including radionuclide bone scans, CT, or MRI.2,4
To ensure a rising trend in PSA level, which is typically the first sign of tumor regrowth, a second measure should be taken ≥3 weeks later for confirmation.2,4
Because patients with nmCRPC are often asymptomatic and there is no radiologic evidence of metastatic disease, it has been a challenging entity for which to develop therapeutic strategies; however, in recent years, interest in treating nmCRPC has grown, with a goal to delay progression to metastatic disease.2
One major drug target that has had several therapeutic developments is the androgen receptor (AR). Even in patients with castration-resistant disease, the AR plays a crucial role in the pathogenesis of prostate cancer.
Antiandrogens: Whom and When to Treat
Since February 2018, the FDA has approved 3 second-generation antiandrogens for men with nmCRPC (Table 1
Although these agents are approved in the United States for any man with nmCRPC, in Europe, 2 of these agents, apalutamide (Erleada) and enzalutamide (Xtandi), are indicated only for men with high-risk nmCRPC.8,9
Subsequently, there has been debate over which patients with nmCRPC should receive antiandrogens and when to start them on treatment.
“PSA has got a bad reputation because it gives mixed information in some settings, but a rapid PSA doubling time in this is telling you the cancer is growing more rapidly, you’re more likely to see something on a PSMA [prostate-specific membrane antigen] PET if you don’t see it on the CT scan, and these are the patients who benefit from it,” panelist Christopher J. Sweeney, MBBS
In the antiandrogen studies, PSA doubling time was considered rapid if it occurred within 10 months. However, Sweeney said that PSA doubling time needs to be viewed in the context of each individual patient, with treatment decision making also considering patients’ age and comorbidities, treatment burden, and treatment benefit. “A rapid PSA doubling time in a 55-year-old, I would say, is less than or equal to 10 months. A rapid PSA doubling time in a frail 86-year-old, I would say, is probably greater than 6 months. I’m willing to watch this a bit longer, so it really depends on context and patient,” he said.
Tombal emphasized the prudent use of modern imaging technologies, such as PSMA PET, for men with biochemical recurrence after radical prostatectomy. He explained that although the European Association of Urology guidelines suggest imaging anyone with a PSA rise of ≥0.2 ng/ mL after radical prostatectomy, this recommendation might not be appropriate for all patients, such as an elderly man who underwent a prostatectomy many years earlier and now has a PSA increase ≥0.2 ng/mL.
“We have learned that we actually have to be careful about what we do here, because we are converting a lot of patients to a stage that may have no clinical significance,” Tombal said, indicating this can lead to treatments that may do more harm than good.
Subsequently, in the setting of nmCRPC, he said, “treating patients should be the exception rather than the rule,” with antiandrogen treatment reserved for high-risk patients, as is the indication in Europe. He clarified that high-risk patients include those with recurrence shortly after local treatment, a high Gleason score, and rapid PSA doubling time. In such patients, he said, he may be inclined just to treat rather than undertake PSMA PET first. “I would even warn against the new imaging technology because what we see now is [that] people say, ‘Oh, OK, I’m going to do a PSMA PET. I see a bone metastasis, and I’m going to give radiotherapy to that bone metastasis as an alternative to starting apalutamide, enzalutamide, darolutamide [Nubeqa],’ and that is absolutely unproven,” he said.
Although all 3 second-generation antiandrogens have a similar median metastasis-free survival, with patients getting at least 2 years of disease control out of these agents compared with placebo (Table 1), a key question has been how these agents ultimately affect quality of life (QOL).
Ryan discussed a presentation at the 2019 American Society of Clinical Oncology Annual Meeting that updated the ARAMIS data and examined the impact of darolutamide on the trial’s secondary end points of pain progression and QOL.10
The data showed that darolutamide was associated with significantly delayed pain progression compared with placebo (40.3 vs 25.4 months, respectively; HR, 0.65; 95% CI, 0.53-0.97; P
<.001) and significantly delayed deterioration in QOL from urinary symptoms (25.8 vs 14.8 months; HR, 0.64; 95% CI, 0.54-0.76; P
“When you put that together aggregately, it says there’s a pretty good case to be made for treating versus not treating nonmetastatic CRPC. I think there are a lot of open questions about when exactly to start that treatment, how to integrate the novel imaging, and which of the drugs to choose. That’s something that we, as a field, must wrestle with for a while,” Ryan said.
Table 1. FDA-Approved Antiandrogens for Men With nmCRPC5-7
Selecting Between Available Antiandrogens
Since efficacy was comparable across the 3 trials and all agents have the same indication, a key question is how to determine which of these agents to use. “If you get past all the controversy we just talked about and you’ve decided, yes, this patient will benefit from treatment, then it really does come down to the adverse effect [AE] profile,” panelist Joe M. O’Sullivan, MD, FRCR, FFRRCSI, FRCPI
, said, noting that reimbursement is also an important consideration.
The most common AEs associated with the 3 FDA-approved antiandrogens are summarized in Table 2
The updated ARAMIS data also provided insights on several AEs of interest regarding darolutamide, which thus far appears to be more tolerable than apalutamide or enzalutamide. One such AE, seizure, was not observed to occur more frequently with darolutamide versus placebo, with the study indicating an exposure-adjusted incidence (patients per 100 years’ exposure) of 0.2 for both cohorts.10
In contrast, apalutamide and enzalutamide both have seizure precautions (Table 2). This difference in seizure risk between darolutamide and the other 2 FDA-approved antiandrogens may be attributed to darolutamide’s negligible ability to cross the blood-brain barrier.14
Exposure-adjusted incidences of other AEs of interest were also found to be similar or lower for darolutamide versus placebo, including fatigue/asthenia (11.3 vs 11.1), hypertension (4.7 vs 5.1), hot f lushes (3.7 vs 4.1), fractures (3.0 vs 3.5), falls (2.7 vs 4.1), and cognitive disorder (0.3 vs 0.2).10
“We see from the agents that there is quite a difference in the adverse effect profile when it comes to physical functioning and even, potentially, cognitive functioning,” O’Sullivan said. In patients who are f it and otherwise active, he said, it is important to use the agent least likely to impair fitness.
Table 2. Adverse Effects and Warnings/Precautions for FDA-Approved Antiandrogens11-13
Metastatic Castration-Sensitive Prostate Cancer
Androgen deprivation therapy (ADT) monotherapy has been the primary strategy for metastatic castration-sensitive prostate cancer (mCSPC) since the 1940s; however, the treatment paradigm has recently shifted to combine ADT with other treatments, including antiandrogens and chemotherapy.15
Currently, 3 second-generation antiandrogens have the FDA’s OK for mCSPC: abiraterone acetate (Zytiga), approved in February 2018 in combination with prednisone for high-risk disease; apalutamide, approved in September 2019; and enzalutamide, approved in December 2019.16-18
Deciding which combinations to use and in which patients has been confusing. A key question has revolved around the optimal use of chemotherapy, including whether disease volume can help guide treatment decision making.
Considering Low- Versus High-Volume Disease
During the European Society for Medical Oncology Congress 2019, an update of the STAMPEDE trial (NCT00268476) assessed whether the benefit of docetaxel added to ADT depends on high metastatic burden, as previously demonstrated in the CHAARTED trial (NCT00309985); in both studies, high-volume disease was defined as the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis.15,19
The STAMPEDE update found no evidence of difference in docetaxel effect between the low- and high-volume subgroups, and the investigators concluded that up-front docetaxel should be considered for low- and high-volume M1 disease.19
In contrast, a 2018 analysis by French and US investigators examining data from the CHAARTED and GETUG0-AFU15 studies concluded that there was no overall survival (OS) benefit with up-front docetaxel in patients with a low volume of disease; however, a consistent OS benefit with early docetaxel was observed in patients with a high volume.20
Sweeney emphasized the importance of looking for patterns, reproducibility, and consistency when considering the CHAARTED, STAMPEDE update, and GETUG0-AFU15 data to guide treatment. This includes classifying each individual patient by subtype and then applying the data in that context. He said that in patients with mCSPS, there are 4 distinct disease states with different prognoses to consider: de novo, high-volume disease; de novo, low-volume disease; rise in PSA after prostatectomy or radiation; and rapidly progressive high-volume disease after prostatectomy or radiation.
In addition to determining subgroup, it is important to consider a patient’s chemotherapy fitness, prognostic factors, comorbidities, and treatment options, which may include second-generation antiandrogens, docetaxel, and radiation. Then, each patient’s overall picture needs to be examined in the context of the 3 clinical trial data sets.
In patients with high-volume disease, Sweeney said, the data consistently support the early use of docetaxel, whereas in patients with low-volume disease, treatment decision-making is more nuanced. Two of the 3 trials showed some treatment effect, although it remains unclear which patients with a low volume of disease are most likely to benefit.
Therefore, in patients with low disease volume who are fit for chemotherapy, docetaxel should be discussed. In those not f it to receive chemotherapy, radiation and antiandrogens can be considered, he said. In patients with relapse after local therapy, Sweeney said, the only data available are for apalutamide and enzalutamide, so either can be considered in this setting.
Metastatic Castration-Resistant Prostate Cancer
In patients with mCRPC, taxanes and androgen receptor–targeted (ART) therapies, including ADT and second-generation antiandrogens, are the standard of care, but how best to treat patients with mCRPC in the second line following disease progression has been unclear. The panelists discussed 2 studies that examined this issue: CARD (NCT02485691), which evaluated a chemotherapy approach using cabazitaxel (Jevtana), and PROfound (NCT02987543), which evaluated the use of the PARP inhibitor olaparib (Lynparza) in biomarker-selected patients.21,22
In the CARD study, patients with mCRPC previously treated with ≥3 cycles of docetaxel who progressed in ≤12 months on an alternative ART therapy were randomly assigned to cabazitaxel/prednisone/granulocyte colony-stimulating factor versus either abiraterone or enzalutamide. The primary end point was radiographic progression-free survival (rPFS).21
Compared with the ART cohorts, the cabazitaxel group experienced significantly improved rPFS (8.0 vs 3.7 months, respectively; HR, 0.54; 95% CI, 0.40-0.73; P
<.0001), OS (median 13.6 vs 11.0 months; HR 0.64; 95% CI, 0.460.89; P
= .0078), and PFS (median 4.4 vs 2.7 months; P
“Clearly, the study should be considered positive,” Tombal, a study investigator, said. “When you have progression on the AR pathway, physiologically speaking, especially for all those patients who won’t hit the magic bullet, going to cabazitaxel is an option that actually may increase overall survival versus switching the AR pathway.”
Sweeney emphasized the importance of clinicians getting over “chemotherapy phobia” but acknowledged that not all patients are chemotherapy candidates. “You’ve got to choose your patients well, who you’re going to use cabazitaxel on. If you’re not having a great response to your prior AR, you’ve got some AR-independent disease…give them the chemotherapy if they’re chemotherapy fit,” he said. In contrast, if a patient has had a long response to abiraterone and their PSA is starting to go up a bit, he said, there are data to support the hormone switch.
PARP inhibitors have shown efficacy in the setting of gene alterations that impair homologous recombination repair (HRR). The PROfound study included 2 cohorts of patients with such alterations in any of 15 predefined genes and whose disease had progressed on prior ART: cohort A, which included those with BRCA1
, or ATM
alterations, and cohort B, which included those with BRIP1
, or RAD54L
Patients in these cohorts were randomly assigned 2:1 to olaparib or physician’s choice of enzalutamide or abiraterone (ART control arm).
“What the study showed was that the progression-free survival with the olaparib-treated patients who have BRCA1
, or ATM
was 7.4 months compared with 3.6 months in the [ART control arm], which is statistically significant. The overall survival in the olaparib arm was 18.5 months versus 15 months in the control arm. The hazard ratio for that is 0.64,” Ryan said. “By taking a patient with the BRCA2
alteration and giving him olaparib, as compared with enzalutamide, for example, you’re reducing his risk of death by 36%— that’s a profound piece of datum.”
Although it is not clear yet exactly which HRR gene alterations respond to olaparib because individual gene alterations were not assessed, the PROfound study is the first to show success using a molecularly selected targeted therapy in mCRPC. “These are exciting data. If we’re not doing it already, it’s going to drive our use of genomics in the clinic. This is more molecular medicine now, and it used to be something that was good to know. Now it’s something that we need to know for our patients. That’s a big step forward for the field,” Ryan said.
Based on these data, the FDA granted a priority review to olaparib in January for the treatment of patients with mCRPC who have deleterious or suspected deleterious or somatic HRR gene mutations and have progressed on prior therapy with a hormonal agent. The FDA is scheduled to make a decision on the supplemental new drug application in the second quarter of 2020.23
- Key statistics for prostate cancer. The American Cancer Society website. cancer.org/cancer/prostate-cancer/about/key-statistics. Updated January 8, 2020. Accessed January 27, 2020.
- Gul A, Garcia JA, Barata PC. Treatment of non-metastatic castration-resistant prostate cancer: focus on apalutamide. Cancer Manag Res. 2019;11:7253-7262. doi: 10.2147/CMAR.S165706.
- Geynisman DM, Plimack ER, Zibelman M. Second-generation androgen receptor-targeted therapies in nonmetastatic castration-resistant prostate cancer: effective early intervention or intervening too early? Eur Urol. 2016;70(6):971-973. doi: 10.1016/j.eururo.2016.05.026.
- Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-1418. doi: 10.1200/JCO.2015.64.2702.
- FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. FDA website. bit.ly/2uXpEyH. Updated July 31, 2019. Accessed January 16, 2020.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. doi: 10.1056/NEJMoa1800536.
- Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi: 10.1056/NEJMoa1715546.
- Janssen announces European Commission approval of Erleada (apalutamide) for non-metastatic castration-resistant prostate cancer patients who are at high risk of developing metastatic disease [press release]. Beerse, Belgium: The Janssen Pharmaceutical Companies of Johnson & Johnson; January 16, 2019. bwnews.pr/37C5PLx. Accessed January 27, 2020.
- Astellas receives European approval for XTANDI (enzalutamide) for adult men with high-risk non-metastatic castration-resistant prostate cancer [press release]. Tokyo, Japan: Astellas Pharma Inc; October 29, 2018. www.astellas.com/en/news/14311. Accessed January 27, 2020.
- Fizazi K, Shore ND, Tammela T, et al. Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 15; abstr 5000). doi: 10.1200/JCO.2019.37.15_suppl.5000.
- Nubeqa [package insert]. Whippany, NJ: Bayer Healthcare Pharmaceuticals Inc; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl.pdf. Accessed January 28, 2020.
- Xtandi [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/203415s015lbl.pdf. Accessed January 28, 220.
- Erleada [package insert]. Horsham, PA: Janssen Products, LP; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/210951s001lbl.pdf. Accessed January 28, 2020.
- El-Amm J, Aragon-Ching JB. The current landscape of treatment in nonmetastatic castration-resistant prostate cancer. Clin Med Insights Oncol. 2019;13:1-5. doi: 10.1177/1179554919833927.
- Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi: 10.1056/NEJMoa1503747.
- FDA approves abiraterone acetate in combination with prednisone for high-risk metastatic castration-sensitive prostate cancer. FDA website. bit.ly/2R2xiAw. Updated February 8, 2018. Accessed January 16, 2020.
- FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA website. bit.ly/30vu3EG. Updated September 18, 2019. Accessed January 16, 2020.
- FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. FDA website. bit.ly/2G0ol46. Updated December 17, 2019. Accessed January 16, 2020.
- Clarke NW, Ali A, Ingleby FC, et al. Docetaxel for hormone-naïve prostate cancer: results from long-term follow-up of metastatic (M1) patients in the STAMPEDE randomised trial. Ann Oncol. 2019;30(suppl 5):v325-v355.
- Gravis G, Boher JM, Chen YH, et al. Burden of metastatic castrate naive prostate cancer patients, to identify men more likely to benefit from early docetaxel: further analyses of CHAARTED and GETUG-AFU15 studies. Eur Urol. 2018;73(6):847-855. doi: 10.1016/j.eururo.2018.02.001.
- de Wit R, Kramer G, Eymard JC, et al. Randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer. Ann Oncol. 2019;30(suppl 5):v851-v934. doi: 10.1093/annonc/mdz394.040.
- Hussain M, Mateo J, Fizazi K, et al. PROfound: phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Ann Oncol. 2019;30(suppl 5):v851-v934.
- Lynparza regulatory submission granted priority review in the US for HRR-mutated metastatic castration-resistant prostate cancer [press release]. Kenilworth, NJ: AstraZeneca and Merck & Co, Inc; January 20, 2020. bit.ly/2TBMsye. Accessed January 27, 2020.